Download Maternal Mineral and Bone Metabolism During Pregnancy

Physiol Rev 96: 449 –547, 2016
Published February 17, 2016; doi:10.1152/physrev.00027.2015
MATERNAL MINERAL AND BONE METABOLISM
DURING PREGNANCY, LACTATION, AND
POST-WEANING RECOVERY
X Christopher S. Kovacs
Faculty of Medicine-Endocrinology, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
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INTRODUCTION
SKELETAL AND MINERAL PHYSIOLOGY...
DISORDERS OF BONE AND MINERAL...
SKELETAL AND MINERAL PHYSIOLOGY...
DISORDERS OF BONE AND MINERAL...
CONCLUSIONS
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I. INTRODUCTION
During pregnancy and lactation, female physiology must
adapt to meet the added nutritional demands of the fetus
and neonate. How much of a demand is there for delivery of
calcium and other minerals? What adaptations are invoked
during pregnancy and lactation to meet these demands? Do
these adaptations alter normal biochemical and hormonal
parameters of mineral and skeletal metabolism? What impact do these adaptations have during pregnancy and lactation
on preexisting disorders of mineral and bone metabolism? Are
there any long-term beneficial or adverse consequences of
pregnancy and lactation on the skeletal health of women? All
of these questions are addressed in this review.
The fetal requirement for mineral, which the pregnant
woman must supply, has been determined by measuring the
ash weight and mineral content of fetal cadavers between
24 wk and term. Multiple studies have demonstrated that
the average full-term fetus has ⬃30 g calcium (77, 196, 289,
332, 868, 930, 982–984, 1022), 20 g phosphorus (289,
984, 1022), and 0.80 g magnesium (289, 332, 984, 1022).
However, that fetal mineral content is not obtained at a
constant rate during pregnancy; instead, at least 80% of the
calcium, phosphorus, and magnesium present in a human
term fetus is accreted during the third trimester (77, 196,
332, 868, 930, 982, 984, 1022). This corresponds to a
mean calcium transfer rate of 100 –150 mg/kg per day (77,
332, 868, 930, 983, 984, 1022), which, for an average-sized
fetus, is ⬃60 mg/day at week 24 and 300 –350 mg/day
between the 35th and 40th week of gestation (1022). Similarly, the rate of phosphorus transport is ⬃40 mg/day at
week 24 and increases to 200 mg/day over the last 5 wk of
gestation (1022). The rate of magnesium transfer increases
more modestly from 1.8 to 5.0 –7.5 mg/day over the last 5
wk (1022). When expressed as hourly rates, during the
third trimester the fetal demand for calcium and phosphorus represent between 5 and 10% of the amounts present in
the mother’s plasma (196, 982). This means that the fetal
demand for calcium and phosphorus has the potential to
provoke maternal hypocalcemia and hypophosphatemia.
449
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Kovacs CS. Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery. Physiol Rev 96: 449 –547, 2016. Published
February 17, 2016; doi:10.1152/physrev.00027.2015.—During pregnancy and
lactation, female physiology adapts to meet the added nutritional demands of
fetuses and neonates. An average full-term fetus contains ⬃30 g calcium, 20 g
phosphorus, and 0.8 g magnesium. About 80% of mineral is accreted during the third
trimester; calcium transfers at 300-350 mg/day during the final 6 wk. The neonate requires
200 mg calcium daily from milk during the first 6 mo, and 120 mg calcium from milk during the
second 6 mo (additional calcium comes from solid foods). Calcium transfers can be more than
double and triple these values, respectively, in women who nurse twins and triplets. About 25%
of dietary calcium is normally absorbed in healthy adults. Average maternal calcium intakes in
American and Canadian women are insufficient to meet the fetal and neonatal calcium requirements if normal efficiency of intestinal calcium absorption is relied upon. However, several
adaptations are invoked to meet the fetal and neonatal demands for mineral without requiring
increased intakes by the mother. During pregnancy the efficiency of intestinal calcium absorption doubles, whereas during lactation the maternal skeleton is resorbed to provide calcium for
milk. This review addresses our current knowledge regarding maternal adaptations in mineral
and skeletal homeostasis that occur during pregnancy, lactation, and post-weaning recovery.
Also considered are the impacts that these adaptations have on biochemical and hormonal
parameters of mineral homeostasis, the consequences for long-term skeletal health, and the
presentation and management of disorders of mineral and bone metabolism.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
Estimates of neonatal mineral accretion are another indication of how much mineral is truly required, but the results
have been much more variable due to different techniques,
variable body sizes, ethnicity, cross-sectional versus longitudinal studies, small sample sizes, and other factors. For
example, direct measurements of ash weight and mineral
content have been made in cross-sectional studies of cadaveric specimens, whereas indirect measurements of mineral
content (such as through radiological techniques) have
been made in vivo in longitudinal studies of healthy neonates and infants. One widely quoted study lacked any
neonatal cadavers, but extrapolated from the mineral
content of newborn, childhood, and adult cadavers to
infer that the calcium content (the most abundant mineral in bone) increased 50 g by the end of the first year,
which corresponds to a daily accretion rate of ⬃140 mg
(546). However, other assessments of cadaveric specimens have suggested lower accretion rates of 30 –50 mg/
day during the first 6 mo (289, 487). When mineral content has been inferred from peripheral radiographs or by
dual X-ray absorptiometry (DXA), the daily accretion
rates have ranged from 80 mg (317, 976) to an unrealistic
380 mg (870); the latter study indicates problems in calibrating DXA against true mineral content of neonates
and infants.
A general consensus is that average milk output, and its
average calcium content, are more robust indicators of the
average neonatal requirement for calcium (430). The Institute of Medicine used these calculations to determine the
estimated average requirement (EAR) for calcium intake,
and concluded that breastfeeding requires that an average
of 200 mg calcium be provided daily through milk to a
singleton during the first 6 mo (430). From this intake the
neonatal skeleton is expected to accrete ⬃100 mg of cal-
450
cium daily (430). However, the output of milk on an individual basis is determined by the suckling demands of the
neonate and can certainly markedly exceed these values.
Women who nurse twins and triplets can have, respectively,
more than double and triple the milk output of women
nursing singletons (233, 792). Individual cases of women
nursing singletons have documented milk output of up to
2.4 –3.1 liters per day that was sustained for more than 12
mo of lactation (583, 838). The composition of milk is
similar between women with average and high outputs
(233, 792), and so producing more milk will cause greater
maternal losses of calcium.
Between 6 and 12 mo of age, more infant nutrition comes
from solid food despite continued breastfeeding. Fewer
studies have examined this time frame, so the data are less
robust. The average calcium content of human milk is
somewhat lower at 200 mg/l (41), and the intake is less at
⬃600 ml/day (246), which means that the infant has an
estimated calcium intake of 120 mg/day from human milk.
An additional 140 mg/day of calcium is estimated to come
from solid foods to bring the total infant calcium intake to
⬃260 mg/day (430). Of previously cited cadaveric studies,
one indicated a continued daily accretion rate of ⬃140 mg
during the 7th to 12th months (546), whereas the other
suggested that calcium accretion is ⬃50 mg/day during this
time (289). An expected average accretion of ⬃100 mg/day
has been assumed by the Institute of Medicine from the
available data (430).
Overall, these studies indicate that pregnant women do not
provide much calcium or other minerals to their fetuses
until the third trimester, when the peak rate of calcium
transfer exceeds 300 mg/day on average. Data for lactating
women and their babies are more variable, but suggest that
the average calcium requirement is more modest, at ⬃200
mg daily during the first 6 mo, and ⬃120 mg daily during
the second 6 mo. All of these values, from 300 mg daily
during the third trimester to 120 mg daily during late lactation, may seem achievable given normal intake of calcium
and normal efficiency of intestinal calcium absorption.
However, fractional calcium absorption is normally ⬃25%
of intake in healthy adults who consume adequate calcium
(420). If normal efficiency of intestinal calcium absorption
were relied upon, pregnant women would have to consume
an extra 1,200 mg/day during the third trimester, whereas
lactating women would have to consume an extra 800 mg
daily during the first 6 mo and 480 mg daily during the
second 6 mo.
These estimated calcium demands during pregnancy and
lactation should also be considered in the context of data
from the United States National Health and Nutrition Examination Survey (NHANES) and Statistics Canada, in
which actual calcium intakes have been determined for
American and Canadian women. Between ages 18 and 50,
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The neonatal requirement for mineral, which may be supplied through breastfeeding, has largely been inferred from
studies in which healthy neonates are weighed before and
after each feed; a few studies have measured change in
weight of the mother or the volume of milk that can be
manually expressed. The calcium intake has been the main
parameter considered in these calculations. Such studies
reveal an average intake of 780 ml of human milk per day
(20, 138, 376, 653), which, combined with an average calcium content in milk of 260 mg/l during the first 6 mo
postpartum (41), reveals a total calcium intake of ⬃200
mg/day. Estimates of fractional calcium absorption from
metabolic balance studies have shown that neonates absorb
⬃60 –70% of calcium from human milk (5, 8, 289, 382),
thereby making ⬃120 –140 mg of calcium available for the
skeleton to potentially take up each day. Fractional calcium
absorption is proportional to intake and facilitated by lactose in neonates and infants (479, 480), and can be as low as
30 – 40% when formula (which has twice the calcium content as human milk) is consumed (6).
CHRISTOPHER S. KOVACS
the 50th percentile for calcium intake ranges from 8001,000 mg daily in both populations (430), for an expected
fractional absorption of 200 –250 mg daily. The 25th percentile of intake is ⬃600 –700 mg daily, while the 5th percentile is about 400 mg daily, in both populations (430).
Consequently, if normal intestinal calcium absorption were
relied upon, most women do not consume sufficient calcium
to meet the combined needs of their babies and themselves.
Having established the magnitude of the demands for mineral that are placed on pregnant and breastfeeding women,
the body of this review will address our current stage of
knowledge regarding the maternal adaptations in mineral
and skeletal homeostasis that occur during pregnancy, lactation, and post-lactation recovery. Also considered are the
impacts that these adaptations have on normal biochemical
and hormonal parameters of mineral homeostasis, the presentation and management of preexisting disorders of mineral and bone homeostasis, and long-term skeletal health of
women.
This paper is a companion to a recent review of fetal and
neonatal mineral and skeletal homeostasis (492), which
may be consulted for additional details and references
that are pertinent to mineral and bone homeostasis of the
offspring. This paper is also a substantial update and
rethinking on the topic since the previous review in 1997
(499).
In the subsequent sections, animal data are discussed first
and followed by relevant human data. Although the focus is
on understanding human mineral and skeletal physiology
during reproduction, it is necessary to discuss animal data
because ethical and practical considerations prevent certain
aspects of the reproductive time frame from being studied in
women. As will be made clear, much of what has been
found in the animal models has been directly or indirectly
confirmed in human studies, but there remain important
areas where this has yet to be done or where it may never be
possible to do so.
The term phosphorus is used for consistency and simplicity,
and because that is what is measured. It is acknowledged
that in serum phosphorus largely exists as inorganic phosphates (dihydrogen and monohydrogen phosphate), in
bone it is largely in the form of hydroxyapatite, while in soft
tissues and extracellular fluid there are an abundance of
organic phosphates complexed with carbohydrates, lipids,
and proteins (53).
II. SKELETAL AND MINERAL PHYSIOLOGY
DURING PREGNANCY
As noted in the introduction, pregnancy requires that a
woman deliver by term to her baby an average of 30 g
calcium, 20 g phosphorus, and 0.8 g magnesium. About
80% or more of these amounts are provided during the third
trimester. Therefore, any adaptations to meet the fetal demand
for mineral are most needed during the third trimester. One
may anticipate finding increased intestinal calcium absorption, decreased renal calcium excretion, and increased skeletal
resorption of calcium. However, as the studies reviewed in this
section will reveal, the dominant adaptation is a twofold increase in intestinal calcium absorption. The kidneys waste calcium in the urine rather than conserving it, and there is usually
at most only a very modest contribution of calcium from skeletal resorption.
Pregnant rats and mice have been commonly used to model
maternal adaptations in mineral homeostasis during pregnancy, while pregnant ewes and pigs have been studied to a
lesser extent. The rat has a much shorter gestation period
(22 days) and may bear 6 –12 fetuses in each litter. The
calcium demands on the pregnant rat are proportionately
greater than in women who typically bear a singleton during a far longer gestational period. The pregnant rat delivers
12 mg calcium per fetus between day 17 of gestation and
term, or more than 95% of mineral during the equivalent of
a rodent’s third trimester (196). Extrapolating from these
studies, the pregnant mouse likely delivers more than 95%
of the mineral content to its fetuses during the last 5 days of
a 19-day gestation. The proportional demand on pregnant
rodents is even more striking when it is considered that the
amount of calcium transferred to a litter of rat fetuses each
hour represents ⬃80% of the amount of calcium present in
the maternal circulation (196), whereas a human fetus receives only ⬃5–10% of the amount of calcium present each
hour in the mother’s circulation (196, 982). Consequently,
pregnancy is far more capable of provoking hypocalcemia
and secondary hyperparathyroidism in rodents than in
women.
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However, increased intakes are not required in women who
consume adequate calcium because of several adaptations
that are invoked during pregnancy and lactation. During
pregnancy, the efficiency of intestinal calcium absorption
doubles to meet the fetal requirement for calcium, whereas
during lactation, skeletal resorption increases to provide
calcium to milk. It is unclear why different adaptations are
invoked during these two reproductive periods. These hormone-mediated adaptations normally meet the daily mineral requirements of the fetus and infant without adverse
long-term consequences to the maternal skeleton. However, exceptions do occur, especially in women with habitually very low intakes of mineral, or preexisting disorders
that cause skeletal fragility.
The original data are described and cited in necessary detail
to justify the conclusions, but each section is followed by a
short summary so that the reader can glean key points at a
glance.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
A. Changes in Mineral Ions and Calciotropic
and Phosphotropic Hormones
Total Ca
(mmol/l)
2.7
Progressive changes in serum calcium, phosphorus, and calciotropic hormone levels during human pregnancy are schematically depicted in FIGURE 1. Important differences
among human, rat, and mouse pregnancies are listed in
TABLE 1.
Ionized Ca2+
(mmol/l)
2.1
1.6
1. Calcium and phosphorus
Phosphorus
(mmol/l)
1.7
0.9
PTH
(pmol/l)
5.0
0.0
Calcitriol
(pmol/l)
300
0.0
Calcitonin
(pmol/l)
20.0
A confounding problem in published rat studies during
pregnancy and lactation is the calcium content of diet. The
original 1976 and subsequently reformulated 1993 standard rodent diets of the American Institute of Nutrition
indicate a 0.50% content of calcium (749). In older studies,
it is typical to see diets with 0.4, 0.45, and 0.5% calcium.
However, a 1% calcium diet is now more commonly used in
rats, and in most studies of mice, and that impacts such
parameters as serum calcium, parathyroid hormone (PTH),
bone turnover, etc., as will be discussed.
0.0
PTHrP
(pmol/l)
5.0
0.0
Estradiol
(nmol/l)
100.0
Mice may differ from rats in their blood calcium parameters
during pregnancy. In multiple studies wherein wild-type
0.0
Prolactin
(ng/ml)
150.0
0.0
1st
2nd
3rd
Trimesters of Pregnancy
452
FIGURE 1. Schematic depiction of longitudinal changes in calcium,
phosphorus, and calciotropic hormone levels during human pregnancy. Shaded regions depict the approximate normal ranges. PTH
does not decline in women with low calcium or high phytate intakes
and may even rise above normal. Calcidiol (25OHD) values are not
depicted; most longitudinal studies indicate that the levels are unchanged by pregnancy, but may vary due to seasonal variation in
sunlight exposure and changes in vitamin D intake. FGF23 values
cannot be plotted due to lack of data. The data from which this
summary figure has been derived are cited in section IIA.
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A) ANIMAL DATA. Serum calcium declines during late pregnancy in rats (90, 105, 117, 313, 315, 425, 519, 714, 735),
guinea pigs (958), sheep (21, 257, 269), goats (21), cows
(21), and white-tailed deer (170). It has commonly been
measured without correcting for any change in the protein
or albumin concentration, even though a progressive 10 –
25% fall in protein and albumin has been found in pregnant
rats (44, 315, 519), guinea pigs (958), and sheep (257). The
drop in serum albumin causes a fall in serum calcium; however, a decrease in serum calcium does not necessarily indicate a change in ionized calcium, which is the physiologically important fraction of extracellular calcium. One study
in rats consuming a 0.75% calcium diet found that the
ionized calcium progressively increased while the serum calcium was falling (735), whereas rats given a 0.4% calcium
diet were found to have a significant fall in the ionized
calcium during late pregnancy (90). The observed declines
in serum calcium during pregnancy generally represent the
effect of reductions in the albumin-bound fraction, while
the ionized calcium may be unchanged unless a lower calcium diet is consumed (such as 0.4% calcium).
0.9
CHRISTOPHER S. KOVACS
Table 1. Key differences in mineral physiology of human and rodent pregnancy
Rat
Mouse
Low
Normal
Normal
Normal
Normal
Low or low-normal*
Increased
Increased
Increased
No data
Increased
Increased
Increased
Slight loss
Low
Low
Low
Normal
Normal
Increased
Increased
Increased
Increased
No data
Increased
Increased
Increased
Small loss
Normal
Normal
Normal
Normal
Normal
Low or normal
Increased
Increased
Increased
Increased
Increased
Increased
Increased
Increased or no change
*Women with low calcium or high phytate intakes have normal or increased PTH.
(WT) mice consumed a standard 1% calcium diet, there was
no change in the ionized calcium or the serum calcium during pregnancy (296, 477, 478, 992, 994). One study measured the ionized calcium every other day in the same mice
from the time of mating and noted no change during pregnancy (827). Fewer studies have assessed the serum albumin, but it was unchanged in pregnant mice compared with
nonpregnant controls and did not decline during the last 7
days of pregnancy (154, 175, 197).
Serum phosphorus remains normal during pregnancy in
rats (117, 314, 718) and mice (477, 478, 580), but may be
modestly reduced in guinea pigs (958), sheep (21, 57), goats
(21, 55), and cows (21). It is especially low during milk
fever of cows (613). One study of pregnant rats differed by
reporting a reduction in serum phosphorus (425). Serum
magnesium has been less commonly measured but is unaltered in pregnant rats (315, 425), mice (580), and goats
(55).
Physiologically important hypocalcemia can occur during
pregnancy when the fetal demand for calcium exceeds the
mother’s ability to maintain her own serum calcium. This
may be especially true in rats where the hourly fetal demand
for calcium almost equals the amount of calcium present in
the maternal circulation (196). Consistent with this, increased litter number and weight are associated with a
lower serum calcium in the mother (90), while pregnant rats
fed a low-calcium (0.1%) diet experienced a marked decline
in both serum calcium and ionized calcium during the last
several days before delivery (321). A low-calcium diet similarly provoked hypocalcemia in pregnant ewes compared
with consumption of a usual and a high-calcium diet (69).
In pregnant or lactating cows, such hypocalcemia is termed
milk fever when it occurs near parturition or during lactation and provokes symptoms such as paresis (21). During
milk fever the serum calcium can be 50% of normal or even
lower despite a compensatory rise in PTH (613); the calcium demand of the fetuses is the precipitating factor. Sudden deaths during late pregnancy from presumed severe
hypocalcemia have occurred in rats rendered severely vitamin D deficient (359, 361–363), and in Vdr null (296, 502)
and Cyp27b1 null mice (330) maintained on a normal 1%
calcium diet.
B) HUMAN DATA.
The earliest studies in pregnant women
found a progressive 5–10% decrease in serum calcium such
that the mean value fell below the normal range, thereby
indicating biochemical hypocalcemia (641, 674). Such results confirmed what had already been observed in animal
models, and suggested that the human fetus drains calcium
from the maternal circulation in sufficient amounts to provoke maternal hypocalcemia and secondary hyperparathyroidism (15). It was not until later that it was better appreciated that the serum albumin falls during pregnancy due to
normal expansion of the intravascular volume, thereby provoking a decline in the albumin-bound fraction of calcium
(720). The decline in the albumin-bound fraction of serum
calcium is physiologically unimportant.
When it became possible to measure the ultrafiltrable fraction of serum calcium (which includes both complexed and
ionized calcium, but not albumin-bound calcium), no
change was seen when prepregnancy and pregnancy measurements were compared (471). Later innovations resulted
in the ability to measure the ionized calcium with ion-specific electrodes. Both cross-sectional (210, 227, 324) and
longitudinal studies (221, 294, 721, 739, 791, 809, 813)
have shown that the ionized calcium does not change during
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Serum calcium
Albumin-adjusted calcium
Ionized calcium
Phosphorus
Magnesium
PTH
Calcitonin
PTHrP
Calcitriol
FGF23
Estradiol
Intestinal calcium absorption
Urinary calcium excretion
Change in bone mass
Human
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
human pregnancy, even though the mean serum calcium
simultaneously drops ⬃10% into the hypocalcemic range
(221).
The albumin-corrected serum calcium is a reasonable substitute for the ionized calcium, as several longitudinal and
cross-sectional studies have shown it to remain stable across
all three trimesters, despite the concurrent fall in serum
albumin (85, 599, 632, 646, 778).
Twin pregnancy does not impair the ability of a woman to
maintain a normal serum calcium, as shown in a comparative study of women bearing twins versus singletons (646).
C) SUMMARY. Expansion of the intravascular volume during
normal human pregnancy causes a fall in serum albumin
and, thereby, the serum calcium. However, the ionized calcium and albumin-corrected serum calcium do not change,
confirming that the physiologically relevant circulating
fraction of calcium concentration remains normal. Either
the ionized calcium or the albumin-corrected serum calcium
may be reliably used to assess adequacy of the blood calcium concentration during pregnancy. Animal models
show a similar albumin-related fall in serum calcium,
whereas both the serum and ionized calcium levels appear
to stay constant in pregnant mice, likely because albumin
does not decline. Ionized calcium is more likely to fall in
rodents when challenged by larger litters, low calcium diets,
or disorders of vitamin D physiology.
2. PTH
A) ANIMAL DATA. Rodents have generally been described as
developing secondary hyperparathyroidism during normal
pregnancy (499), although the extent to which this occurs
depends on the calcium content of the diet. One of the
earliest studies of pregnant rats found that both COOHterminal and NH2-terminal PTH concentrations declined
between gestational days 16.5 to 21.5 to reach the lower
end of the normal range (NH2-terminal values became undetectable) before increasing significantly postpartum (the
calcium content of the diet was not specified) (309, 311).
However, several other studies in rats used 0.4 to 0.75%
calcium diets and found that PTH is modestly increased in
late pregnancy compared with nonpregnant rats (90, 105,
735); one of these studies simultaneously found increased
PTH bioactivity (105). A more recent study used a 1.18%
calcium diet and found lower baseline PTH levels that almost tripled by late pregnancy (920). Parathyroid gland
454
More recently, pregnant mice consuming a standard 1%
calcium diet have been consistently found to have mean
PTH values reduced to ⬃20% of the nonpregnant value,
with many individual values being undetectable, as determined by rodent or mouse-specific PTH immunoradiometric assays (IRMAs) and enzyme-linked immunoassays (ELISAs or EIAs) (477, 478, 992, 994). Consumption of a 2%
calcium diet resulted in even lower PTH levels in nonpregnant mice that declined slightly but nonsignificantly during
pregnancy (296, 330).
These findings confirm that whether the PTH concentration
changes during pregnancy, and the direction of that change,
are dependent on the rodent’s dietary calcium intake. Rats
appear more prone to develop secondary hyperparathyroidism than mice during pregnancy. As will be made clear
in subsequent sections, the proportionately greater calcium
demand faced by the pregnant rodent mandates that calcium be provided from both intestinal absorption and skeletal resorption. Secondary hyperparathyroidism enables the
rodent to upregulate both routes of mineral delivery, especially when the fetal demand is at its peak during late pregnancy.
B) HUMAN DATA.
The earliest data on PTH measurements in
pregnant women used first-generation radioimmunoassays
that yielded inconsistent results (23, 209, 219, 255, 329,
387, 721, 754, 760, 876, 975, 981, 985), with many of
these studies finding significantly increased PTH concentrations in the latter half of pregnancy (209, 219, 255, 721,
754, 760, 975). Taken together with the concurrent decline
in serum calcium, this resulted in the concept that pregnancy represents a physiological state of secondary hyperparathyroidism. It was not until some years later that it
became clear that this conclusion was erroneous. As noted
above, the fall in serum calcium is caused by a fall in albumin levels, while the ionized calcium remains normal during
human pregnancy. Furthermore, these early, insensitive
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Serum phosphorus shows no change in most studies during
human pregnancy (33, 207, 221, 294, 468, 632, 641, 674,
791) and was similarly unchanged during twin pregnancies
(646). There is also no change in the renal tubular reabsorption of phosphorus (207, 329, 468). Serum magnesium is
similarly unaltered during pregnancy (33, 207, 221, 294,
721).
volume is doubled in normal pregnant rats compared with
virgins (784, 842), while in vitro studies suggest that, for
any level of extracellular calcium, parathyroids from pregnant rats secrete more PTH than those from virgin rats
(806). In addition to the obvious effect of the varying calcium content of the rodent diets, there may be additional
variability between studies due to rats strains, and differing
NH2-terminal or COOH-terminal radioimmunoassays
(RIAs) that were designed to detect human PTH. In most of
these studies the serum calcium alone was measured without correction for the lower serum albumin. But a 0.4%
calcium diet provoked a decrease in the ionized calcium
together with an increase in PTH in pregnant rats (90),
while more marked hypocalcemia and secondary hyperparathyroidism developed when pregnant rats were challenged by a 0.1% calcium-restricted diet (321).
CHRISTOPHER S. KOVACS
PTH radioimmunoassays measured multiple biologically
inactive fragments of PTH (725, 959).
Newer “bio-intact” assays exclude NH2-terminal truncated, inactive PTH7– 84 fragments that accumulate in
chronic renal failure patients (931), but no studies have
reported use of these assays in pregnant women. It is expected that these assays would similarly demonstrate low
concentrations of PTH during pregnancy.
Despite the preponderance of evidence that PTH becomes
suppressed during human pregnancy, some modern medical textbooks still claim incorrectly that pregnancy represents a state of physiological hyperparathyroidism (899).
Although suppression of PTH with modern assays has also
been shown in pregnant women from Asia and Africa (11,
33, 813, 826), several cohort and longitudinal studies from
these regions have found that PTH did not decline during
pregnancy and in some cases it rose above normal (585,
601, 778, 805, 844). The lack of suppression of PTH during
pregnancy in women from these regions is likely the consequence of diets that are traditionally low in vitamin D or
calcium, and high in phytate (which blocks calcium absorption). Low calcium intake or absorption will provoke compensatory secondary hyperparathyroidism during pregnancy.
C) SUMMARY. During normal human pregnancy, serum or
plasma PTH typically declines to low levels early on, before
returning to the mid-normal range by term. This suppression may not occur (and secondary hyperparathyroidism
may develop) in women who have especially low intakes of
calcium or vitamin D, or high intakes of phytate; such diets
are more common in certain regions of Asia and Africa. In
rodents, the ambient PTH level is influenced by the dietary
intake of calcium, with rats typically having increased PTH
during pregnancy that rises even higher with a calciumrestricted diet, whereas mice typically have reduced PTH
levels on a standard diet that fall even further on a highcalcium diet.
3. Parathyroid hormone-related protein
A) ANIMAL DATA. Parathyroid hormone-related protein
(PTHrP) was first cloned in 1987 from human tumors that
cause humoral hypercalcemia of malignancy (593, 882,
889). It is a prohormone that is processed into several moieties, each of which has been postulated to have its own
receptor and function(s) (682). The NH2-terminal region of
PTHrP has partial homology to PTH within its first 13
amino acids, and a similar structure within the first 34
amino acids, which enables it to activate the common PTH/
PTHrP receptor and have near-identical functions as PTH
(494). The mid-molecular region of PTHrP has been shown
to stimulate placental calcium transport in fetuses, but
whether it has any role in the mother is unknown (152,
500). The COOH-terminal regions of PTHrP have been
shown to inhibit osteoclast-mediated bone resorption both
in vitro (280, 281) and in vivo (202), so it is conceivable that
this portion of PTHrP could act to prevent excessive resorption of the maternal skeleton during pregnancy. The midmolecular and COOH-terminal regions of PTHrP have no
homology to PTH.
PTHrP conceivably reaches the maternal circulation from
several sources, including the parathyroids, placenta (496,
817), mammary tissue (738), and uterus (66). Its expression
in rat mammary tissue is increased by prolactin (906), while
its expression within the uterine myometrium of the rat
increases in response to estradiol (909). Consequently, high
prolactin and estradiol levels associated with pregnancy
may drive increased expression of PTHrP within these tissues. Although PTHrP is expressed by day 14 of pregnancy
in rat mammary glands (738), the level remains quite low
compared with the expression achieved in the immediate
postpartum (738, 1004) and with suckling (907, 911).
Studies in sheep have determined that clearance of PTHrP1–
1– 86
34, PTHrP
, or PTHrP1–141 do not change during pregnancy (741, 743).
PTHrP has been assumed to circulate at increased levels in
pregnant animals because it does so in humans, but surprisingly few measurements have been made in animals. No
significant increase in PTHrP was detected in one study of
pregnant versus nonpregnant mice (956). In another study,
PTHrP was detected in the circulation of pregnant rats, and
the value did not change over the last 5 days of pregnancy,
but no measurements were done in nonpregnant rats, so it is
unclear if the concentration was increased (364). PTHrP
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Two-site immunoradiometric (IRMA) PTH assays are more
sensitive and accurate (725). In cross-sectional studies of
North American and European women consuming a diet
adequate in calcium, PTH is typically suppressed to the
lower end of the normal range during all three trimesters
(207, 227, 294, 324, 791, 809, 905). In longitudinal studies
from North America, Europe, and Asia, the mean PTH level
was suppressed to the lower end of the normal range or
below it during the first trimester, and either remained suppressed or increased to mid-normal by the end of pregnancy
(33, 85, 207, 221, 304, 632, 739, 813). Twin pregnancy did
not change the serum PTH value compared with women
bearing singletons (646).
The influence of PTH in regulating mineral metabolism during pregnancy is further discussed in subsequent sections
that address the synthesis of calcitriol (sect. IIA4) and the
adaptations that occur in the intestines (sect. IIB), kidneys
(sect. IIC), and bone (sect. IID). PTH’s role is also illuminated by data on the effects of primary hyperparathyroidism (sect. IIIB), hypoparathyroidism (sect. IIID), and pseudohypoparathyroidism (sect. IIIE) during pregnancy.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
PTHrP1–74 in plasma of patients with humoral hypercalcemia of malignancy, but PTHrP1–36 was not assayed in that
study (137)]. This problem may be less of a concern in
rodents since there is no alternative splicing and only one
full-length form. A PTHrP1–34 assay should detect each of
PTHrP1–36, PTHrP1–139, PTHrP1–141, and PTHrP1–173, and
may be the preferred assay to use but only with optimally
collected and processed plasma samples.
B) HUMAN DATA. Before discussing data on circulating PTHrP
values during human pregnancy, it is important to review
common problems of sample collection and preparation,
and available assays.
As noted earlier, there are predicted mid-molecular and
COOH-terminal forms of biologically active PTHrP. In the
human these include PTHrP38–94, PTHrP38–101, PTHrP107–139,
and possibly PTHrP141–173, each of which may have its own
receptor and distinct role (494, 682, 712, 996). The clinically available PTHrP1–34 and PTHrP1– 86 assays do not
detect these forms. Consequently, no data are available on
concentrations of mid-molecular or COOH-terminal
PTHrP during pregnancy.
First, PTHrP is rapidly cleaved and degraded in serum. Appropriate samples for PTHrP measurement should be collected as EDTA plasma in a chilled tube that also contains a
protease inhibitor (such as aprotinin), kept chilled on ice
during transport to the laboratory, and (within 15 min)
spun in a refrigerated centrifuge, separated, and frozen.
Even with these rigorous steps taken to reduce proteolytic
cleavage, PTHrP begins to degrade in EDTA-aprotinin
plasma within 15 min of sample collection (423). In contrast to this ideal sample collection and processing, many
studies used stored sera that had been allowed to clot at
room temperature for 60 min before routine processing
(925). Improper sample collection and processing leads to
failure to detect the true concentration of PTHrP, and may
even result in undetectable values when high values of
PTHrP are likely to be present (such as in lactation or humoral hypercalcemia of malignancy). These issues confound individual case reports and small case series, wherein
a clinician’s request for a PTHrP level on a patient is likely
to lead to routinely collected and processed sera or EDTAplasma being sent out to a reference laboratory, and an
undetectable result obtained despite the likely presence of
PTHrP in that patient’s circulation.
Second, the most widely used assays in clinical studies are
those that measure PTHrP1– 86. Such a length does not exist
in humans (or animals) based on the predicted cleavage sites
of the translated product (494, 682). There are three predicted full-length forms of human PTHrP that arise through
alternative splicing, including PTHrP1–139, PTHrP1–141, or
PTHrP1–173 (rodents have only a single full-length form)
(682). A PTHrP1– 86 assay will detect all three of these
forms, but it will not detect PTHrP1–36. This is a significant
problem because PTHrP1–36 is expected to derive in vivo
from posttranslational processing of all three full-length
forms of PTHrP (682), and conceivably may be the most
abundant of the biologically active NH2-terminal forms of
PTHrP. The presence of PTHrP1–36 has been confirmed in
the media of cultured human and rodent cell lines (682,
853, 1007), but the relative abundance of PTHrP1–36 versus
the other circulating forms has not been determined in humans [PTHrP37–74 was shown to be 9-fold higher than
456
Despite the aforementioned problems with the PTHrP1– 86
assay, four longitudinal studies have shown a significant
increase in PTHrP across the three trimesters, beginning as
early as 3–13 wk of gestation and reaching up to triple the
first-trimester value by term (33, 75, 304, 1001). A crosssectional study found that the PTHrP level in women at
term was twice that of nonpregnant controls (333). Other
studies have found elevated levels at term based on the
expected values in nonpregnant adults, but did not include
a nonpregnant control group (111, 278). These results contrast with smaller cross-sectional studies that found
PTHrP1–34 (473) or PTHrP1– 86 (262, 697) concentrations
were no different than in unrelated nonpregnant controls or
the expected normal range, and two longitudinal studies
that found a nonsignificant increase (390) and no change
(85) in PTHrP1– 86. In the latter study, all PTHrP1– 86 values
were undetectable, which raises the concern that improper
methodology was the cause (sample type, collection, and
processing were not specified) (85).
Longitudinal studies are more sensitive and robust in detecting differences in a time course compared with crosssectional studies. With the assumption that the four longitudinal studies (33, 75, 304, 1001) are correct in demonstrating a gestational increase in PTHrP that reaches peak
levels in the third trimester, PTHrP may importantly contribute to the regulation of maternal mineral homeostasis
during pregnancy, including an upregulation in calcitriol
(see sect. IIA4) and suppression of PTH.
Which tissue sources contribute to the increasing concentrations of PTHrP in the maternal circulation during human
pregnancy has not been established. Candidate sites include
the placenta, breasts, parathyroids (39, 222, 252, 426,
610), amnion (278, 283), decidua and myometrium (283),
umbilical cord (284), and other fetal tissues. The potential
importance of placental sources of PTHrP has been illus-
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increased in pregnant goats beginning a day or two before
expected delivery and even further during parturition (744,
771) compared with nonpregnant animals. Most of the
measurements were with assays designed to detect human
PTHrP1– 86 (364, 744, 956) rather than species-specific assays, and such assays will not detect the potentially more
abundant (and biologically active) PTHrP1–36 (this issue is
discussed in more detail in the next section).
CHRISTOPHER S. KOVACS
trated by two clinical cases. One woman experienced a
late-term hypercalcemic crisis with a high plasma concentration of PTHrP; an urgent C-section was followed within
6 h by symptomatic hypocalcemia and an undetectable
PTHrP level (270). A second woman with known hypoparathyroidism was able to gradually eliminate use of calcitriol and halve the dose of calcium taken during her pregnancy. Immediately after delivery, she developed sudden
and symptomatic hypocalcemia that resolved after breastfeeding was initiated (890). In both cases, removal of placental PTHrP was the likely factor causing a rapid fall in
serum calcium, and in the first case a rapid and marked
decline in circulating PTHrP was confirmed.
The gradual rise in PTHrP across the trimesters, as demonstrated in four longitudinal studies (33, 75, 304,
1001), parallels a progressive increase in serum calcitriol
to peak levels in the third trimester (see sect. IIA4). The
increase in PTHrP may imply that it is responsible for
stimulating renal 1␣-hydroxylase (Cyp27b1). However,
other data suggest that PTHrP may not be as potent as
PTH in stimulating Cyp27b1 in vivo (308, 413, 414, 494,
988). The extent to which PTHrP stimulates the rise in
calcitriol during pregnancy remains to be tested in animal
models.
There are no data on blood levels or potential roles of
mid-molecular and COOH-terminal PTHrP during pregnancy. Fetal-placental calcium transport is regulated by
mid-molecular PTHrP within the fetal circulation, but
whether maternal PTHrP plays a role in regulating this
process is unknown (2, 152, 500).
That the rise in PTHrP during normal pregnancy is physiologically important has been made most evident in hypoparathyroid women, as discussed in sections IIID and VD.
C) SUMMARY. PTHrP reaches the maternal circulation during
pregnancy, most likely from the placenta and breasts, as
well as possibly the uterus and fetal tissues. PTHrP1– 86
progressively increases in maternal plasma to reach peak
levels in the third trimester, and likely contributes to the
normal regulation of mineral homeostasis during pregnancy. This includes maintenance of the ionized calcium,
stimulation of Cyp27b1 to produce increased levels of calcitriol (see sect. IIA4), and suppression of PTH. Several case
reports support these findings.
PTHrP’s role in regulating mineral metabolism during pregnancy is further addressed in section III, D and F. Its role to
regulate placental calcium transport and fetal mineral homeostasis has been addressed in the companion review
(492)
4. Calcitriol and calcidiol
A) ANIMAL DATA.
Serum calcitriol concentrations increase
two- to sevenfold during normal pregnancy in rats, mice,
sheep, guinea pigs, and rabbits (90, 92, 358, 477, 478, 502,
512, 718, 735, 775, 1021). The vitamin D binding protein
level increased slightly in mice and declined modestly in rats
and guinea pigs (104, 478, 958). This confirms that the free
concentration of calcitriol must be substantially increased
during late pregnancy in these species. Longitudinal studies
in rats have shown that the increase in total calcitriol does
not occur until the last several days of pregnancy (90, 358,
735), during which time fetal mineral accretion is rapidly
occurring. Larger litter sizes or weights correlate with
higher maternal calcitriol (90). In guinea pigs, the free level
of calcitriol increased before the third trimester and before
total calcitriol increased (958).
The rise in serum calcitriol is the result of upregulated synthesis of calcitriol, and not reduced catabolism or metabolic
clearance, as confirmed by studies in pregnant rats, sheep,
and rabbits (238, 702, 775, 776). Renal Cyp27b1 has been
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Other clinical cases have demonstrated that the breasts are
also a physiologically relevant source of PTHrP during
pregnancy, and can provoke hypercalcemia when PTHrP
production is overabundant. Such hypercalcemia has developed in late pregnancy and the puerperium, and even in
nonpregnant women who simply have large breasts (603,
800). In one case of marked hypercalcemia during pregnancy, serum PTH was undetectable, PTHrP expression
was increased within the mammary tissue, and a bilateral
mastectomy was required in the second trimester to correct
the hypercalcemia (435, 474). A postpartum PTHrP-mediated hypercalcemic crisis has also occurred when a woman
was unable to breastfeed because her newborn baby was in
an intensive care unit (800). The hypercalcemia was first
noted on the second postpartum day, and persisted into the
third day with a plasma PTHrP concentration that was
markedly elevated at 28.4 pM (normal ⬍1.1 pM). The delayed time course with elevated PTHrP on the third postpartum day did not implicate the placenta because of
PTHrP’s short half-life of minutes in the circulation. In
another longitudinal study the plasma PTHrP level rose
higher by 48 h after delivery rather than declining, which
supports sustained PTHrP production by the breasts that
rises further with the onset of lactation (1001). Colostrum
and milk expressed from pregnant women have also been
show to contain PTHrP, with the content in colostrum being no different from breastfeeding women, whereas the
PTHrP content rises in milk during each breastfeeding episode (575).
The high levels of estradiol may be contributing to stimulation of PTHrP production during pregnancy. In vitro studies have demonstrated that estradiol increases PTHrP
mRNA expression from cultured human myometrial cells
(160), but it did not stimulate mammary epithelial cells to
produce PTHrP (808).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
shown to be upregulated two- to fivefold from in vitro analysis of homogenates obtained from kidneys of pregnant
rabbits and guinea pigs (282, 512). Consequently, the maternal kidneys are likely the source of increased production
of calcitriol, as they are in the nonpregnant adult.
The authors of the 5/6 nephrectomy study concluded that
the rise in calcitriol during pregnancy could only be due to
contributions from extra-renal sources of 1␣-hydroxylase.
However, the result is still compatible with the remnant
kidneys, which achieved a calcitriol level 60% of normal in
the nonpregnant state, being able to increase calcitriol production in response to the increased stimulation that occurs
during pregnancy. The normal peak calcitriol level achieved
in 5/6-nephrectomized pregnant rats (89) contrasts with the
substantial reduction in calcitriol production during pregnancy in completely nephrectomized rats (345), and supports that the 1/6 remnant kidney was likely responsible for
the increased production of calcitriol during pregnancy.
Subsequent studies in the 5/6 nephrectomy model have
shown that it creates only mild renal insufficiency with creatinine clearance reduced ⬃50% of normal in nonpregnant
or pregnant rats (794).
Taken together, these studies in partly and completely nephrectomized rats showed that extra-renal tissues can contribute some calcitriol to the maternal circulation, but
whether this means the placenta, fetus, or other maternal
tissues was not ascertained. These extra-renal sources likely
do not explain the high calcitriol levels that are normally
achieved during pregnancy in rodents. Additional studies in
1␣-hydroxylase null Hannover pigs also support that the
458
What is driving the increased production of calcitriol during
pregnancy? Circulating PTH is increased at this time in
some but not all studies of pregnant rats (90, 105, 309,
735), yet there was no correlation between the PTH concentration and the achieved calcitriol level (90). Moreover,
PTH fell over 80% in 5/6-nephrectomized rats during
which time the calcitriol level tripled (89). PTH is reduced
in pregnant mice (296, 330, 477, 478, 992, 994), which
achieve up to sevenfold increases in serum calcitriol. These
finding suggest that PTH is not responsible for stimulating
the Cyp27b1 to increase the concentration of calcitriol in
the maternal circulation.
This hypothesis has been confirmed through two independent lines of investigation. First, despite parathyroidectomy
in rats, there was a threefold increase in calcitriol during
pregnancy to achieve peak levels nonsignificantly lower
than in intact rats (658). Second, when the Pth gene was
ablated, such Pth null mice have undetectable circulating
PTH but achieve a fivefold increase in calcitriol during pregnancy that is modestly but not significantly lower than that
achieved by their pregnant WT sisters (478).
Pregnant Pth null and WT mothers had similarly increased
expression of Cyp27b1 mRNA in the kidneys compared
with their nonpregnant counterparts, whereas 24-hydroxylase (Cyp24a1) mRNA expression was fivefold higher in
pregnant Pth null mice compared with their WT sisters
(478). These results are consistent with the known role of
PTH to suppress Cyp24a1 activity and expression (752,
835, 1023, 1024); therefore, in the absence of PTH,
Cyp24a1 expression and activity increase. Parathyroidectomized rats also had consistently higher 24,25-hydroxyvitamin D concentrations throughout pregnancy compared
with intact rats (658). Consequently, the modest blunting of
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However, the maternal decidua, placenta, and fetus are also
potential sources of calcitriol due to expression of Cyp27b1
in these tissues (334, 346, 896, 977, 978). The placenta has
often been assumed to account for the rise in maternal calcitriol during pregnancy, but this appears to be incorrect.
The same gene is responsible for renal, decidual, placental,
and fetal expression of Cyp27b1 (334). The ability of nonrenal tissues to contribute to the production of calcitriol has
been tested by administering tritiated 25-hydroxyvitamin D
(calcidiol or 25OHD) immediately after nephrectomy to
pregnant and nonpregnant rats. Some tritiated calcitriol
appeared in the circulation of pregnant nephrectomized
dams (much reduced compared with normal), whereas
none appeared in the circulation of nonpregnant nephrectomized dams (345, 978). Additional studies examined 5/6nephrectomized rats, a model of chronic renal insufficiency,
which as virgins have marked secondary hyperparathyroidism and calcitriol concentrations that are reduced 40%
compared with intact virgin rats (89). During subsequent
pregnancies, calcitriol tripled in the 5/6-nephrectomized
rats to the same high level achieved by intact pregnant rats,
while PTH decreased by 80% in the 5/6-nephrectomized
rats to near-normal values (89).
fetus and placenta likely do not contribute substantial calcitriol to the maternal circulation, because maternal calcitriol levels are very low during pregnancy and similar to
nonpregnant values, even when bearing heterozygous fetuses that produce calcitriol (520, 521). Furthermore, in a
preliminary study, Cyp27b1 null mice had calcitriol levels
near the detection limit during prepregnancy, and these values were not significantly different during pregnancy despite the presence of Cyp27b1⫹/⫺ placentas (330). Additionally, the expression of Cyp27b1 mRNA is 35-fold
higher in maternal kidneys during pregnancy compared
with placentas obtained from the same mouse (478). This
suggests that the relative activity of Cyp27b1 in the placenta
is too low to account for the rise in calcitriol in the maternal
circulation. However, the expression of Cyp24a1 (24-hydroxylase) in normal mouse placentas was about one-third
the level of expression in maternal kidneys; therefore, the
multiple placentas in one pregnant rodent may substantially
contribute to the conversion of calcitriol and 25OHD into
24-hydroxylated forms (478).
CHRISTOPHER S. KOVACS
the peak calcitriol level during pregnancy in parathyroidectomized rats and Pth null mice may be the result of increased 24-hydroxylation of calcitriol and 25OHD, and not
reduced synthesis of calcitriol (478, 658). Therefore, although PTH is the dominant stimulator of Cyp27b1 in
nonpregnant rodents, it clearly does not have this role during pregnancy.
The multiple fetuses in rodent pregnancies represent a potential drain on maternal stores of 25OHD, the substrate
for calcitriol, since 25OHD readily crosses the placenta
(353) whereas calcitriol does not (665). The concentration
of 25OHD decreased ⬃50% on day 20 of pregnancy in rats
consuming a vitamin D-replete diet (358, 735), which appears to confirm that rodent fetuses are a significant drain
on the maternal supply of 25OHD. However, in guinea pigs
that bore 3– 4 pups/litter, there was no decline in 25OHD
during pregnancy (960). Two cross-sectional studies found
that the 25OHD level was 20 –30% lower in pregnant versus nonpregnant sheep (57, 703).
B) HUMAN DATA.
Similar to the findings in the animal models,
cross-sectional studies have found a doubling or tripling of
serum calcitriol that begins early in the first trimester and
reaches the highest levels in the third trimester (81, 207,
287, 324, 387, 578, 599, 632, 764, 981, 987). Longitudinal
studies have confirmed a progressive increase in free and
bound calcitriol that is maintained to term (33, 81, 764,
809, 813, 959, 987). Free calcitriol was reported to be increased in the third trimester in one study (81). However,
the more modest (20 – 40%) increase in vitamin D binding
In a large cross-sectional study, serum calcitriol increased
threefold in women with singleton and twin pregnancies,
and there was no difference between the two groups (646).
There was also no difference in vitamin D binding protein
and albumin levels, which means that singleton and twin
pregnancies likely resulted in identical increases in free calcitriol (646). A smaller longitudinal study also found no
difference in serum calcitriol between twin and singleton
pregnancies at any time point during pregnancy (746).
PTH is normally the dominant regulator of Cyp27b1 in
adults, and without it (such as in hypoparathyroidism), calcitriol levels are quite low (782). A substantial curiosity
about the marked pregnancy-related increase in calcitriol is
that it occurs while PTH is often suppressed to low levels,
which suggests that PTH is not responsible for the upregulation of Cyp27b1.
Estradiol, prolactin, and placental lactogen levels are high
during human pregnancy and may in part stimulate
Cyp27b1, as suggested by data from animals cited above.
The potential role of estradiol is supported by the finding
that estrogen replacement therapy in postmenopausal
women causes an increase in free and total calcitriol levels
in serum (172). Conversely, the elevated prolactin levels of
pregnancy seems unlikely to stimulate Cyp27b1 because
chronic hyperprolactinemia in nonpregnant individuals does
not alter calcitriol (514). However, chronic hyperprolactinemia differs in that estradiol levels are low, in contrast to the
high levels during pregnancy. The possibility that high estradiol and high prolactin (or placental lactogen) act in concert
during pregnancy to stimulate Cyp27b1 has not been examined in any human studies. An additional analysis in pregnant
women found that the increased calcitriol did not correlate
with PTH, prolactin, estrone, estradiol, estriol, or human placental lactogen (746).
That the placenta and other extrarenal sources of Cyp27b1
do not contribute a substantial amount of calcitriol to the
maternal circulation is supported by the finding that an
anephric woman on dialysis had low calcitriol levels before
and during a pregnancy (937). The author is aware of other
unpublished cases in which calcitriol remained low in pregnant anephric women.
There is conflicting evidence as to whether serum 25OHD
changes during human pregnancy. In several large studies
there was no significant change (121, 200, 386, 399, 764,
778, 809, 966) or even a slight increase (637). This includes
the placebo arm of a study in which women were vitamin
D-deficient at baseline (mean 25OHD level of 20 nM or 8
ng/ml) (121), and two studies in which women had a mean
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If not PTH, what stimulates the renal expression and activity of Cyp27b1 during pregnancy? Among known hormones that could be potential regulators are PTHrP, estradiol, calcitonin, placental lactogen, and prolactin. However, very few studies have tested the roles of these
hormones. As mentioned, PTHrP mimics the actions of
PTH on the PTH/PTHrP receptor and likely contributes to
the stimulation of Cyp27b1 activity and expression. However, other investigators have suggested that PTHrP is less
potent than PTH at stimulating Cyp27b1 due to PTHrP’s
somewhat different receptor binding, signaling characteristics, and crystal structure (308, 494, 988). Estradiol (51),
calcitonin (464), placental lactogen (866), and prolactin
(866, 867) have acutely stimulated renal Cyp27b1 in vitro,
whereas placental lactogen increased calcitriol in hypophysectomized, nonpregnant rats in vivo (894). Calcitriol has
also been shown to have the reciprocal effect of suppressing
calcitonin (647, 840). It is conceivable that a combination
of factors (increasing concentrations of PTHrP, estradiol,
calcitonin, and placental lactogen, for example) contribute
to upregulation of Cyp27b1 during pregnancy, rather than
one factor being primarily responsible. It is also possible
that an unidentified factor stimulates Cyp27b1 during pregnancy.
protein during pregnancy, and the decline in serum albumin, indicate that free calcitriol is likely increased in all
three trimesters (33, 399, 599, 764, 1019).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
25OHD of about 60 nM (24 ng/ml) prior to being randomized to receive up to 4,000 IU of vitamin D per day (399,
966). Conversely, two longitudinal studies found a modest
but significant decline in total 25OHD (33, 1019) or calculated free 25OHD values (1019) during pregnancy. These
latter studies were smaller and may have been influenced by
seasonal and late-pregnancy alterations in sunlight exposure and diet. The bulk of the data indicate that maternal
25OHD is not substantially drained into the fetal circulation, or consumed by conversion into calcitriol.
While the threshold level of 25OHD that indicates optimal
vitamin D sufficiency during pregnancy continues to be debated (401, 430, 495, 773), it should be clear that the observed suppression of PTH and doubling or tripling of calcitriol during pregnancy are not attributable to maternal
vitamin D deficiency. Moreover, supplementation with
the equivalent of 1,000 to as much as 5,000 IU vitamin D
daily during pregnancy did not alter maternal serum calcium, albumin-corrected calcium, phosphorus, or PTH,
nor did it blunt the rise in calcitriol (239, 399, 778, 966).
The increase in free and bound calcitriol, despite a decline in PTH, is evidently a programmed response to
pregnancy, with the key stimulators of Cyp27b1 remaining unidentified. In a study in which intakes of 400 IU,
2,000 IU, and 4,000 IU vitamin D were compared, mean
calcitriol levels reached a plateau at a 25OHD level of
100 nM regardless of vitamin D intake (399). This plateau may indicate the maximal capacity of renal
Cyp27b1 to convert 25OHD into calcitriol, balanced
against probable upregulation of Cyp24a1 to catabolize
25OHD and calcitriol. Moreover, the plateau does not
necessarily mean that 100 nM is the target level of
25OHD to be achieved in pregnancy, as the authors of
that study concluded (399), since no benefit of this high
level of 25OHD or calcitriol has been demonstrated.
460
Total and likely free levels of calcitriol begin to
increase in the first trimester and may reach triple or more
the nonpregnant value by the third trimester. This increase
likely contributes to upregulation of intestinal calcium absorption during pregnancy and, indirectly, to suppression
of PTH. Increased production of calcitriol comes almost
entirely from maternal kidneys and not the placenta or fetus, but the factors that stimulate renal Cyp27b1 during
pregnancy remain to be elucidated. 25OHD levels are stable
during pregnancy despite increased conversion to calcitriol
and transplacental passage of 25OHD to the baby, and
even in the face of a twin pregnancy. Conversely, 25OHD
has been shown to decline by 50% in rats that bear large
litters, with more modest to no change in animals bearing
several pups (pigs) or singletons (sheep).
The influence of calcitriol in regulating mineral metabolism
during pregnancy is further discussed in the sections that
address adaptations that occur in the intestines (see sect.
IIB) and bone (see sect. IID). Calcitriol’s role is also illuminated by data on the effects of vitamin D deficiency and
genetic vitamin D resistance syndromes (see sect. IIIG) during pregnancy.
5. Calcitonin
A) ANIMAL DATA. Serum calcitonin is increased during pregnancy in rats (315), mice (615), monkeys (759), sheep (58,
310, 316), deer (170), and goats (58, 310). In addition to
increased production by the C-cells of the thyroid (316),
additional sources of expression that may contribute to the
circulating level of calcitonin include mammary tissue (450,
938), placenta (450, 496), and pituitary (755, 887). Increased synthesis of calcitonin reasonably explains the
higher levels, but clearance of calcitonin has not been measured. Studies in pregnant rhesus monkeys support that
synthesis is likely increased, since acute calcium infusions
caused a progressively greater calcitonin increment during
pregnancy (760). This increase in calcitonin occurs despite
high levels of calcitriol, which has been shown to suppress
calcitonin (647, 840). Estradiol stimulates calcitonin expression in the rat thyroid (840), so the high levels of estradiol during pregnancy may contribute to increased calcitonin in the circulation.
B) HUMAN DATA. Serum levels of calcitonin generally increase
during pregnancy compared with nonpregnant values and
may exceed the normal range (33, 221, 255, 388, 503, 797,
839, 981, 985, 990). But the evidence is not entirely consistent, since other longitudinal studies have found no changes
(764) or decreased calcitonin in all three trimesters (632).
Several longitudinal studies found no increase in pregnancy
compared with postpartum values (209, 721, 813). However, since calcitonin has also been shown to be elevated
postpartum (see sect. IVA4), the lack of change compared
with postpartum does not rule out an increase during pregnancy.
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A large cross-sectional study found that the maternal
25OHD was also stable across all trimesters in both singleton and twin pregnancies; however, the 25OHD level was
⬃30% lower in women carrying twins at all time points
(646). It is unknown whether this difference was due to
twin babies draining the maternal supply of 25OHD, or
lower sunlight exposure or vitamin D intake in women
bearing twins. The lack of a progressive change in 25OHD
during pregnancy, especially a progressive difference between mean values in women bearing singletons versus
twins, makes it less likely that two babies represent a drain
on the maternal supply of 25OHD. A smaller longitudinal
study found no difference in 25OHD levels between women
bearing twins versus singletons (746), which may be an
indication that the larger cross-sectional study was confounded by inherent differences between the two groups of
mothers rather than demonstrating an effect of twin pregnancy. There are no data from women bearing triplets.
C) SUMMARY.
CHRISTOPHER S. KOVACS
Higher estradiol, estrone, and estriol levels during pregnancy may stimulate calcitonin synthesis. This is supported
by the observation that in reproductive-age women, mean
plasma calcitonin was three to five times higher in women
who were pregnant or taking oral contraceptives, compared
with nonpregnant women who did not use oral contraceptives (388). Moreover, treatment of postmenopausal
women with either estradiol or a synthetic estrogen (ethinylestradiol) resulted in a significant increase in plasma calcitonin (877).
C) SUMMARY.
Calcitonin increases during pregnancy in
women and animals, evidently coming from placenta and
breasts in addition to the C-cells of the thyroid. Calcitonin’s
possible physiological role in protecting the maternal skeleton during pregnancy is discussed in section IIIH.
6. Fibroblast growth factor-23
A) ANIMAL DATA.
Fibroblast growth factor-23 (FGF23) is
predominantly expressed in osteocytes and osteoblasts
(841); a low level of Fgf23 mRNA expression was also
found in the murine placenta when WT and Fgf23 null
placentas were compared (581). FGF23’s apparent function
is to control the availability of phosphorus at mineralizing
surfaces of bone, and it does so by regulating the serum
phosphorus through actions on the kidneys, intestines, and
parathyroids (841). It downregulates the expression of sodium-phosphate cotransporters 2a and 2c (NaPi2a and
NaPi2c) in proximal renal tubules (834), thereby causing
excretion of phosphorus into the urine. It inhibits Cyp27b1
and increases expression of Cyp24a1, which will respectively decrease synthesis and increase catabolism of calcitriol, thereby leading to reduced calcitriol concentrations
in the circulation (834). By lowering serum calcitriol and
also by directly reducing the intestinal expression of
NaPi2b, FGF23 should also lead to reduced intestinal phosphorus absorption (834). FGF23 also inhibits PTH release
from the parathyroids (834). High circulating levels of
FGF23 cause hypophosphatemia characterized by renal
phosphate wasting and low calcitriol, while absence of
FGF23 causes hyperphosphatemia with impaired renal
phosphate excretion and inappropriately elevated calcitriol
(70).
B) HUMAN DATA.
No published data are available on intact
FGF23 levels during human pregnancy. One study did report intact FGF23 values obtained within 24 h after delivery (678). The mean values were similar to the levels observed in unrelated adult controls, and about three times the
values obtained in cord blood from the mothers’ babies. But
FGF23 levels obtained within 24 h after delivery may no
longer reflect what was present during late pregnancy.
C) SUMMARY. FGF23 doubles its concentration in the mother’s circulation during murine pregnancy; whether it has a
similar increase in women is unknown. Its physiological
importance during pregnancy is uncertain given the unchanging serum phosphorus in human and rodent pregnancies, and because markedly increased FGF23 in Phex null
mice did not blunt the pregnancy-related rise in calcitriol.
X-linked hypophosphatemic (XLH) rickets is a disorder of
FGF23 excess caused by an inactivating mutation in PHEX
(the equivalent of the Phex null mice); any known effects of
XLH during pregnancy are addressed in section IIIK.
7. Sex steroids and other hormones
A) ANIMAL DATA.
Pregnancy induces changes in other hormones that may influence bone metabolism. Estradiol, estriol, estrone, progesterone, prolactin, placental lactogen,
and placental growth hormone each increases significantly
(232, 268, 852, 979). Conversely, IGF-I decreases during
late pregnancy in rats, consistent with a suppression in pituitary growth hormone (268, 645). Oxytocin increases
fivefold during pregnancy in rats and reaches its highest
levels during parturition (1010).
B) HUMAN DATA.
During human pregnancy there are similar
changes in these hormones that may influence skeletal metabolism and mineral homeostasis. Estradiol increases up to
100-fold, accompanied by lesser increases in estriol and
estrone (632, 670, 933), while progesterone increases up to
10-fold (670, 933). Prolactin increases 10-fold or more (33,
207, 632, 670, 695), placental lactogen increases ⬃10- to
100-fold (33, 649, 695), and these similar hormones will
each activate prolactin receptors. Placental growth hormone increases 25-fold while pituitary growth hormone
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The thyroid C-cells are often assumed to be the only site of
calcitonin synthesis, but the breast and placenta become
significant production sites during pregnancy (52, 131).
This has been most clearly demonstrated in women who
have previously undergone a total thyroidectomy. During
subsequent pregnancies the mean serum calcitonin has risen
from undetectable to 16 pg/ml, and exceeded the value of
11 pg/ml in nonpregnant women with intact thyroids (131).
The potency of the breasts is indicated by the finding of
calcitonin in colostrum and milk at 45 times its concentration in serum, with no difference in the values between
thyroidectomized and intact women (131).
Longitudinal studies in several mouse models have shown
that FGF23 increases twofold during pregnancy over nonpregnant values (198, 478). The physiological significance
of this increase is unclear given that serum phosphorus
shows no change during pregnancy in mice. Moreover, although increased levels of FGF23 have been shown to reduce serum calcitriol in nonpregnant Phex (Hyp) null mice
(564) and in Fgf23 overexpressing mice (531), no effect on
calcitriol concentrations was seen from increased or decreased FGF23 during pregnancy. Specifically, the serum
calcitriol was no different among pregnant Phex null, WT,
or Fgf23⫹/⫺ mothers (581, 679).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
becomes suppressed (174). IGF-I may decrease to as low as
50% of basal values during the second trimester before
rising two- to threefold above nonpregnant values by term
(85, 174, 632, 649). In one study the rise in IGF-I during the
third trimester correlated with the increase in bone turnover
markers, and the rise in placental lactogen paralleled the
increase in IGF-I, leading the authors to infer that placental
lactogen was driving the increases in IGF-I and bone turnover (649). Oxytocin shows a slow but modest increase
during pregnancy to reach peak levels near term (231).
C) SUMMARY.
Numerous hormones show progressive increases or decreases in their circulating concentrations during pregnancy. But the extent to which these hormones may
have direct or indirect effects on skeletal and mineral homeostasis during human pregnancy has been largely unexplored. Within animal models, limited data about these hormones are discussed in the relevant sections. Prolactin and
placental lactogen have been shown to stimulate intestinal
calcium transport (see sect. IIB), reduce urinary calcium
excretion (see sect. IIC), and stimulate both PTHrP and
calcitriol (see sect. II, A3 and A4, respectively). Oxytocin
and its receptor have been proposed to have possible effects
on bone formation and resorption (see sects. IID and IVD).
B. Upregulation of Intestinal Absorption of
Calcium and Phosphorus
1. Animal data
The two main routes of calcium absorption are an active,
saturable, transcellular pathway that is stimulated by calcitriol and a passive, nonsaturable, paracellular pathway
that is also stimulated in part by calcitriol (181, 247). Rapid
and active calcium absorption is thought to represent
⬃20% of net absorption, and it takes place largely in the
duodenum of the rodent, while ⬃80% of calcium absorption occurs through slower, passive mechanisms in the jejunum and ileum, with lesser amounts in the colon (181,
694). Active intestinal calcium absorption is more important when dietary intake of calcium is limited.
Studies using 45Ca have demonstrated that the fractional
absorption of calcium doubles in pregnant rats. Three-day
metabolic balance studies found that fractional 45Ca absorption doubled at days 20 –22 of gestation compared with
nonpregnant controls (173). At days 13–15 in that study,
net 45Ca absorption was 20% higher and urinary excretion
of 45Ca was double that in nonpregnant controls, confirming that intestinal calcium absorption was also increased at
462
An increase in intestinal calcium absorption beginning at
mid-pregnancy may enable the pregnant rodent to accrete
mineral in advance of the peak demands that occur during
late pregnancy and lactation. Balance studies have shown
pregnant rats to achieve a net gain in calcium at mid-pregnancy that is sustained to term (339). Consistent with this,
an increase in femoral ash weight and calcium content has
been found in rats and sheep at mid-pregnancy and term
(69, 629), which correlates with an increasing calcium content of the diet (818), while a progressive 10 –15% increase
in total body mineral content during pregnancy has been
observed by DXA in normal Black Swiss mice (296, 478,
827, 994). However, not all studies are consistent with this
since no change in femoral or tibial ash weight or calcium
content was observed in several studies of rats (362, 598,
628, 972), decreases in lumbar spine BMD by DXA and
histomorphometry have been observed at mid-pregnancy
and term in rats (408), and BMD of the whole body and
lumbar spine decreases by DXA in C57BL/6J mice (477,
580). Some of these differences are likely due to differing
calcium contents of the diet, with dietary calcium restriction
consistently causing reduced skeletal mineral content by the
end of pregnancy in rats (64, 271, 740) and goats (55). The
differences between Black Swiss and C57BL/6J mice must
be due to genetic differences because both strains were
maintained on the same 1% calcium diet in the author’s
laboratory. It has been estimated from radioisotope studies
that 92% of fetal skeletal calcium content is absorbed from
the maternal diet of the rat during pregnancy while consuming a 1% calcium diet (974), but this will likely vary by
dietary calcium intake. Clearly if calcium intake is insufficient to meet the needs of the fetuses, then increased skeletal
resorption will occur.
In the transcellular pathway, calcium enters enterocytes
through apical calcium channels (TRPV6, TRPV5), is shuttled through the cytoplasm while bound to proteins (calbindin-D9k), and is extruded from the cell under the actions of
Ca2⫹-ATPase (PMCA1) and the sodium-calcium exchanger
NCX1 (247). Each of these factors is dependent on calcitriol for normal expression in nonpregnant animals (127,
181, 182, 596, 854). Each is upregulated in the intestines of
pregnant mice and rats, and reaches the highest levels of
expression by mid to late pregnancy (126, 237, 949, 1021).
Taken together with the observation that calcitriol also
reaches peak levels in the last few days of pregnancy, and
that duodenal expression of VDR increases at the same time
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Prolactin and placental lactogen have been shown to stimulate synthesis of PTHrP in human cultures of extraembryonic membranes (262). Beyond this, no clinical studies have
tested whether these pregnancy-related hormones play an
important role in regulating maternal bone metabolism.
mid-pregnancy (173). When the absorption of 45Ca in 15
min across an in situ isolated loop of duodenum was measured, the value was increased 30% at day 14 and doubled
at day 20 of pregnancy, similar to the results of the metabolic balance studies (735). 45Ca absorption across everted
gut sacs in rats also revealed that calcium absorption at day
20 of pregnancy was double that of nonpregnant controls
(360).
CHRISTOPHER S. KOVACS
(1021), these findings are compatible with the doubling of
intestinal calcium absorption being the result of increased
calcitriol-mediated effects. However, the increase in intestinal calcium transport precedes the rise in calcitriol by at
least 1 wk in pregnant rats (735), and in another study the
increment in calcitriol was concluded to be insufficient to
explain the magnitude of increase in intestinal calcium
transport during pregnancy (360).
A pregnancy-induced increase in fractional calcium absorption occurs despite severe vitamin D deficiency in rats (116,
360), absence of the vitamin D receptor in mice (296), or
maternal parathyroidectomy in rats (425). In severely vitamin D-deficient pregnant rats, a doubling to tripling in the
efficiency of intestinal calcium, phosphorus, and magnesium absorption was observed that reached levels equivalent to normal (116), which suggests that full upregulation
occurs during pregnancy despite the absence of calcitriol. In
another study intestinal calcium absorption doubled over
baseline in severely vitamin D-deficient rats, but reached
two-thirds of the value achieved by pregnant vitamin D-replete rats (360). And so the pregnancy-related increase may
not always fully compensate for the absence of calcitriol.
The upregulation in intestinal calcium and phosphorus absorption that occurs in severely vitamin D-deficient rats is
physiologically important because by the end of pregnancy,
significant increases were seen in femoral ash weight and
calcium content (362) and serum calcium and phosphorus
(915). Moreover, Vdr null mice (Boston strain) increased
their skeletal mineral content by 55% as assessed by DXA,
had a marked reduction in secondary hyperparathyroidism,
normalized serum calcium, and increased renal calcium excretion during pregnancy (296). In a separate study of Vdr
null mice (Leuven strain), pregnancy resulted in an increased serum calcium, a reduction in calcitriol from higher
levels, an increase in trabecular BMD of the femur by quantitative computed tomography (QCT) an increase in femoral ash weight, and reduced osteoid and osteoclast parameters as assessed by histomorphometry (786).
In both Vdr null models (i.e., both Boston and Leuven
strains), a calcium-enriched diet had been started at the time
of mating, and this partly confounded the increase in bone
mass and some of the improvements in mineral homeostasis
that were observed (296, 786). More recently, a preliminary
report in pregnant Cyp27b1 null mice, which lack the abil-
Not all studies agree with the findings of skeletal improvements during pregnancy in severely vitamin D-deficient
rats, Vdr null mice, and Cyp27b1 null mice. Two histomorphometric studies in pregnant vitamin D-deficient rats
found significant decreases in mineralized bone, increased
unmineralized osteoid, and increased resorptive parameters
(598, 628). The calcium content of the diet (0.45%) was the
same among the rat studies but the rat strains differed, and
that may account for the varying skeletal response to pregnancy.
The increment in calcitriol was prevented in pregnant rats
by administering ketoconazole, which blocks the steroid
synthesis pathway. This resulted in an 80% reduction in
serum calcitriol of pregnant rats and a 50% reduction in
intestinal calcium absorption, which suggests that intestinal
calcium absorption is partly dependent on calcitriol during
pregnancy (92). The serum calcium of the mothers and
weight of the pups were unaffected. The finding of reduced
intestinal calcium absorption contrasts with negative findings from the same study during lactation (see sect. IVC).
What could explain calcitriol-independent upregulation of
intestinal calcium absorption during pregnancy? Vdr null
mice show downregulation of intestinal TRPV6 when nonpregnant but a marked upregulation during pregnancy
while on a calcium-enriched “rescue diet” (296, 949),
whereas upregulation in calbindin-D9k was found during
pregnancy on a normal-calcium diet (786). Prolactin, placental lactogen, and growth hormone have been shown to
stimulate intestinal calcium absorption independently of
calcitriol, possibly through actions to increase expression of
TRPV6, TRPV5, calbindin-D9k, and PMCA1 (12, 171,
586, 690, 894, 901). As noted above, growth hormone is
normally suppressed during pregnancy, but placental
growth hormone is increased and may stimulate intestinal
calcium absorption. Prolactin’s effect to increase intestinal
calcium absorption was confirmed in pregnant, severely vitamin D-deficient rats (690). An effect of prolactin and
placental lactogen was also observed in everted gut sacs of
nonpregnant, hypophysectomized rats, which thereby removed the confounding effects of prolactin release from the
pituitary (586, 894). Estradiol also has effects independent
of calcitriol to stimulate intestinal calcium absorption and
expression of TRPV6 and TRPV5 (192, 949). Calcitonin
stimulated intestinal calcium absorption although the
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Calcitriol regulates that paracellular or passive route of calcium absorption by stimulating the expression of claudin-2
and claudin-12, which form tight junctions between intestinal epithelial cells (181). These claudins are expressed in
the jejunum, ileum, and colon, but most abundantly in the
ileum where the bulk of calcium is absorbed (298, 406).
Expression of claudin-2 and claudin-12 are reduced in Vdr
null mice (298).
ity to make calcitriol, has shown a 45% increase in bone
mineral content by DXA, a marked lessening of secondary
hyperparathyroidism, and normalization of serum calcium
and phosphorus (330). Intestinal calcium absorption has
not yet been measured but is likely to be increased, based on
these observed changes. The Cyp27b1 null mice had been
maintained on the same diet since 3 wk of age, so all of the
improvements in skeletal mineral metabolism are attributable to pregnancy.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
mechanism appeared to be through increased production of
calcitriol, rather than being independent of it (436).
2. Human data
In humans active transport of calcium occurs in the duodenum and proximal jejunum, with passive absorption in the
distal jejunum and ileum accounting for the bulk of calcium
absorption (181, 247). Active transport is more rapid and
becomes especially important when the dietary supply of
calcium is low. Stable calcium isotopes (48Ca, 44Ca, 42Ca)
and mineral balance studies have consistently determined
that women are in a positive calcium balance during early
pregnancy, with fractional absorption of calcium doubling
by as early as 12 wk of gestation and maintained to term
(207, 324, 372, 467, 469, 764).
The doubling to tripling of serum calcitriol, with increased
free calcitriol, has also been assumed to explain the increased efficiency of intestinal calcium absorption during
human pregnancy. Compelling animal data described in the
preceding section support that this increase in intestinal
calcium absorption may not be fully due to calcitriol, and
have raised the possibility that prolactin, placental lactogen, growth hormone, and other factors stimulate calcium
absorption by enterocytes. However, there are no compelling clinical data because few studies have examined the
mechanism of calcium absorption during human pregnancy.
An independent effect of prolactin to stimulate intestinal
calcium absorption was not evident when seven hyperprolactinemic subjects were found to have intestinal calcium
absorption within the expected normal range (514); however, estradiol should be low in these patients, in contrast to
the high levels during pregnancy. Intestinal calcium absorption has not been formally measured during pregnancy in
women who are severely vitamin D-deficient or who have
genetic disorders of impaired vitamin D physiology. However, the first-trimester rise in intestinal calcium absorption
464
3. Summary
Intestinal calcium absorption increases twofold beginning
in the first trimester of human pregnancy, and a similar
doubling of intestinal calcium and phosphorus absorption
occurs by mid-pregnancy in rats. The increase in calcium
absorption is probably mediated in part by calcitriol-induced increases in TRPV5/6, calbindin-D9k, PMCA1,
NCX1, claudin-2, and claudin-12. Many but not all studies
in rodents have shown that a normal or near-normal increase in intestinal calcium and phosphorus absorption occurs during pregnancy without requiring calcitriol. Prolactin, placental lactogen, growth hormone, and other factors
may contribute to the normal pregnancy-related doubling
of fractional calcium absorption. An increase in intestinal
calcium absorption early in pregnancy may allow the maternal skeleton to store calcium in advance of peak demands
that occur later in pregnancy and during lactation.
Overall, this doubling in the fractional absorption of calcium from the intestines appears to be the major maternal
adaptation to meet the fetal requirement for calcium in
humans and rodents. In rats it accounts for more than 90%
of the mineral present in the fetus at birth.
C. Altered Renal Mineral Handling
1. Animal data
Glomerular filtration rate and creatinine clearance increase
during rodent pregnancy (65). In 3-day metabolic studies in
rats, a twofold increase in urinary calcium excretion has
been observed by mid-pregnancy that rises even higher by
late pregnancy (173). This hypercalciuria develops concurrently with the significant increase in intestinal calcium absorption (173), confirming that hypercalciuria is a consequence of the increased renal filtered load, or absorptive
hypercalciuria. Such 24-h renal calcium excretion studies
have not been done in pregnant mice. However, in longitudinal studies carried out in the author’s laboratory, the
calcium-to-creatinine ratio in a spot urine is normal or significantly increased during pregnancy when the samples are
obtained from nonfasted mice (296, 477, 994), whereas the
result is reduced below the nonpregnant level when the mice
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The implication of these studies is not to suggest that calcitriol plays no role in upregulating intestinal calcium absorption during pregnancy. Instead, it is quite likely that the
two- to fivefold increase in calcitriol contributes to the doubling in the efficiency of intestinal calcium absorption in
normal, vitamin D-replete animals. Additional factors (possibly prolactin, placental lactogen, placental growth hormone) likely contribute to the normal upregulation of intestinal calcium absorption during pregnancy. What may be
indicated by these findings in severe vitamin D-deficient
rats, Vdr null mice, and Cyp27b1 null mice is that in the
absence of calcitriol (or the inability to respond to it), these
pregnancy-related factors compensate to upregulate intestinal calcium absorption, with the resulting efficiency of calcium absorption reaching the normal peak levels of pregnancy in some rodents, but falling below it in others.
precedes the more marked increase in calcitriol and free
calcitriol during the third trimester, which may indicate that
the early increase is not wholly driven by calcitriol. Moreover, the extremes of severe vitamin D deficiency or genetic
disorders of vitamin D physiology in the mother do not alter
serum calcium, ionized calcium, phosphorus, PTH, or skeletal mineral content of the baby, as detailed in the companion review (492). These normal fetal parameters imply that
maternal delivery of mineral is normal, or that the placenta
is capable of extracting needed mineral regardless of a deficit in the maternal supply.
CHRISTOPHER S. KOVACS
are fasted overnight (478, 580). This supports that absorptive hypercalciuria also occurs in pregnant mice. Additional
evidence in support of this comes from pregnant Vdr null
mice, which had significantly increased urine calcium/creatinine ratios, concurrent with their increase in intestinal
calcium absorption (296).
2. Human data
As in rodents, pregnancy causes increased creatinine clearance and glomerular filtration rate (303). As early as the
12th week of gestation, the 24-h urine calcium excretion
increases significantly, with mean values reaching the upper
limit of normal, and values in the hypercalciuric range often
observed (18, 207, 221, 324, 707, 764, 809). Fasting urine
calcium concentrations are normal or low, confirming that
the increase in 24-h urine calcium is due to absorptive hypercalciuria, i.e., that increased intestinal calcium absorption leads to an increased renal filtered load and excretion
of calcium (304, 324, 468). Since the fetal demand for calcium does not occur until the third trimester, but intestinal
calcium absorption increases in the first trimester, this explains why absorptive hypercalciuria is an obligatory, physiological consequence of pregnancy. It is one of the factors
that contributes to an increased risk of kidney stones during
pregnancy (815).
Many recent clinical studies have eschewed the use of 24-h
urine collections during pregnancy and have relied solely on
calcium/creatinine values in spot urines to assess renal calcium excretion. When second morning void spot urines
were obtained in longitudinal studies from women who
were not required to fast, the Ca/Cr ratios during pregnancy
reached double the value of those obtained prior to pregnancy (85, 632), and the mean values were at the upper end
of the normal range in one of the studies (85). Conversely,
fasting Ca/Cr ratios were no different between singleton
and twin pregnancies, and the mean values showed no
change between 10 and 38 wk of pregnancy, consistent
with failure to detect absorptive hypercalciuria on fasted
urine specimens (646).
In this context, it is relevant to mention that hypocalciuria
during pregnancy has been associated with preeclampsia
and pregnancy-induced hypertension (42, 293, 524, 707,
810). In turn, the hypocalciuria has been reported in association with low serum calcitriol (293, 524, 707, 810),
whereas PTH, calcitonin, and ionized calcium are normal
(42, 293, 707, 810). The calcitriol levels are reduced to
values seen in nonpregnant women. The possibility that low
maternal 25OHD or low vitamin D intake could explain
the increased risk of preeclampsia (and, thereby, low calcitriol) has been investigated with a similar number of studies supporting (46, 95, 370, 768) and refuting (294, 726,
810, 823) an association.
The low calcitriol, hypocalciuria, and reduced creatinine
clearance that occur in preeclampsia and PIH are likely
secondary to disturbed renal function, rather than being
causes of the hypertension (293). Consistent with this, in a
longitudinal study, calcitriol levels were normal earlier in
pregnancy and became low only after hypertension and
proteinuria developed (357). Another study found that serum levels of the fat-soluble vitamins A, D, and E were each
lower in preeclamptic women compared with normotensive
pregnant and nonpregnant controls (485), which raises the
possibility that confounding from overweight, obesity, and
poor nutrition may explain why the levels of several fatsoluble vitamins were all lowered in preeclamptic women.
A placental abnormality has been hypothesized to explain
lower calcitriol levels in preeclampsia, with conflicting results obtained showing decreased (248) and increased (286)
placental expression of Cyp27b1. However, since the placenta contributes very little calcitriol to the circulation of
pregnant women (see sect. IIA4), it is unlikely that loss of
placental Cyp27b1 leads to reduced serum calcitriol in preeclamptic women. Alternatively, abnormal placental function could indirectly reduce maternal calcitriol concentrations if placental hormones (such as placental lactogen) are
important stimulators of Cyp27b1 in the maternal kidneys.
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Prolactin and placental lactogen reduce urinary calcium excretion in nonpregnant rabbits (135, 136). Whether these
hormones are helping the kidneys conserve calcium during
pregnancy has not been tested. An increase in urine calcium
excretion during pregnancy suggests that the kidneys are
not conserving calcium; the suppressed PTH levels may be a
contributing factor. This is supported by the observation
that urinary calcium excretion was no different in pregnant
Pth nulls and their WT sisters, despite the lower filtered
load of calcium in Pth nulls (478). An additional consideration is that intestinal calcium absorption increases before
the fetal demand for calcium; consequently, the excess absorbed calcium must be excreted.
The Ca/Cr ratio in a random spot urine has been used in
several recent randomized trials that studied the apparent
safety of high-dose vitamin D supplementation during pregnancy. No adverse increase in Ca/Cr ratio was reported
when 5,000 IU vitamin D per day was compared with placebo (778), when 4,000 IU daily and 400 IU daily were
compared (399), or when 4,000 IU daily and 2,000 IU daily
were compared (966). These findings have been interpreted
to mean that high-dose vitamin D supplementation does not
cause hypercalciuria during pregnancy (399, 778, 966).
However, since it is absorptive hypercalciuria that occurs
during pregnancy, and random spot urines are neither sensitive enough nor timed appropriately to detect absorptive
hypercalciuria, the available data have not adequately excluded whether hypercalciuria worsens during pregnancy
when high-dose vitamin D is taken. Twenty-four hour urine
collections are needed.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
However, plasma concentrations and placental expression
of placental lactogen are not reduced in preeclamptic
women (73, 74, 561, 595, 623, 675, 1027).
Numerous clinical trials have been carried out to assess the
efficacy of calcium supplementation at preventing preeclampsia or pregnancy-induced hypertension, and a net
benefit has been seen for women with the lowest intakes of
calcium, whereas no effect is evident for women with adequate calcium intake (398). In multiple clinical trials, no
effect of high-dose vitamin D supplementation has been
seen on the incidence of preeclampsia in pregnant women
(183, 184, 399, 710, 966).
Increased intestinal calcium absorption during pregnancy
leads to increased urine calcium excretion, with 24-h urine
values near or above the upper limit of normal. This is
absorptive hypercalciuria, which will not be present on
Ca/Cr ratios in fasting urine specimens, and not well discriminated from Ca/Cr ratios obtained from random spot
urine samples. The pregnancy-related suppression of PTH
to low values may contribute to increased renal calcium
excretion. Hypocalciuria with low calcitriol occurs in preeclampsia, likely as a consequence of disturbed renal function. Calcium supplementation reduces the risk of preeclampsia in women with the lowest calcium intakes, while
vitamin D supplementation has had no effect.
D. Altered Skeletal Turnover and Mineral
Metabolism
1. Animal data
The maternal skeleton is a storehouse of mineral that can be
resorbed during pregnancy if needed to provide mineral to
the fetuses. Earlier it was cited that 92% of fetal skeletal
calcium content has been estimated to come from the maternal diet of the rat during pregnancy (974). Additional
radioisotope studies have confirmed that some calcium in
the maternal skeleton will be resorbed to enter the fetal
skeleton, especially during the last few days of gestation
(706). However, much less 45Ca from the maternal skeleton
ends up in the fetuses compared with how much enters the
milk and the pups during lactation, which confirms that
skeletal resorption during pregnancy is quite modest compared with that during lactation (706).
The extent to which bone turnover is altered during pregnancy may be deduced from relative changes in biochemical
markers of bone formation and resorption. These measurements are fraught with confounding problems of changes in
intravascular volume and glomerular filtration rate (discussed in section IID2). In most studies they were measured
in late pregnancy only. The available indices suggest at most
466
The effect that pregnancy has on bone mass or mineralization has been serially assessed by DXA measurements done
every day (827) and every other day (993) during reproductive cycles in outbred Black Swiss mice. There is a progressive 10 –20% increase in whole body mineral content that
begins early in pregnancy and reaches a peak on the day
before birth (827, 993). The hindlimb increases by a similar
amount while the lumbar spine remains unchanged. The
increase in whole body bone mineral content is not attributable to calcium in the fetuses since the maternal value
increases further by the second postpartum day, while in
control experiments, removal of fetuses at C-section revealed that they accounted for ⬍2% of the maternal mineral content at term (827). This increase in whole body bone
mineral content is consistent with the previously noted upregulation of intestinal calcium absorption and positive calcium balance. It is noteworthy, in these studies at least, that
the maternal skeleton continues to accrete mineral during
the last 5 days of gestation despite calcium being transferred
to the fetuses at a peak rate.
Apart from serial assessment of bone mineral content by
DXA at multiple time points during pregnancy in Black
Swiss mice, most studies in rodents have simply compared
end-of-pregnancy BMC or BMD to prepregnancy in the
same mice, or to age-matched virgin mice, without determining whether any changes in bone mass occurred earlier
in pregnancy. This approach has shown that bone mass or
mineral content at the end of pregnancy varies significantly
by skeletal site and genetic background in mice. Outbred
Black Swiss mice consistently show a 10 –20% increase in
whole body bone mineral content at the end of pregnancy,
the lumbar spine remains unchanged, and the hindlimb may
gain 10 –15% (296, 478, 827, 994). Conversely, inbred
C57BL/6J mice show a 5% decline in whole body bone
mineral content, a 15% drop in lumbar spine bone mineral
content, and a 10 –20% gain in the hindlimb (477, 580).
CD-1 mice show no significant changes in mineral content
during pregnancy at any skeletal site (35, 956). Rats
showed no change in whole body BMD and nonsignificant
declines in BMD of femora and tibiae at the end of pregnancy (816), whereas another study found a modest but
significant decline in lumbar spine BMD (920), and a third
study found a gain in femoral and vertebral BMC and BMD
(888). Another study found that femoral calcium content at
the end of pregnancy was linearly related to the calcium
content of the diet (818). Overall, apart from the serial
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3. Summary
a mild uncoupling in favor of resorption during pregnancy
in mice, as indicated by normal to modestly increased deoxypyridinoline and CTX, normal P1NP, and decreased
osteocalcin (296, 477, 478, 580, 994). A decline in osteocalcin has also been noted during pregnancy in guinea pigs
(958) and sheep (277), and contrasts with increased osteocalcin found in rats during early pregnancy and at term
(816, 961).
CHRISTOPHER S. KOVACS
studies in Black Swiss mice, none of the other studies in
rodents can confirm or refute whether bone mass increases
earlier in pregnancy before declining.
Histomorphometry and DXA studies have not been carried
out in pregnant sheep; however, calcium balance studies
inferred that a 20% decrease in skeletal calcium content
occurs by the end of pregnancy (108), consistent with net
bone resorption. A calcium-restricted diet in ewes leads to
increased resorption and reduced ash weight, particularly
within the vertebrae and the pelvis by the end of pregnancy,
with relative sparing of the long bones (69). A high calcium
diet prevents these changes.
In most histomorphometry, microCT, and electron microscopy studies, despite this apparent increase in bone turnover, there was no net change in femoral or tibial bone mass
at the end of pregnancy in Cobs, Holtzman, Lister, and
Sprague-Dawley rats on a 0.45% calcium diet (362, 598,
628, 972) or in beagles on a 2% calcium diet (300). Exceptions include reduced bone volumes and trabecular thickness in the lumbar spine at the end of pregnancy in SpragueDawley rats consuming 1.2% calcium (920), and the opposite result of increased trabecular number, thickness, and
bone volume of the vertebrae, and increased calcein labeling
and bone formation rates throughout the vertebrae, in
Wistar rats on a 0.88% calcium diet (822). Other studies
have found increases in cortical volumes of the femora (106,
548, 947), increased cortical porosity in the femora (548),
The available data discussed in this section may seem inconsisent and contradictory. For example, within some of these
studies there is histomorphometric evidence of markedly
increased bone turnover in late pregnancy but little or no
change in bone mass. A problem contributing to the inconsistency is the comparison of a single time point (end of
pregnancy) to prepregnancy or age-matched virgins, without any assessment at intermediate time points. If a net
increase in bone mass and mineralization occurs earlier in
pregnancy (as suggested by calcium balance studies, upregulated intestinal calcium absorption, and serial DXA
studies in Black Swiss mice), and is then followed by upregulated bone resorption with net bone loss during the
latter third of pregnancy (corresponding to when fetal demand for mineral is at its peak), then that can certainly
explain why bone mass may appear relatively unchanged at
the end of pregnancy despite objective evidence of significantly increased bone resorption. Furthermore, even if there
was no increase in bone mass earlier in pregnancy, if bone
resorption increases only in late pregnancy, that may be too
short of a duration to detect a loss in bone volumes by
histomorphometry. There are likely site-specific differences
as well, with trabecular-rich vertebrae possibly differing in
their response to pregnancy compared with more corticalrich sites such as the tibiae and femora. Increased weightbearing during pregnancy may contribute to a gain in bone
mass of the limbs, as shown in some of the studies.
As noted earlier, when a low calcium diet is consumed, the
skeleton will be markedly resorbed, leading to consistently
reduced bone mass by the end of pregnancy in rats (64, 271,
740) and goats (55). This resorption is mediated in part by
compensatory secondary hyperparathyroidism, which is
more marked on a calcium-restricted diet (see sect. IIA2).
Conversely, a high-calcium diet (1.6 or 1.2% calcium) leads
to a higher femoral calcium content at the end of pregnancy
in rats compared with consuming 0.5% calcium (719, 818),
which is compatible with the high-calcium diet facilitating
reduced resorption of the maternal skeleton.
Does the lack of change or small net change in bone mass or
volumes at the end of pregnancy have any effect on bone
strength? No differences have been found in the biomechanical properties of the trabecular bone in the vertebrae
(crush test) of Sprague-Dawley rats (947), or the cortical
bone of the femora (3-point bend test and rotational stress)
of C57BL/6 mice and Sprague-Dawley rats (489, 548, 947).
However, the material properties of rat femora were deduced to show reduced shear stress and increased stiffness
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Static and dynamic histomorphometry have been carried
out in the femora of pregnant rats and compared with agematched virgins. The results are inconsistent across studies
and not clearly explainable by variations in the calcium
content of the diet or the strain of rat. One reported marked
increases in bone resorption (osteoclast number, resorptive
surfaces) and bone formation (osteoblast number, osteoblast surface, osteoid volume) during pregnancy in Cobs
rats consuming a 0.45% calcium diet (598). Another found
that osteoclast parameters increased three- to sixfold while
bone formation parameters were unchanged in SpragueDawley rats on a 1.2% calcium diet (920). A third study
used a 1.1% calcium diet in Sprague-Dawley rats and found
divergent effects with reduced bone formation parameters
in the vertebrae but increased bone formation parameters
within cortical bone of the femora; bone resorption parameters were not assessed (947). Pregnant beagles consuming a
2% calcium diet also showed significantly increased bone
formation parameters in the ilium, whereas bone resorption
parameters were not assessed (300). In all four studies bone
turnover was found to be increased on the basis of at least
one parameter (i.e., either bone resorption or formation),
but the failure to assess bone resorptive parameters in two
of the studies makes it difficult to be certain whether net
bone formation or resorption is occurring in these pregnant
animals.
and reduced trabecular bone volumes of the tibiae (107), all
in Sprague-Dawley rats with no correlation to the dietary
calcium content. A microCT study found that C57BL/6
mice consuming 2% calcium increased cortical area and
trabecular volume of the femora at day 16 of pregnancy
compared with day 9 (489).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
when subjected to rotational stress (548). Two studies from
the same investigator provided contradictory results in that
load to failure in the three-point bend test was increased
(216) and reduced (217) at the end of pregnancy in Wistar
rats compared with age-matched virgins. The work to failure did not differ between pregnant and age-matched virgins in both studies (216, 217), suggesting that there was no
real change in bone strength.
Bone turnover during pregnancy may be impacted by diverse hormones, including the previously noted increases in
estradiol, PTHrP, prolactin, placental lactogen and growth
hormone, and oxytocin. That prolactin or placental lactogen may influence bone metabolism directly has been suggested by the finding that osteoblasts express prolactin receptors (188, 888), and prolactin receptor deficient mice
exhibit decreased bone formation (188). Furthermore,
when the prolactin increase during pregnancy was reduced
by treating Sprague-Dawley rats with bromocriptine, it
blunted the pregnancy-related gain in femoral and vertebral
bone mineral content (888).
The oxytocin receptor is expressed by osteoclasts and osteoblasts (195), which may enable oxytocin to regulate
bone metabolism during pregnancy. In support of this, oxytocin and oxytocin receptor-null mice of both sexes have
reduced bone formation and an osteoporotic phenotype
(895). Oxytocin also stimulates osteoblast differentiation
and function, whereas it stimulates osteoclast formation
but inhibits osteoclast function and skeletal resorption
(565, 895). An in vivo role for oxytocin has not been examined in these mice.
2. Human data
Intestinal calcium absorption increases in the first trimester,
months before the fetal demand for mineral in the third
trimester. Metabolic studies have shown that women are in
a positive calcium balance by mid-pregnancy (372), so skeletal mineral content may become increased at that timepoint to explain where that calcium is stored. However,
mid-pregnancy remains a relative “black box” due to the
468
Some maternal bone resorption during late pregnancy may
contribute mineral to the fetus. This has shown by study of
women living near the Techa River in Russia, who inadvertently ingested 90Sr from water contaminated by nuclear
waste during the 1950s. Years after the exposure ended,
90
Sr could be detected in the skeletons of their fetuses,
which could only have come from resorption of 90Sr that
had been previously fixed in the maternal skeleton (921,
922). But women who ingested 90Sr during pregnancy, especially during the third trimester, gave birth to babies with
10-fold higher 90Sr content, consistent with dietary absorption of mineral being responsible for much more of the
mineral content of the fetal skeleton (819, 921, 922).
The sole study reporting iliac crest histomorphometry during human pregnancy was carried out in 15 women who
planned to have elective first trimester abortions, 13 women
scheduled to have C-sections in the third trimester, and 40
nonpregnant women (some living and some cadaveric specimens) (732). At the first trimester time point, bone resorption indexes were increased, bone formation indexes were
decreased, and trabecular bone volume was significantly
lower, compared with nonpregnant women (732). Conversely, the third-trimester biopsies were no different from the
nonpregnant values for bone mass and indexes of bone resorption and formation (732). Taken at face value, these results
suggest that early pregnancy is a bone-resorptive state, which
induces bone loss that is later recovered by the end of pregnancy. That interpretation does not fit easily with the fact that
little transfer of calcium is occurring from mother to offspring
during the first trimester; consequently, skeletal resorption
should not be increased at this time point, especially given that
intestinal calcium absorption is already upregulated. Instead,
increased bone resorption is more likely to occur in the third
trimester when the fetal demand for mineral is at its peak. The
observed differences may be the result of small sample sizes
with confounding among the groups. Age matching was poor
and may have contributed to apparent differences, with mean
ages of 22.4 in the first trimester group, 25.1 in the late pregnancy group, and 32.6 in the nonpregnant group. More histomorphometric data from pregnant women are needed.
Cross-sectional and serial measurement of bone turnover
markers have been carried out in pregnant women. These
indexes are generally considered more accurate at detecting
changes in bone resorption compared with bone formation
and are subject to diurnal variation as well as differences
between fasted and postprandial values (142, 235, 570).
Pregnant women were often compared with nonpregnant
controls or normal ranges, rather than prepregnancy measurements from the same women. Additional potential confounders include hemodilution affecting serum measurements (confirmed to affect osteocalcin and CTX, Ref. 461),
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Although there may be no net change or modest changes in
bone mass by the end of pregnancy when a calcium-replete
diet is consumed by rodents, there is other evidence that the
macro structure of bone may be altered. In Sprague-Dawley
rats, an increase in femoral cortical bone volumes, radii,
and cortical thickness have been found at the end of pregnancy, which appear to result from increased periosteal
bone formation during pregnancy (106, 216, 548, 947).
These changes are conceivably a compensatory response to
the increased weight bearing during pregnancy and the resorption of trabecular bone. The change in bone volumes
and radii may become more marked during lactation (see
sect. IVG).
absence of data on bone mass, structure, or mineralization
at this time point.
CHRISTOPHER S. KOVACS
increased GFR and altered creatinine excretion affecting
urinary measurements, possible contributions from placenta and other tissues, increased degradation or clearance
by the placenta (confirmed to affect osteocalcin, Ref. 769),
and lack of fasted or diurnally timed specimens.
The overall pattern of results suggests that bone turnover
may be relatively normal earlier in pregnancy but that it
increases during the third trimester to create a net resorptive
state. Such a pattern would be consistent with the expected
late-pregnancy demand for mineral and, thereby, a concurrent need to resorb from the maternal skeleton, especially if
intestinal absorption of mineral is not sufficient to meet the
combined needs of mother and fetus. Consistent with this, a
randomized trial found that consuming a mean 2,300 mg of
calcium daily resulted in a 15% lower NTX level during the
second and third trimesters compared with women consuming 1,100 mg calcium daily (274). Twin pregnancy resulted in slightly higher urinary NTX and CTX, and
a slightly increased bone-specific alkaline phosphatase at
term; these findings are compatible with further increased
resorption to meet the needs of two fetuses (646).
Cross-sectional and serial studies of areal bone mineral density have been carried out in pregnant women. Most studies
have been done before and after a planned pregnancy to
avoid fetal radiation exposure, so very limited information
is available about changes in maternal BMD during pregnancy. The readings may also be affected by altered body
composition, weight, and skeletal volumes during preg-
More modern studies have used DXA at two time-points,
1– 8 mo before planned pregnancy and 1– 6 wk after delivery (85, 462, 633, 649, 705, 764, 943). These generally
small studies found 0% to at most a 5% decrease in lumbar
spine bone density between the two measurements, and
little to no change at other skeletal sites. However, the largest study involved 92 women who had DXA of hip, spine,
and radius done at baseline (up to 8 mo prior to planned
pregnancy); DXA of the forearm repeated during each trimester; and DXA of hip, spine, and radius repeated 15 days
postpartum. Seventy-three women completed the postpartum visit and were compared with 57 nonpregnant women
who had DXA measurements done at similar intervals. The
findings included that BMD decreased during pregnancy by
4% at the ultradistal radius but increased by 0.5% at the
proximal one-third of the forearm (633). At the total forearm a 1% lower value in pregnant women versus nonpregnant controls became discernible with the third trimester
measurement, coinciding with the peak interval of placental-fetal calcium transfer. When the prepregnancy to postpregnancy readings were compared, BMD was reduced by
1.8% at the lumbar spine, 3.2% at the total hip, and 2.4%
at the whole body (633). Overall, this study found statistically significant but small declines in BMD at several skeletal sites. For perspective, it is important to realize that such
changes would not be distinguishable from error of measurement in an individual subject, but were resolvable in
this study due to the large cohort. Whether all of these small
changes in BMD are attributable to pregnancy is also unclear, because all women went on to breastfeed before the
day 15 ⫾ 7 postpartum measurement, and bone loss occurs
rapidly during lactation (see sect. IVE). In contrast, radial
BMD was measured in a longitudinal study of 22 women
and a cross-sectional study of 75 women, and no change
was seen across the three trimesters in either study (609).
Peripheral ultrasound has been used during pregnancy.
Cross-sectional (307, 698) and longitudinal studies (234,
307, 378, 504, 722, 918, 1002) have found lower apparent
BMD in the os calcis or phalanges at the end of pregnancy,
but no effect was seen on the mid-tibial shaft (1015). How
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Given these caveats, several markers of bone resorption
[urine N-telopetide (NTX) or C-telopeptide (CTX), serum
CTX, tartrate-resistant alkaline phosphatase, deoxypyridinoline/creatinine, pyridinoline/creatinine, and hydroxyproline/creatinine] have been found to be low in the first
trimester but to increase steadily thereafter, rising to as
much as twice normal in the third trimester (85, 206, 207,
304, 461, 632, 695, 764, 1002). Correcting for the decline
in serum albumin obliterated the apparent fall in serum
CTX earlier in pregnancy (461). Osteocalcin has been the
most widely used marker of bone formation, and its values
have been low to undetectable in the first trimester, after
which it may stay low or rise to normal values by term (33,
329, 458, 632, 695, 764, 769, 813, 1002). Its apparent
decline early in pregnancy was attributable to hemodilution
of pregnancy in one study (461), whereas a surge in osteocalcin after delivery of the placenta is compatible with loss
of placental degradation or clearance (769). Procollagen I
N-telopeptides (P1NP) and carboxypeptides, and bone specific alkaline phosphatase, are also low in the first trimester,
and have either remained low (304), or risen to normal or
above by term (85, 206, 207, 461, 632). Total alkaline
phosphatase increases mainly due to the placental fraction
and is not a useful indicator of the relative changes in bone
formation during pregnancy (33, 85, 221, 304, 769).
nancy. An early study used X-ray spectrophotometry of the
radius and femur during the first or second trimester and
found that trabecular but not cortical bone density had
decreased by the time of a postpartum measurement (526).
Several prospective studies used single- or dual-photon absorptiometry (SPA or DPA) of the forearm serially during
and after pregnancy (18, 185, 468), or of the femur before
and after a planned pregnancy, and found no significant
changes in cortical or trabecular bone density (858). Another study compared preconception SPA and DPA measurements to those taken 6 wk postpartum and found a
2.4% decrease in the femoral neck, a 2.2% decrease in
radial shaft, a 3.4% increase in the tibiae, and no change in
lumbar BMD (256).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
relevant peripheral ultrasound at the heel or a finger during
pregnancy is for revealing changes in bone mass or mineralization at the spine or hip is uncertain. Notably, although
bone mass declines significantly during lactation, with the
most marked changes in the lumbar spine (see sect. IVE),
ultrasound of the os calcis and mid-tibial shaft showed no
changes (533, 917, 1015).
Overall, available data suggest that bone turnover increases
during pregnancy, especially during the third trimester.
There are real but small declines in BMD throughout the
skeleton that require a sufficiently large cohort to be detected with confidence.
For balance, a few studies have found that parity is associated with reduced BMD (17, 80, 375, 472, 559, 686, 699)
or increased vertebral (97) or hip fracture risk (299). However, these reports are substantially outnumbered by the
aforementioned studies that found a neutral or protective
effect of parity. There are also divergent effects seen among
the different studies. For example, one study reported that
parity reduces femoral neck BMD but had no effect on
lumbar spine (416). Another found that parity reduces total
hip and femoral neck BMD in postmenopausal women, but
not in premenopausal women who are closer in time to the
event and therefore less likely to show confounding (1020).
Several studies also found that adolescent pregnancy was
associated with decreased bone density (292, 861, 864),
even though parity was not a significant factor in the overall
cohort. However, an NHANES study of 819 women ages
20 –25 found that adolescent pregnancy did not reduce
peak bone mass as previously feared, since BMD was no
different regardless of whether these women had experienced an adolescent pregnancy, an adult pregnancy, or no
prior pregnancies (169).
These epidemiological studies have a number of limitations.
It is difficult to separate the effects of parity from those of
470
3. Summary
Animal models suggest that bone mass may increase earlier
in pregnancy, whereas by the end of pregnancy bone mass is
approximately equal to or slightly lower than prepregnancy
or age-matched virgin values. Bone turnover (as assessed by
histomorphetry and bone resorption and formation markers) increases during late pregnancy in a pattern that predicts that some degree of bone loss has occurred in these
animal models. Whether there is any net loss of bone mass
by the end of pregnancy depends on the degree to which
bone mass increased earlier in pregnancy. Late pregnancy is
the interval of increased secondary hyperparathyroidism in
rat studies. Bone strength is probably unchanged at the end
of pregnancy. Some inconsistencies among the rat data (increased, decreased, or no change in bone turnover, mass, or
strength) are not obviously explainable by the calcium content of the diet or the rat strain used. However, it is clear
that skeletal resorption and net bone loss increase in animal
models when a calcium-restricted diet is given during pregnancy.
Available data from pregnant women indicate that a positive calcium balance also occurs by mid-pregnancy, but
whether BMD is objectively increased at this time point has
not been determined. Upregulation of bone resorption occurs in the third trimester and likely causes some bone loss,
with most women ending up with either no change or a very
modest decrease in BMD by term. Increased resorption and
net bone loss are more likely to occur in women who do not
absorb sufficient calcium to meet the combined needs of
themselves and their babies. Inadequate dietary calcium intake probably contributes to an increased risk of pregnancy-associated osteoporosis (see sect. IIIA). In the long term,
these pregnancy-related changes in bone metabolism or
bone mass appear to have no adverse effect on the calcium
content or strength of the maternal skeleton, and may even
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Are there any long-term impacts of skeletal changes induced
by pregnancy? This has been examined through numerous
epidemiological studies that have ascertained whether parity confers any risk of lower BMD, an osteoporotic level of
BMD, or fragility fractures. The majority of such studies
have found either a neutral effect of parity (16, 38, 63, 71, 83,
144, 158, 162, 203, 212, 356, 368, 374, 383, 443– 445, 457,
463, 482, 506, 507, 509, 525, 541, 547, 619, 636, 648, 683,
704, 715, 761, 770, 828, 833, 845, 846, 861, 864, 865, 935,
951, 969) or that parity confers greater BMD (27, 215, 244,
290, 292, 336, 341, 365, 522, 597, 611, 642, 661, 700, 804,
864, 879, 881, 934). Additional studies have reported that
parity decreases the risk of hip fractures (384, 397, 421, 460,
625, 689, 869, 997). One of the studies reporting a protective
effect of parity was particularly strong because it involved
1,852 twins and their female relatives, including 83 identical
twins who were discordant for ever being pregnant (700).
lactation. Decades have passed in some cases between the
reproductive years and the time of the first BMD measurement or fracture, such that confounding factors and events
in the elapsed time may have influenced the outcome. Such
confounding may be less likely in the NHANES study involving women ages 20 –25 since the pregnancies were only
a few years earlier, wherein no detrimental effect of parity
was seen. Overall, it seems most likely that parity has no
long-term adverse effect on BMD or fracture risk for most
women. It is not recognized as a significant factor for estimating 10-yr risk of fracture in FRAX (929). However,
there may be a subset of women in whom parity does adversely affect bone mass. These may include women in
whom significant nutritional deficiencies lead to increased
skeletal resorption during pregnancy to meet the fetal mineral requirements, and some of these women may present
with fractures from pregnancy-associated osteoporosis (see
sect. IIIA).
CHRISTOPHER S. KOVACS
have a protective effect against low BMD and future risk of
fractures.
III. DISORDERS OF BONE AND MINERAL
METABOLISM DURING PREGNANCY
A. Osteoporosis in Pregnancy
1. Animal data
2. Human data
Osteoporotic fractures during pregnancy are very uncommon, but they do occur. They have probably been occurring
in association with reproduction for the past five millennia,
because vertebral compression fractures and low BMD
have been found in Egyptian mummies and other archaeological skeletons of women who were 16 –30 yr of age when
they died (883).
Osteoporosis presenting in pregnancy has been reviewed in
depth recently (501), and will be covered more briefly here.
There are two main presentations: vertebral fractures and
so-called transient osteoporosis of the hip.
A) VERTEBRAL AND OTHER FRACTURES IN PREGNANCY. Fragility
fractures of the spine (and less commonly other skeletal
sites) have occurred during the third trimester, and in the
puerperium of women who did not breastfeed. In both situations these fractures may be considered to have been
provoked by pregnancy (fractures during lactation are considered separately in sect. VA). In most affected women
there is no preceding bone mineral density (BMD) reading
because of no prior indication for it to have been done.
Serum chemistries and calciotropic hormone levels are usually unremarkable. However, bone loss is likely a factor in
pregnancy-related vertebral fractures, because the BMD is
usually low at presentation (475, 713, 849, 1005), and it
spontaneously improves afterward (259, 433, 713). In the
few cases where bone biopsies were done, mild osteoporosis
was observed (849, 850, 1005).
Insufficient calcium absorption (from dietary calcium deficiency, lactose intolerance, celiac disease, other malabsorp-
Another potential cause of physiological bone loss during
pregnancy is greater than normal release of PTHrP from the
placenta and breasts. The gradual rise in plasma PTHrP
(sect. IIA3) likely contributes to upregulation of calcitriol
synthesis, intestinal calcium absorption, and bone turnover
in all pregnant women. However, in individual reported
cases, high circulating levels of PTHrP have arisen from the
breasts or placenta and led to pseudohyperparathyroidism,
which is characterized by increased bone resorption and
severe hypercalcemia (see sect. IIIF) (270, 435, 474, 549).
High circulating levels of PTHrP that contributed to bone
resorption have also been noted in women who presented
with fragility fractures weeks after delivery (29, 751); such
high levels may have begun in pregnancy and contributed to
bone loss before delivery.
Additional factors that contribute to fracture risk during
pregnancy include increased weight-bearing (average
weight gain of 12 kg), lordotic posture, reduced bone mass
or strength that precedes pregnancy, and conditions that
cause bone loss during pregnancy. Published cases have
revealed such diverse conditions as anorexia, longstanding
hypomenorrhea or relative estradiol deficiency, premature
ovarian failure, petite stature or body frame, mild osteogenesis imperfecta, inactivating mutations in LRP5, dietary
calcium deficiency, renal calcium leak (hypercalciuria),
bedrest and inactivity, and pharmacotherapy before or
during pregnancy that may induce bone loss [heparin,
oral glucocorticoids, gonadotropin releasing hormone
(GnRH) analogs, depot medroxyprogesterone acetate,
and certain anticonvulsants] (501). A maternal family
history of severe osteoporosis is likely to be present in
women with pregnancy-associated fragility fractures
(259), which implies that genetic causes of low bone mass
or skeletal fragility may be present.
Pregnancy-associated osteoporosis typically occurs in a first
pregnancy, higher parity does not increase the risk, and
fractures usually do not recur in subsequent pregnancies
(243, 259, 475, 666, 713). These observations imply that in
many cases reversible factors (such as nutritional deficiencies) may have been corrected after the first pregnancy.
Permanent disorders such as osteogenesis imperfecta or
LRP5 mutations should be anticipated to maintain an in-
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Fragility fractures do not normally occur as a result of pregnancy in animal models. This is consistent with upregulation of intestinal calcium absorption usually being sufficient
to meet the mineral requirements of the fetuses, and the
finding that bone strength is unchanged at term. However,
it is clear that the maternal skeleton will be resorbed when
the maternal diet is inadequate. A low-calcium diet provokes marked secondary hyperparathyroidism during pregnancy (321), but even then, spontaneous fractures have not
been noted until lactation (350).
tive disorders, and vitamin D deficiency) is likely to induce
resorption of the maternal skeleton during the third trimester. A recent report described a woman with a calcium
intake of 229 mg daily, who developed multiple vertebral
compression fractures during pregnancy (501). Since that
amount was insufficient for her own nonpregnant needs,
the normal upregulation of intestinal calcium absorption
during pregnancy would not have benefited her. Significant
skeletal resorption was an inevitable consequence of her
pregnancy.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
creased risk of vertebral and other fractures in subsequent
pregnancies.
B) TRANSIENT OSTEOPOROSIS OF THE HIP. Transient osteoporosis
of the hip in pregnancy (also known as bone marrow edema
syndrome) is a rare condition of skeletal fragility. It appears
to be a form of chronic regional pain syndrome 1 or reflex
sympathetic dystrophy that most often involves the hips
(112, 147, 335, 351, 571). When it occurs in association
with pregnancy, its onset is usually during the third trimester or the puerperium with unilateral hip pain, limp, or a hip
fracture; it can also be bilateral at presentation (112, 272,
301, 335, 573, 688). The femoral head and neck are osteopenic and radiolucent on plain radiographs (147, 218,
571), while DXA suggests that the hip BMD is quite low
(301). The lumbar spine BMD is usually normal but if it is
also low, it is usually substantially higher than the femoral
neck BMD (31). Magnetic resonance imaging (MRI) studies
have revealed that the radiolucent femoral head and neck
are edematous, which suggests that the low DXA values in
the hip may be an artifact of that increased water content
(31, 523, 688, 892). Nevertheless, that bone marrow edema
is still an indication of fragility in the affected femora, and
prophylactic arthroplasties have been carried out in women
in whom the fracture risk was considered to be high. In
women who do not fracture, the MRI and DXA abnormalities typically resolve rapidly within several months to a
year, leading to a 20 – 40% increase in femoral neck BMD
as the edema subsides (31, 43, 128, 147, 301, 335, 573,
892). Whether that is a real increase in mineralization or
removal of an artifact from bone marrow edema remains
uncertain.
The etiology of this condition is uncertain. It occurs
equally in men and women, and its occurrence during
pregnancy may simply be by chance. It might also be
triggered by pregnancy-related factors. Femoral venous
stasis caused by pressure from the pregnant uterus, relative immobilization from bed rest, and fetal pressure on
472
On the other hand, some patients who clearly had transient
osteoporosis of the hip also had very low spine BMD, vertebral fractures, severe vitamin D deficiency, and prolonged
pregnancy/lactation cycles that may have caused generalized bone loss (43, 48, 98, 691). Therefore, the two conditions can coincide, despite evidence that they appear to have
a different pathogenesis and outcome.
3. Summary
Vertebral and (less commonly) other fractures may occur
during pregnancy in women with preexisting disorders of
skeletal fragility, and in women who experience greater
than expected skeletal resorption during gestation. Nutritional deficiencies and malabsorptive disorders are particularly likely to cause problems because insufficient mineral
delivery to the fetus will prompt compensatory resorption
of the maternal skeleton. Transient osteoporosis of the hip
may be a distinct disorder that does not occur from generalized bone resorption, but instead results in focal edema
and fragility of the femoral head and neck.
B. Primary Hyperparathyroidism
1. Animal data
Several mouse models for primary hyperparathyroidism,
such as mutations in Men1, have been created, but as yet
none has been studied during pregnancy. Maternal hypercalcemia induced by calcium infusions causes increased fetal calcium and suppressed fetal PTH concentrations in
ewes, confirming that maternal hypercalcemia adversely affects fetal and neonatal parathyroid function (456).
Heterozygous inactivating mutations in the calcium sensing
receptor (CaSR) create a condition similar to primary hyperparathyroidism, and relevant data from pregnant
Casr⫹/⫺ mice are discussed in section IIIC. A postpartum
surge in serum calcium occurs in normal rodents, and the
peak serum calcium should be even higher in rodents with
underlying primary hyperparathyroidism.
2. Human data
The exact prevalence of primary hyperparathyroidism during pregnancy is uncertain. A recent retrospective series
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Many uncontrolled treatments [nasal calcitonin (263, 687,
885), bisphosphonates (43, 143, 178, 263, 438, 475, 671,
677, 685, 799, 885, 897), strontium ranelate (897, 1016),
and teriparatide (98, 178, 377, 527, 544, 885)] have been
reported in various case series. Most of the authors of these
reports evidently did not appreciate that substantial spontaneous recovery of bone mass occurs even in women who
fractured, with BMD increases in the range of 20 –70% in
individual cases. For example, a 50% increase in BMD
demonstrated by QCT in a woman who presented with a
compression fracture 1 wk postpartum (556). Therefore,
the attributable effect of pharmacological therapy may have
been greatly overestimated. It may be reasonable to wait
12–18 mo for spontaneous recovery to occur before evaluating whether the fracture risk remains high enough to warrant pharmacological therapy (501).
the obturator nerve are among the theories proposed to
explain its occurrence in pregnant women (112, 147,
218, 335, 499, 571). It is considered separately here because, unlike the vertebral and other fractures that sometimes occur during pregnancy, it does not seem to result
from systemic bone resorption. It also has different epidemiological characteristics, including that it can occur
in any pregnancy, and it has recurred in the other hip
either during a subsequent pregnancy or when not pregnant.
CHRISTOPHER S. KOVACS
found that it occurred in 0.03% of reproductive age women
who underwent routine screening of serum calcium (391).
Several hundred cases have been described in English-language medical journals (354, 391, 466), while the author’s
advice has been sought for several cases each year by clinicians around the globe. Primary hyperparathyroidism is
10 –20 times more likely to occur in women over age 45
than in women of child-bearing age (373, 980), but in two
case series, ⬃1% of all parathyroidectomies were done in
pregnant women (466, 490). The pathology is similar to
nonpregnant cases: a predominance of single adenomas followed by four-gland hyperplasia (267, 466).
The physiology of normal pregnancy can worsen hypercalcemia caused by primary hyperparathyroidism since both
conditions cause increased intestinal calcium absorption,
hypercalciuria, and some degree of increased bone resorption. This may explain the perceived increased risks of severe hypercalcemia, pancreatitis, and kidney stones when
primary hyperparathyroidism occurs during pregnancy.
Conversely, rapid placental calcium transfer and uptake of
calcium by the fetal skeleton during the third trimester may
help protect against severe hypercalcemia in the mothers.
Loss of outflow to the placenta likely explains why hypercalcemic crises have occurred after delivery of the placenta
(612, 662, 701, 795). Physical inactivity and bedrest will
add an additional component of skeletal resorption. Consistent with the animal models, maternal hypercalcemia will
increase the flow of calcium across the placenta, thereby
suppressing the developing fetal parathyroids. The increased fetal serum calcium may in turn cause increased
renal water excretion, thereby explaining association of
maternal primary hyperparathyroidism with polyhydramnios (825).
Historically, primary hyperparathyroidism had been considered to be an adverse condition that should be dealt with
during pregnancy. Older cases series suggested that significant maternal morbidity and mortality occurred in up to
67% of mothers, while up to 80% of fetuses and neonates
experienced morbidity or mortality (803). Hypercalcemia
causes nonspecific, constitutional symptoms that are difficult to distinguish from normal symptoms encountered during pregnancy, including nausea, hyperemesis, constipation, fatigue, weakness, and mental symptoms (508). More
marked hypercalcemia during pregnancy has been associated with hyperemesis, weight loss, seizures, and preeclampsia (418, 466, 490). Additional maternal morbidity
This historic view has led to a general preference for parathyroidectomy to be done during the second trimester to
prevent fetal and neonatal morbidity and mortality, and a
postpartum parathyroid crisis in the mother. There are no
randomized trials comparing surgical, medical, and observational approaches, while consensus guidelines for the management of primary hyperparathyroidism have not addressed
pregnancy (82). A retrospective review found significantly
fewer neonatal deaths and complications in surgically treated
mothers compared with the medically managed group (466).
The second trimester is considered to have a lower risk of
anesthetic or surgical complications, precipitated delivery, and
neonatal death, compared with surgery during the third trimester (153, 236, 508, 824), although individual case reports
have supported the apparent safety of third trimester surgery
(354, 662, 711, 802).
A more modern view is that the maternal and fetal risks of
primary hyperparathyroidism may have been exaggerated
by reporting bias of more severe cases in the older literature,
with the often milder cases seen today not necessarily requiring intervention during pregnancy. However, the most
recent consensus guidelines for management of asymptomatic primary hyperparathyroidism recommend surgery for
all individuals under age 50, which should encompass all
pregnant women (82). From that perspective the only question is whether surgery should be done during the second
trimester or postpartum.
A recent retrospective analysis of a database registry found
1,057 reproductive-aged women with primary hyperparathyroidism, of whom ⬃60% had been pregnant before the
diagnosis and ⬃15% had been pregnant after the diagnosis
(3). Compared with 3,171 age-matched women, there was
no apparent difference in the incidence of spontaneous
abortions, but the rate of C-sections was twice that of controls in women who had a pregnancy after the diagnosis
was known (3). That study is limited because no data were
available on the mothers during the pregnancies or on neonatal complications. Another retrospective study reported
on 74 women with primary hyperparathyroidism who had
had 134 pregnancies and who were compared with 175
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The dilutional fall in serum albumin and calcium (see sect.
IIA1) and suppression of PTH (see sect. IIA2) during normal pregnancy may mask the hypercalcemia and delay the
diagnosis. An elevation in ionized or albumin-corrected calcium, combined with a nonsuppressed PTH level, confirms
the presence of primary hyperparathyroidism during pregnancy.
includes nephrocalcinosis, nephrolithiasis, urinary tract infections, acute pancreatitis, and increased bone loss (508,
824). Fractures are uncommon but have occurred with
more severe primary hyperparathyroidism and parathyroid
carcinoma (381, 651). In up to 15% of cases women presented with pancreatitis during the second or third trimester
(153, 186, 205, 429, 508, 511). Hypercalcemic crises have
occurred during the third trimester (153, 186, 662, 795),
which coincides with peak release of PTHrP by the placenta
and breasts. There are risks to the fetus and neonate that
must be considered, including miscarriage, stillbirth, and
hypoparathyroidism, and these are discussed in more detail
in the companion review (492).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
3. Summary
Key points about primary hyperparathyroidism during
pregnancy are that maternal and fetal complications appear
to be less likely with the milder forms of the condition that
are usually encountered today; however, the risks are not
absent. If surgery is to be carried out it should be safer to do
this in the second trimester. In cases that are only observed,
the clinician should be aware of the potential for a hypercalcemic crisis to occur during the third trimester and even
more abruptly after delivery. The baby must be watched for
neonatal hypocalcemia that can have a delayed onset, a
prolonged course, and even be permanent (492).
C. Familial Hypocalciuric Hypercalcemia
1. Animal data
ciuria, and nonsuppressed PTH (122). It is asymptomatic
because its origin in utero causes all tissues to be fully adapted
to a higher level of calcium, while the relative hypocalciuria
protects against nephrocalcinosis and nephrolithiasis. The hypercalcemia with elevated PTH persists during pregnancy as
expected (727); however, increased intestinal calcium absorption during pregnancy causes absorptive hypercalciuria and
not the expected diagnostic finding of hypocalciuria (638,
968). Consequently, the diagnostic criteria for FHH can be
confounded during pregnancy by results that suggest primary
hyperparathyroidism may be present. Pregnancies in affected
women are uneventful; in fact, many documented cases involve the diagnosis being made in the mothers only after their
babies presented with neonatal hypocalcemia or seizures (727,
913, 914). This neonatal hypoparathyroidism originates in
utero with increased flux of calcium across the placenta causing suppression of the fetal parathyroids (as in the animal
model), and that suppression can last for days to months after
birth. Suppression has even occurred in a baby carrying the
inactivating CASR mutation, who presented with neonatal
hypocalcemia, but later went on to develop the expected hypercalcemia with high PTH (912). Babies who are homozygous or compound heterozygous for inactivating CASR
mutations (297, 579), and occasionally babies with only a
single known mutation that may exert a dominant-negative
effect (45, 673), develop life-threatening neonatal severe
hypercalcemia that can be rescued by three-and-a-half
gland parathyroidectomy.
It is important to consider the possibility of FHH whenever
a woman presents with hypercalcemia during pregnancy,
and to be wary that the urine calcium excretion will not be
reduced as expected. Surgery is not indicated for FHH, and
if the serum calcium were to be reduced to “normal,” it
would cause symptomatic hypocalcemia. Unfortunately, at
least one woman with FHH underwent a three-and-a-half
gland parathyroidectomy during the second trimester when
she presented with marked hypercalcemia and hypercalciuria, and she was only recognized to have FHH when hypercalcemia persisted and her baby was affected too (968).
Casr⫹/⫺ mice have an inactivating mutation in one allele of
the gene encoding the CaSR and are the murine equivalent
of familial hypocalciuric hypercalcemia (FHH). They have
classical findings of chronic hypercalcemia, relative hypocalciuria, and increased PTH (394); the condition develops in utero with hypercalcemia (498). Pregnancies are uneventful, but maternal hypercalcemia leads to suppressed
PTH in the fetuses compared with offspring of the same
genotype borne by their WT sisters (498). Homozygous
offspring provide a model for neonatal severe hypercalcemia in humans, and die within 3 wk after birth unless rescued by surgical parathyroidectomy or genetic ablation of
Pth or Gcm2 (394, 491, 498, 562, 932).
D. Hypoparathyroidism
2. Human data
1. Animal data
FHH is caused by autosomal dominant, inactivating mutations in CASR that lead to chronic hypercalcemia, hypocal-
The role that PTH might play in regulating maternal mineral and bone homeostasis during pregnancy has been in-
474
3. Summary
Key points about FHH in pregnancy are that it is uneventful
in the mother, it may be confused with primary hyperparathyroidism because the normal physiological changes of
pregnancy lead to hypercalciuria, and it is not necessarily
benign for the offspring who are at risk for developing
neonatal hypocalcemia.
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normocalcemic women who had experienced 431 pregnancies over the same interval (391). There was no difference in
the rate of spontaneous abortions or pregnancy-related
complications between women with and without primary
hyperparathyroidism during pregnancy, but neonatal complications were not reported (391). Additional cases suggest
that the rate of still birth, neonatal death, and neonatal
tetany are far less with modern compared with older case
series (824). But even in modern cases fetal death still occurs, such as in 30/62 medically managed cases that ended
in a late spontaneous abortion (the risk correlated with the
level of maternal serum calcium), whereas no complications
were seen in 15 cases operated upon during the second
trimester (667). Neonatal hypocalcemia and tetany still occur after supposed mild primary hyperparathyroidism in
the mothers (716) and the hypoparathyroidism can be prolonged and permanent (125, 576, 824). A twin pregnancy
illustrated the variability of responses to maternal primary
hyperparathyroidism, with one neonate having hypocalcemic seizures and the other staying normocalcemic (616).
CHRISTOPHER S. KOVACS
vestigated by studies in parathyroidectomized rats and Pth
null mice.
On the other hand, in a series of related studies from one
laboratory, parathyroidectomized Wistar rats on a 0.9%
calcium diet developed worsening hypocalcemia and hyperphosphatemia between 16.5 and 21.5 days of gestation, and
up to 40% experienced tetany or sudden death either during late pregnancy or while giving birth (163, 313, 314,
328). Serum calcitriol and intestinal expression of
calbindin9K-D levels in parathyroidectomized rats were
⬃50% of the values in intact rats at day 21.5 of pregnancy
(313), but no earlier measurements were done. Therefore,
whether the calcitriol level or calbindin9K-D expression had
increased from earlier in pregnancy in parathyroidectomized or intact rats remains unknown.
Parathyroidectomized Sprague-Dawley rats maintained on
a 0.75% calcium diet also became hypocalcemic in late
gestation, but serum calcitriol more than tripled over the
last several days of pregnancy, and achieved a mean value
that was modestly but not significantly lower than the calcitriol level of intact pregnant rats (658). Moreover, 24,24dihydroxyvitamin D, a product of the Cyp24a1 enzyme,
showed consistently higher levels in parathyroidectomized
rats throughout pregnancy (658). This is consistent with the
known effect of PTH to suppress Cyp24a1 activity and
expression (752, 835, 1023, 1024); consequently, loss of
PTH causes increased Cyp24a1-mediated catabolism of 25hydroxyvitamin D and calcitriol.
Collectively these studies support that PTH-independent
upregulation of calcitriol synthesis and intestinal calcium
absorption occur during pregnancy, but they differ in
whether the parathyroidectomized rodent’s ability to maintain her own serum calcium is improved or worsened during
pregnancy. Since late pregnancy is the interval when rapid
fetal accretion of calcium is occurring, it is clear that flux of
calcium to the fetuses provokes some parathyroidectomized
rats to become hypocalcemic, whereas others normalize serum calcium.
Why do some PTH-depleted rodents become hypocalcemic
while others become normocalcemic during pregnancy?
Genetic differences may account for Sprague-Dawley rats
and Black Swiss mice upregulating calcitriol synthesis and
intestinal calcium absorption through PTH-independent
mechanisms during pregnancy, whereas Wistar rats may
not do this. However, another relevant factor is the calcium
content of the diet, with parathyroidectomized rats more
likely to have hypocalcemia during pregnancy when consuming a moderately restricted (0.45%) calcium diet. Despite increased intestinal calcium absorption, intact rats
consuming a 0.45% calcium diet have secondary hyperparathyroidism with increased skeletal resorption during
the last several days of pregnancy (see sect. II, A2 and D),
but parathyroidectomized rats lack the ability to upregulate
PTH-mediated skeletal resorption. Instead, parathyroidectomized rats must rely on dietary calcium intake alone to
meet the fetal demand for mineral. A 0.45% calcium diet is
clearly insufficient despite any upregulation of intestinal
calcium absorption and calcitriol that may occur in the
absence of PTH. A previously cited study showed that a
1.0% calcium diet enables 92% of the calcium in the fetuses
to come from the maternal diet during pregnancy in intact
rats (974), but on a 0.45% calcium diet, more of the calcium in the fetuses must have been resorbed from the maternal skeleton.
A series of studies in an unspecified rat strain, likely consuming a 0.45% calcium diet, found that thyroparathyroidectomy reduced the number of implantations, embryos, and
live pups. The mothers also had a lower unadjusted serum
calcium at day 14 and 20 of pregnancy compared with
sham-operated rats (49, 50). Sequential treatments with
PTH, calcitonin, and thyroid hormone revealed that these
reductions in offspring numbers were due to the hypothyroidism, whereas the hypoparathyroidism itself had no effect (49, 50).
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When hypocalcemic, parathyroidectomized Sprague-Dawley rats maintained on a 1.2% calcium diet became pregnant, the serum calcium increased to near-normal, serum
phosphorus reduced to normal, and intestinal calcium absorption more than doubled compared with nonpregnant,
parathyroidectomized rats (425). In fact, the increased rate
of intestinal calcium absorption during pregnancy was not
significantly different between intact and parathyroidectomized rats (425). Similarly, studies in pregnant Pth null
mice consuming a 1% calcium diet found that serum calcium increased to normal, serum phosphorus normalized,
serum calcitriol increased over fivefold, and bone mineral
content increased by 15% over prepregnancy values (478).
The mean peak serum calcitriol concentration was nonsignificantly lower than in pregnant WT mice, while increased
renal expression of Cyp24a1 in Pth nulls suggested that
increased catabolism of calcitriol likely explained any reduction in its peak level (478). In these studies in rats and
mice, the sole intervention was that the animals became
pregnant; there was no change in diet to explain the observed biochemical and physiological changes. These findings indicate that PTH is not essential for regulating mineral
homeostasis during pregnancy, and that in particular, other
factors stimulate synthesis of calcitriol and upregulation of
intestinal calcium absorption in the absence of PTH.
A set of studies done in 1936 remain illuminating. When parathyroidectomized rats from an unspecified strain consumed a
1.2% calcium diet with low phosphorus content, the serum
calcium at term was normal or elevated (94). On the other
hand, when a 0.45% calcium diet was provided, the serum
calcium in pregnant parathyroidectomized rats was ⬃50% of
the value of intact rats on the same diet (94).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
2. Human data
Hypoparathyroidism is usually known to be present prior
to pregnancy. However, in specific cases, asymptomatic
women have not been recognized until the newborn presented with severe secondary hyperparathyroidism, hypercalcemia, increased bone resorption, and fractures (242,
912). If the mother remains hypocalcemic during pregnancy, maternal hypoparathyroidism can have a serious
adverse impact on the fetus and neonate (492).
Multiple case reports described that hypoparathyroidism
improves during pregnancy, with subjective evidence of
fewer hypocalcemic symptoms or objective evidence of reduced maternal requirement for calcitriol, 1␣-hydroxyvitamin D, vitamin D, and supplemental calcium (88, 120, 213,
285, 340, 343, 747, 777, 785, 890). In the most well documented of these cases, calcitriol had to be progressively
decreased and then stopped due to recurrent hypercalcemia,
and the patient was then managed solely on 1.2 g calcium
daily during the third trimester (890). The author is aware
of other unpublished cases in which hypoparathyroidism
improved during pregnancy and calcitriol was either significantly decreased or stopped. A report of 10 cases of hypoparathyroidism found that the ionized calcium was normal
during pregnancy with 2 g supplemental calcium and either
vitamin D2 or D3 but no calcitriol, and that the only change
that occurred was a marked decrease in the albumin-bound
fraction of serum calcium (340). These improvements in
hypoparathyroidism during pregnancy imply that upregulation of calcitriol and/or intestinal calcium absorption occurs, which is consistent with the rodent models. However,
in at least one case where subjective improvement in maternal symptoms was reported but no objective monitoring of
serum calcium had been done, a fetus had secondary hyperparathyroidism, which implied that maternal serum calcium was not optimal (120).
Some reports have found no change in the serum calcium
during pregnancy while on a stable dose of calcium with
vitamin D or calcitriol (213, 264, 995), with two of these
reporting a small increase in serum calcium in the last few
days before delivery (264, 995). Since the serum calcium
was not adjusted for the serum albumin in these cases (213,
264, 995), the lack of fall in unadjusted serum calcium
during pregnancy may indicate that the ionized calcium had
increased. Two reports found that the ionized calcium did
not change throughout pregnancy (30, 302), but in one of
these cases it abruptly fell and became symptomatic during
labor (302).
476
Among some of the reports suggesting that hypoparathyroidism may worsen during pregnancy, it appears that the
normal dilutional fall in serum calcium during pregnancy
prompted an increase in doses of calcium, vitamin D, or
vitamin D analogs. For example, in one case in which a
significant fall in serum calcium had been inferred, and
increases in both calcium and calcitriol intakes were done,
the albumin had fallen from 4.2 to 2.0 g/dl (837). With the
use of the data in that report, it is evident that the albumincorrected serum calcium was 9.5 mg/dl (normal) when
pregnancy was diagnosed and 10.2 mg/dl (normal) 2 wk
before delivery, with an increase and not a decline evident.
Treatment of the albumin-related fall in serum calcium resulted in a woman being made iatrogenically hypercalcemic
(2.80 – 4.0 mM) for the duration of pregnancy (600), while
another woman became hypercalcemic in late gestation
(411). This iatrogenic hypercalcemia must be avoided since
maternal hypercalcemia suppresses the fetal parathyroids
and increases the risk of spontaneous abortion (492). In
another case the physiological, absorptive hypercalciuria of
pregnancy was misinterpreted as evidence of worsening hypoparathyroidism, and resulted not only in increases to the
calcium and calcitriol doses, but the addition of a thiazide
diuretic to reduce renal calcium excretion (thiazides are
category C medications for pregnancy) (517). Clear worsening of hypoparathyroidism during pregnancy occurred in
a woman taking high-dose prednisone and azathioprine due
to a kidney transplant (736), and it is likely that the effect of
high-dose prednisone to reduce intestinal calcium absorption was a significant factor in the apparent worsening during pregnancy.
Why do hypoparathyroid women exhibit such markedly
different responses to pregnancy, with evidence of clear
improvement in some cases and clear worsening in others?
This may be explained in part by variations in the adaptive
responses or achieved concentrations of other hormones
that are thought to stimulate intestinal calcium absorption
or calcitriol synthesis. For example, high estradiol concentrations of pregnancy may cause more suppression of bone
turnover in some women, and more potent stimulation of
Cyp27b1 in other women. Calcium intake is likely an im-
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The animal data discussed above indicate that hypoparathyroidism can improve or worsen during pregnancy, and
the same divergent outcomes are true for hypoparathyroidism in women.
In contrast to these reports of improved or stable calcium
metabolism, other reports have found that hypoparathyroidism significantly worsens during pregnancy: serum calcium falls, hypocalcemic symptoms may or may not increase, and the doses of supplemental calcium and vitamin
D, 1␣-hydroxyvitamin D, or calcitriol have been increased
(96, 141, 148, 411, 434, 510, 517, 600, 669, 790, 796, 821,
837, 884, 936). In one woman the endogenous calcitriol
level was low at mid-pregnancy, but measurements in the
third trimester were not reported (510). In most cases calcitriol levels cannot be interpreted due to ongoing treatment
with exogenous calcitriol or 1␣-hydroxyvitamin D (endogenous and exogenous calcitriol are indistinguishable).
CHRISTOPHER S. KOVACS
To avoid confusion, the ionized calcium or albumin-corrected calcium must be followed during pregnancy. Adjustments will need to be made to calcitriol and calcium intake
as determined by the individual woman’s response to pregnancy, with some women requiring decreases in both supplements, others requiring progressive increases, and still
others requiring no changes. PTH itself is not normally
replaced because of its expense and short half-life, but one
case demonstrated that a continuous infusion of teriparatide can normalize calcium homeostasis during pregnancy (427).
The treatment target in nonpregnant adults is to maintain
the albumin-adjusted calcium at or just below the lower end
of normal, to minimize symptoms while protecting the kidneys
from an increased filtered load of calcium and consequent
nephrocalcinosis. However, for the 9 mo of pregnancy, the
target should be to maintain the ionized or albumin-corrected
calcium within the normal range, thereby minimizing the risk
of fetal and neonatal complications from maternal hypocalcemia, including premature labor and severe secondary hyperparathyroidism (492, 528). Conversely, hypercalcemia must
also be avoided because of the adverse effects that it has on
fetal development (492).
3. Summary
Available animal and human data indicate that two polar
opposite outcomes can occur with hypoparathyroidism
during pregnancy: it can become objectively improved (normalization of serum calcium and phosphorus with reduced
need for supplemental calcium and calcitriol) or worsen
(more marked hypocalcemia requiring significant increases
in supplemental calcium and calcitriol). It may also exhibit
no significant changes during pregnancy. Furthermore, reliance on the unadjusted serum calcium has led to unneeded
interventions in some cases where clinicians did not appre-
ciate that the serum calcium normally falls during pregnancy.
The variability in responses to pregnancy may be related to
the calcium content of the diet, contributions of PTHrP and
other pregnancy-related hormones to regulating maternal
mineral homeostasis, and genetic or ethnic differences. Significant maternal hypocalcemia must be avoided during
pregnancy because it increases the risk of fetal mortality
(spontaneous abortion and still birth) and severe secondary
hyperparathyroidism with fractures in the fetus and neonate. Iatrogenic hypercalcemia should also be avoided. The
albumin-corrected or ionized calcium should be monitored
for certainty about when a change in therapy is needed.
E. Pseudohypoparathyroidism
1. Animal data
A mouse model of pseudohypoparathyroidism has not been
studied during pregnancy (322).
2. Human data
Pseudohypoparathyroidism results from genetically inherited, post-receptor defects in Gs␣ that create end-organ resistance to PTH (61). Characteristic findings include hypocalcemia, hyperphosphatemia, blunted phosphaturic response to
PTH, and high concentrations of PTH. Type I demonstrates
blunting of PTH-induced urinary excretion of both phosphate
and cAMP, while type II has blunting of PTH-induced urinary
excretion of phosphate only.
Type I pseudohypoparathyroidism appeared to improve
during pregnancy in two women who maintained 1 g supplemental calcium intake daily during four pregnancies, including that hypocalcemic symptoms abated, normocalcemia was achieved, PTH levels decreased to near-normal,
calcitriol levels increased three- to fourfold, urinary excretion of calcium after a 1 g calcium load normalized (an
indicator of normal intestinal calcium absorption), and supplemental vitamin D or vitamin D analogs were no longer
required (110). In both women the hypocalcemic symptoms
promptly returned within 3 wk after delivery (they did not
breastfeed) (110). These reports suggest that PTH-independent increases in intestinal calcium absorption and calcitriol
synthesis occur during pregnancy in pseudohypoparathyroidism type I, and that the effects are sustained for some
time after delivery.
On the other hand, four case reports involving seven pregnancies in women with types I and II pseudohypoparathyroidism found that the dose of calcium, calcitriol, or 1␣calcidiol had to be increased to maintain a normal serum
calcium during pregnancy (668, 676, 793, 814). In the first
report involving two pregnancies in type I pseudohypopara-
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portant factor, as it is in the rodent models, with the ideal
minimum intake considered to be 1.2 g daily based on the
Institute of Medicine guidelines (774). In half of the reports
in which hypoparathyroidism appeared to worsen during
pregnancy, either no supplemental calcium or at most 300
mg daily was being taken, and the dietary intake of calcium
was unknown (96, 411, 434, 510, 600, 669, 790, 936).
Lack of adequate intake of calcium in the first half of pregnancy likely prevents the net positive calcium balance being
achieved that most women experience during pregnancy,
and increases the likelihood of problems in the third trimester. There may be variations in the degree to which PTHrP
release from breasts and placenta, or increases in other
pregnancy hormones (placental lactogen, oxytocin, etc.),
contribute to regulating maternal mineral homeostasis during pregnancy. A more recent series of 10 cases from one
group of investigators suggests the same variability in response to the challenge of pregnancy (369).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
An older case predating the availability of calcitriol involved a woman who presented in the second trimester, had
normal serum calcium and phosphorus, and was prospectively given 4 g calcium daily. Her unadjusted serum calcium remained normal, but the supplemental calcium was
increased to 5 g daily, and 1,000 IU vitamin D daily was
added when she reported intermittent mild paresthesias
(323).
As with hypoparathyroidism, PTH-independent upregulation of calcitriol synthesis or intestinal calcium absorption
could explain why pseudohypoparathyroidism may improve during pregnancy. Calcitriol doubled during the second and third trimester for two women in which pseudohypoparathyroidism improved and supplemental calcitriol
was stopped (110). In one woman whose serum calcium
was stable in the first two trimesters before hypocalcemia
occurred in the third trimester, this was paralleled by increases in endogenous calcitriol during the first two trimesters and a decline to prepregnancy values in the third trimester (814). The change in serum calcitriol among these
478
women suggests that whether or not the expected pregnancy-related increase in serum calcitriol occurs during the
third trimester predicts whether pseudohypoparathyroidism objectively improves or worsens during pregnancy.
In addition to the possibility that hormones of pregnancy
stimulate Cyp27b1 or intestinal calcium absorption directly, it is possible that the hormonal changes during pregnancy (such as higher estradiol levels) could improve postreceptor signaling. The level of calcium intake is likely an
important variable. In the four pregnancies in which pseudohypoparathyroidism objectively improved, 1 g supplemental calcium was taken throughout (110), whereas in
four of the pregnancies where it worsened, the women took
no supplemental calcium (793, 814), and in the remaining
three pregnancies the worsening occurred when the supplemental intake was 250 or 500 mg daily (668, 676). In none
of these pregnancies was the dietary intake of calcium reported. As noted in sections I and IIB, the normal physiology of pregnancy means that recommended dietary intake
of calcium (1.25 g daily) (430), combined with doubling of
efficiency of intestinal calcium absorption, should be more
than sufficient to meet the combined needs of mother and
fetus during the third trimester. Women normally achieve a
positive calcium balance in the first half of pregnancy which
likely facilitates meeting the fetal demand for calcium in the
third trimester. But if calcium intake is below 1.25 g daily in
normal women, then secondary hyperparathyroidism must
be invoked to provide additional mineral, so it should not
be surprising that pseudohypoparathyroidism will worsen
if calcium intake is inadequate during pregnancy.
Placental production of calcitriol is unlikely to improve
pseudohypoparathyroidism, given the evidence cited in section IIA4 that the placenta contributes little to the rise in
calcitriol during human pregnancy. This was further confirmed by analysis of placentas from four pseudohypoparathyroid women, which revealed that calcitriol production
was no different than in placentas from normal women
(1017).
3. Summary
As with hypoparathyroidism, it seems that pseudohypoparathyroidism can have polar opposite outcomes during
pregnancy: objectively improved or objectively worsened.
In the absence of dietary intake data, a minimum supplemental calcium intake of 1 g taken throughout pregnancy is
likely necessary for the physiological adaptations of pregnancy to be able to meet the fetal demand for mineral.
Additional variability may be due to relative contributions
of pregnancy-related hormones to regulating maternal mineral homeostasis, and genetic or ethnic differences that influence the pregnancy-related adaptations and the phenotype of pseudohypoparathyroidism. PTHrP may work on
bone but would not be expected to contribute to the increase in renal Cyp27b1 activity because of the absence of
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thyroidism complicated by severe nausea and vomiting, a
woman experienced an asymptomatic drop in the unadjusted serum calcium during a first pregnancy that
prompted an increase in both calcium and calcitriol, while
during her second pregnancy she proved intolerant of more
than 500 mg calcium per day and had a modest decline in
the ionized calcium during the third trimester (668). In the
second report a woman who was diagnosed to have type II
pseudohypoparathyroidism years after her two pregnancies, recalled that worsening of hypocalcemic-like symptoms had occurred during the second half of each pregnancy, and a single low value of serum calcium from the
second pregnancy (left untreated) was found in an old document to corroborate her statement (793). She had not
taken any calcium supplements during those pregnancies.
The third report involved two pregnancies in the same
woman with type I pseudohypoparathyroidism who took a
fixed dose of 1␣-calcidiol but no supplemental calcium
throughout each pregnancy, and the albumin-adjusted serum calcium declined in the latter half of both (814). In the
second pregnancy serum calcitriol doubled during the first
half, before declining to the prepregnancy value in the second half, accompanied by the fall in albumin-adjusted calcium and a rise in PTH (814). In a fourth case, the proteinadjusted serum calcium was followed during a pregnancy of
a woman with type I pseudohypoparathyroidism, the dose
of calcitriol remained unchanged, but the dose of calcium
was increased from 250 mg in the first trimester to a median
1 g during the third trimester (676). There is a fifth report
involving a woman with type I pseudohypoparathyroidism
who presented at the 24th week of pregnancy and was
placed on calcium and calcitriol, but the lack of baseline
data means that it is unknown whether the condition was
altered at all by pregnancy (843).
CHRISTOPHER S. KOVACS
Gs␣ activity in the proximal tubule of women with pseudohypoparathyroidism.
The goal of management during pregnancy should be to
maintain a normal ionized or albumin-corrected serum calcium in the mother, thereby minimizing the risk of fetal and
neonatal complications from maternal hypocalcemia or hypercalcemia (492). This means expectant management with
appropriate increases or decreases in calcium and calcitriol
as required during each pregnancy.
F. Pseudohyperparathyroidism
1. Animal data
2. Human data
As noted in section IIA3, the breasts and placenta are
sources of PTHrP in the maternal circulation during pregnancy. The achieved release of PTHrP appears to be relatively autonomous, independent of serum calcium but correlating with the amount of mammary tissue.
Pseudohyperparathyroidism is PTHrP-mediated hypercalcemia. Its occurrence during pregnancy confirms the potential physiological importance of the breasts and placenta in
contributing to the regulation of maternal mineral homeostasis.
Separating out the potential effects of breasts and placenta
as sources of excess PTHrP has been possible based on
individual case reports. PTHrP-mediated hypercalcemia
has occurred in women with massive mammary hyperplasia
while pregnant or nonpregnant, and in pregnant women
with normal-sized breasts (435, 474, 549, 603, 639, 800).
In several cases hypercalcemia became evident during pregnancy, serum PTH was undetectable, PTHrP was either
increased in plasma or high levels of PTHrP expression were
found in the breasts, and the hypercalcemia resolved only
after bilateral mastectomy or weaning (435, 474, 549). In
another case a woman with normal-sized breasts was unable to breastfeed because her neonate was critically ill, and
she went into a postpartum hypercalcemic crisis (800). The
cord blood serum calcium was higher than normal, confirming that mother and baby had been hypercalcemic prior
to delivery (800). Furthermore, the mother was hypercalcemic 3 days after delivery with a PTHrP level of 28.4 pM.
Since PTHrP has a half-life of minutes in the circulation,
Pseudohyperparathyroidism also occurs during lactation,
and the ability of breast-derived PTHrP to normalize mineral homeostasis in lactating women with hypoparathyroidism is further validation of the importance of the
breasts as a physiologically relevant source of PTHrP (see
sections IVA3 and V, D and F).
But pseudohyperparathyroidism has also occurred from excess PTHrP that clearly originated from the placenta. This
has been demonstrated in a woman with normal-sized
breasts who developed severe hypercalcemia (21 mg/dl or
5.25 mM), undetectable PTH, and a serum PTHrP of 21
pM in the third trimester (270). Six hours after an urgent
C-section, she was profoundly hypocalcemic with undetectable PTHrP and elevated PTH (270). The rapid reversal in
status is most consistent with placental-derived PTHrP
causing hypercalcemia.
3. Summary
Hypercalcemia can occur during pregnancy as a result of
excess physiological release of PTHrP from the breasts and
placenta; this differs from pathological release that occurs
in hypercalcemia of malignancy (see sect. IIIJ). When the
placenta is the cause, the hypercalcemia should be corrected
within hours of delivery, whereas production by the breasts
is more likely to lead to sustained hypercalcemia after delivery.
G. Vitamin D Deficiency and Genetic
Disorders of Vitamin D Physiology
1. Animal data
Calcitriol regulates the active, saturable, transcellular
mechanism of intestinal calcium delivery, as well as the
passive, paracellular mechanism of absorption (181). After
pups are weaned and in adult animals, severe vitamin D
deficiency and genetic absence of either calcitriol or VDR
lead to the common phenotype of reduced intestinal calcium absorption, hypocalcemia, hypophosphatemia, and
rickets. Intestinal mineral delivery appears to be the main
route through which calcitriol has direct and indirect actions on mineral and bone metabolism. Several lines of evidence have confirmed this, including that the abnormal
mineral homeostasis and rachitic phenotype of Vdr null
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Animal models have confirmed the production of PTHrP by
mammary tissue and placenta, but the extent to which these
sites contribute to mineral homeostasis during pregnancy
has not been determined. Conversely, it is clear from animal
models that PTHrP derived from mammary tissue is an
important regulator during lactation, as discussed in sections IV, A3, B, D–F, and VD.
similar to PTH, this confirms that the breasts must have
been the sustained source of PTHrP, and not (as the authors
of that report inferred) the placenta. Another pregnant
woman presented with marked hypercalcemia (serum calcium 4.00 mM) associated with high calcium intake and
elevated PTHrP of 34.9 pM (639). The hypercalcemia resolved promptly, and she did not breastfeed, but the elevated PTHrP did not become undetectable until 3 mo postpartum.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
What is the impact of disordered vitamin D physiology on
rodent pregnancy? In several models the mothers conceive
less frequently and bear fewer pups in each liter. This includes severely vitamin D-deficient rats (359, 361–363),
Cyp27b1 null mice that cannot make calcitriol (330), and
Vdr null mice that lack the receptor for calcitriol (296, 502),
but not Cyp27b1 null (Hannover) pigs which have either
singleton or twin pregnancies (520, 521). The low conception rate and smaller litter sizes of rodents are rescued by
administering a high-calcium diet (223, 330, 446, 502, 553,
693, 886), which indicates that calcium and not calcitriol is
the missing component responsible for these fertility issues.
Normal pregnancies still occur in Vdr null mice maintained
on a normal-calcium diet (502), but the increased frequency
of pregnancies on the high calcium diet facilitates their
study during reproductive cycles.
What is the role of calcitriol in regulating intestinal calcium
absorption and mineral metabolism about during pregnancy? This has been studied in severely vitamin D-deficient
rats (117, 358, 362, 363), Cyp27b1 null pigs (520, 521),
Cyp27b1 null mice (330), and Vdr null mice (296, 1026). In
these models occasional sudden deaths occur during late
pregnancy, suggesting that rapid placental calcium transfer
can overwhelm the ability of the mother to maintain her
own ionized calcium level. The pregnancies are otherwise
uneventful and result in fetuses that have normal ionized
calcium, phosphorus, PTH, weight, skeletal development,
and mineralization (see companion review for details, Ref.
492). A notable abnormality is that offspring of Vdr null
females were globally but proportionately smaller than offspring of their WT and Vdr⫹/⫺ sisters, a difference that was
not seen between offspring of vitamin D-deficient and replete rats. This may indicate that maternal absence of VDR
affects offspring growth independent of the fetal genotypes
and that it is exerted by the receptor but not calcitriol.
More recently, severe vitamin D deficiency has been studied
in mice, which had identical litter sizes but bore pups of
480
modestly greater weights and slightly increased lengths,
compared with vitamin D-sufficient mothers (563). The diet
was deficient in vitamin D but not enriched in calcium. No
mention was made as to whether maternal vitamin D deficiency led to a reduced conception rate, and no measurements of bone mass or mineralization were performed. The
placentas from vitamin D-deficient pregnancies were of
identical weight but had smaller diameters, and histological
evidence of reduced vascular diameters within the labyrinthine placenta, compared with pregnancies from vitamin
D-sufficient mothers (563).
As noted earlier, severely vitamin D-deficient rats, Vdr null
mice, and Cyp27b1 null mice achieve significant gains in
bone mineral content during pregnancy, with reduced secondary hyperparathyroidism and increased mineralization
of osteoid (296, 362, 489, 786). An increase in intestinal
calcium absorption during pregnancy has been confirmed in
severely vitamin D-deficient rats (116, 360) and Vdr null
mice (296), and inferred to be present but not yet studied in
Cyp27b1 null mice (330). During pregnancy serum calcium
and phosphorus increased in severely vitamin D-deficient
rats (915), Vdr null mice (Boston and Leuven strains) normalized serum calcium and increased renal calcium excretion (296, 786, 1026), and Cyp27b1 null mice also normalized serum calcium and phosphorus (330). In all of these
studies the main intervention was that the animals became
pregnant, thus confirming that pregnancy invokes improvements in intestinal calcium absorption and mineral homeostasis that are independent of vitamin D, calcitriol, and
VDR.
Nonskeletal outcomes of pregnancy have received little attention in these animal studies, but the recent study of vitamin D-deficient mice found higher systolic and diastolic
blood pressure, and upregulation of renal expression of
renin and angiotensin II receptor mRNA, compared with
vitamin D-sufficient mice (563). These findings support the
possibility that vitamin D deficiency may increase the risk of
pregnancy-induced hypertension.
2. Human data
As in rodents, calcitriol-dependent active absorption of calcium represents ⬃20% of net calcium absorption, with the
rest occurring by passive, nonsaturable mechanisms. Active
absorption is considered to be more important when dietary
intake of calcium is limited. Multiple dual or single isotope
studies carried out in adults and adolescents have examined
the level of 25OHD at which intestinal calcium absorption
is maximized or reaches a plateau, and have established that
a plateau occurs below 20 nM 25OHD, with very little
increase (if any) in intestinal calcium absorption above that
value (7, 24, 26, 306, 650, 774). Secondary hyperparathyroidism occurs at lower levels of 25OHD and maintains
high levels of calcitriol despite the reduced availability of
substrate, which may be why vitamin D deficiency does not
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mice is rescued by expressing Vdr in intestinal cells (555,
1000), whereas selective ablation of Vdr from intestinal
cells (555) or dietary calcium restriction create the rachitic
phenotype (555). Moreover, ablating Vdr from chondrocytes, osteoblasts, or osteocytes, or Cyp27b1 from chondrocytes, do not cause rickets either (555, 606, 644, 1006).
Also, a high calcium diet bypasses the need for calcitriol and
intestinal expression of its receptor, and normalizes serum
chemistries, skeletal morphology, and skeletal mineral content in severely vitamin D-deficient, Cyp27b1 null, and Vdr
null models (28, 102, 103, 224, 241, 273, 553, 554, 693,
874, 875, 948, 1011). However, remaining evidence for a
direct role of calcitriol or VDR in regulating bone cells is
that Cyp27b1/Vdr null double mutants have a skeletal phenotype that is not fully prevented by a high-calcium diet
(692).
CHRISTOPHER S. KOVACS
impair intestinal calcium absorption until the 25OHD level
is below 20 nM (650).
What evidence is there that maternal vitamin D deficiency,
or genetic disorders causing loss of calcitriol or VDR, affect
maternal mineral metabolism and obstetrical or fetal outcomes?
Unfortunately, no study has measured intestinal calcium
absorption during pregnancy in vitamin D-deficient compared with vitamin D-sufficient women, so it remains unknown whether or not intestinal calcium absorption doubles in pregnant, vitamin D-deficient women.
Because the potential adverse effects of vitamin D deficiency
during pregnancy have garnered much recent attention, the
individual studies will be described in sufficient detail to
understand the doses of vitamin D tested, the sizes of the
studies, the achieved increment in 25OHD between groups,
and any obstetrical (maternal) benefit observed. The companion review should be consulted for details of any fetal or
neonatal benefits (492).
Brooke et al. (121) studied 126 severely vitamin D-deficient
Asian women living in England, beginning at 28 –32 wk of
gestation. At term the mean serum 25OHD was 16 nM (6.4
ng/ml) in the placebo group and an exuberant 168 nM (67
ng/ml) in women who received 1,000 IU vitamin D daily
(the dose was likely higher given the 25OHD increment
achieved). By comparing these two extremes of severe vitamin D deficiency versus repletion to a high 25OHD level,
this study was well poised to demonstrate any obvious ma-
Cockburn et al. (191) randomized 164 women to 400 IU
vitamin D versus placebo beginning at the 12th week of
pregnancy, and achieved maternal 25OHD of 42.8 vs.
32.5 nM (17 vs. 13 ng/ml) at term, but no obstetrical
benefit was described (191). Mallet et al. (588) randomized 77 women to receive 1,000 IU vitamin D2 daily
during the third trimester, or 200,000 IU vitamin D2 at
the start of the third trimester, or no supplementation
(588). The respective maternal 25OHD levels were 25.3,
26.0, and 9.4 nM (10, 10.4, and 3.8 ng/ml) with no effect
on maternal serum calcium or calcitriol, and no obstetrical benefit reported.
Delvin et al. (239) randomized 40 women in France to
1,000 IU vitamin D3 daily versus placebo beginning at 6 mo
of pregnancy. Maternal 25OHD increased to 56 nM (22
ng/ml) compared with 27.5 nM (11 ng/ml) in the placebo
group, but there was no difference in ionized calcium, serum calcium, calcitriol, or PTH, and no reported obstetrical
benefit.
Marya and co-workers (604, 605) performed two studies in
vitamin D-deficient Asian women in India. In each of these,
severe vitamin D deficiency was presumed to be present on
the basis of estimated dietary intakes of vitamin D at ⬍35
IU/day, but 25OHD was not measured and sunlight exposure leading to vitamin D formation was not considered.
The first study involved 20 women who received 800,000
IU vitamin D2 in the seventh and eighth months of pregnancy, 25 women who received 1,200 IU vitamin D2 per
day during the third trimester, and 75 women who received
nothing (605). No significant effect on serum calcium or
phosphorus was noted, but the alkaline phosphatase was
reduced in vitamin D-treated subjects. The second study
gave 100 women 600,000 IU of vitamin D2 in the seventh
and eighth months of pregnancy and compared the results
to 100 women who received nothing (604). The unadjusted
serum calcium and phosphorus were slightly but statistically significantly higher in the women who received vitamin D, and the alkaline phosphatase was lower, but there
were no significant differences in reported constitutional
symptoms.
In the studies cited thus far, there are concerns as to whether
or not subjects were properly blinded and randomized, the
sample sizes were small, and obstetrical data were not fully
reported. In contrast, the following studies were carried out
within the past decade, used modern randomization methods and clinical trial protocols, and reported more obstetrical outcomes.
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The most robust clinical data generally come from large,
randomized, blinded clinical trials, which control for confounding through the randomization of subjects into two or
more treatment groups. Several modestly sized clinical trials
have examined the effects of vitamin D supplementation on
obstetrical and fetal/neonatal outcomes, and the maternal
results will be discussed in the following paragraphs. The
fetal and neonatal outcomes of these studies have been described in the companion review (492); in brief, no consistent change in cord blood calcium, phosphorus, PTH, birth
weight, or anthropometric measurements were observed
when babies of vitamin D-supplemented mothers were
compared with babies of placebo-treated mothers. Several
studies did note a reduction in the incidence of neonatal
hypocalcemia after 48 h when the babies of placebo-treated
mothers had cord blood 25OHD levels below 20 nM (492).
This is consistent with the aforementioned adult data that
intestinal calcium absorption is reduced when the 25OHD
level is below 20 nM. However, calcium absorption across
the fetal intestines is a trivial circuit not relevant to fetal
mineral homeostasis, whereas the main route of calcium
delivery is transportation across the placenta through
mechanisms that do not require calcitriol (492).
ternal benefit of vitamin D repletion. A greater weight gain
and a small increase in the unadjusted serum calcium were
observed in the vitamin D-treated group, but no other obstetrical benefit was seen (121).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
Yu et al. (1013) randomized 180 women in London to
receive unblinded treatment beginning at week 27 of pregnancy: 800 IU vitamin D2 per day, a single dose of 200,000
IU vitamin D2, or no treatment (1013). Mean 25OHD increased to 42 and 34 nM (16.8 and 13.6 ng/ml) in the
respective treatment groups at term compared with 27 nM
(10.8 ng/ml) in the untreated women. There was no effect
on preterm delivery and no other obstetrical outcomes.
Hashemipour et al. (367) randomized 160 women in Iran to
receive 50,000 IU vitamin D per week or 400 IU daily
beginning at 26 –28 wk. Maternal 25OHD was 120 nM (48
ng/ml) versus 40 nM (16 ng/ml), and the unadjusted serum
calcium was modestly higher in the vitamin D-treated
women. There was no difference in gestational age of delivery; no other obstetrical outcomes were reported.
Grant et al. (342) randomized 260 women in New Zealand
(ACTRN12610000483055) to placebo, 1,000 IU vitamin
D daily, or 2,000 IU vitamin D daily. Maternal 25OHD
levels at term were 50, 98, and 103 nM (20, 39, and 41
ng/ml), respectively. There was no difference in serum calcium or gestational age of delivery; no other obstetrical data
were reported (342).
Kalra et al. (455) randomized 97 women in India to one
dose of 60,000 IU vitamin D in the second trimester or
120,000 IU vitamin D in each of the second and third trimesters; 43 “usual care” women were the controls. Maternal 25OHD levels at term were 26.2, 58.7, and 39.2 nM
(10.5, 23.5, and 15.7 ng/ml), respectively (455). There were
no differences in obstetrical outcomes, including gestational age at delivery, intrauterine death, pregnancy-induced hypertension, cephalopelvic disproportion, nonprogression of labor, cesarean section, and placenta previa
(455).
Hollis and Wagner (399) reported on 350 women
(NCT00292591) randomized at 12–16 wk of gestation to
receive 400, 2,000, or 4,000 IU vitamin D3 per day. Maternal 25OHD levels at term were 79, 98, and 111 nM (31.6,
39.2, and 44.4 ng/ml), respectively. There was no significant difference in serum calcium across the treatment
groups, but there was a borderline-significant reduction in
PTH when the high-dose and low-dose groups were com-
482
A second study by Hollis and Wagner and co-workers (966)
reported on 160 women (NCT00412087) randomized at
12–16 wk to receive 2,000 or 4,000 IU vitamin D3 daily.
Achieved maternal 25OHD was 90.5 nM (36.2 ng/ml) and
94.8 nM (37.9 ng/ml), respectively. There was no effect on
any obstetrical outcome, including mode of delivery, preterm labor, preterm delivery, hypertension, infection, gestational diabetes, or combinations of these outcomes (966).
Hollis and Wagner have subsequently carried out several
post-hoc analyses of these two trials, including analyses in
which selective data from both studies were pooled, out of
which some borderline significant results have been obtained (399, 401, 963, 964, 967). However, these analyses
suffer from lack of adjustment for multiple comparisons,
arbitrary grouping of outcomes, and exclusion of some ethnicities from the analysis. For example, the combination of
infection/preterm labor/preterm birth/gestational diabetes/
preeclampsia/hypertension/HELLP had a P value of 0.03
(not adjusted for multiple comparisons), whereas excluding
preterm labor (which is linked to preterm birth and likely
means women are counted twice) resulted in a P value of
0.06, including all ethnicities resulted in a P value of 0.17,
while multiple other subgroupings and the individual outcomes were not statistically significant (401, 963).
Dawodu et al. (229) studied Arab women who had mean
25OHD concentrations of 20.5 nM (8.2 ng/ml) at baseline
and were randomized to 400, 2,000, or 4,000 IU vitamin
D/day. Achieved 25OHD levels at delivery were 40 nM
(19.3 ng/ml), 65 nM (25.9 ng/ml), and 90 nM (35.9 ng/ml),
respectively (229). There were no differences in maternal
serum calcium or urine calcium/creatinine between groups
at any time point during pregnancy, PTH was reduced in
the high-dose group but correlated poorly with 25OHD, no
effect was seen on gestational age at delivery or the babies’
anthropometric parameters at birth, and no other obstetrical outcomes were reported.
Most recently, Cooper and Harvey and co-workers (199,
200) provided preliminary results of the MAVIDOS study
from the United Kingdom. The 900 women who completed
the study randomly received either 1,000 IU vitamin D or
placebo beginning at 14 wk of pregnancy. Baseline 25OHD
was ⬃45 nM (18 ng/ml), did not change in placebo-treated
women, and rose to 68 nM (27 ng/ml) near term in the
vitamin D-supplemented women. During the oral and
poster presentation of results (199, 200), the study was
revealed to be negative in its primary outcome (neonatal
bone area, bone mineral content, and bone mineral density
within the first 14 days after birth) and secondary outcome
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Roth et al. (778) randomized 160 women in Bangladesh
(NCT01126528) to receive 35,000 IU vitamin D3 per week
or placebo beginning at 26 –29 wk. Maternal 25OHD was
134 nM (53.6 ng/ml) in the supplemented women versus 38
nM (15.2 ng/ml) in the placebo group. There was no effect
on maternal serum calcium, but a borderline significant
increase in albumin-adjusted calcium and decrease in PTH
were found (779). There was no effect on mode of delivery,
C-section rates, adverse events, live versus stillbirths, or
gestational age at delivery.
pared. There were no differences in any obstetrical outcomes, including mode of delivery, gestational age at delivery, preterm birth, preterm labor, preeclampsia, and infection (399, 963).
CHRISTOPHER S. KOVACS
(anthropometric and body composition parameters within
48 h of birth). No obstetrical benefit was reported. A posthoc analysis, which was not prespecified in the clinical trial
registrations (ISRCTN 82927713 and EUDRACT 2007001716-23), suggested a possible benefit on bone mineral
content of winter-born babies. If the apparent benefit on
winter-born babies is real and not a chance result, it may
not be an indication of an effect on the fetus but instead a
postnatal effect, since (as noted earlier) the neonatal skeleton should gain 100 mg calcium per day over the first 14
days after birth. A measurement at 14 days does not indicate bone mineral content at term.
Pregnancies have been unremarkable in women with genetic absence of Cyp27b1 (vitamin D-dependent rickets
type 1, VDDR-I) or relatively inactive VDRs (VDDR-II)
(266, 589, 602). In one case of VDDR-II, the pregnancy was
unremarkable while the woman was maintained on her
prepregnancy doses of calcium (800 mg) and high-dose calcitriol (602). The clinicians did increase the dose of calcitriol during that pregnancy “because of the knowledge
that the circulating 1,25-(OH)2D concentration normally
rises during pregnancy,” but not because of any change in
the albumin-adjusted serum calcium (602). In multiple
cases of VDDR-I, the dose of calcitriol was unchanged in
one-third of pregnancies and increased 1.5- to 2-fold in
others (266). In both disorders, calcium and calcitriol or
1␣-cholecalciferol should be adjusted as needed to maintain
a normal ionized or albumin-corrected serum calcium.
More recently, hereditary absence of Cyp24a1 has been
shown to lead to maternal and fetal hypercalcemia (249,
820), likely because reduced catabolism of calcitriol leads to
relatively unopposed actions of the active hormone to stim-
On the basis of associational studies, vitamin D deficiency
has been suggested to have nonskeletal effects during pregnancy, such as increasing the risk of preterm delivery, Csections, low birth weight, preeclampsia/pregnancy-induced hypertension, and vaginal infections. One can find
approximately as many studies suggesting these associations (46, 95, 370, 622, 768, 832) as there are studies indicating no association (47, 276, 294, 618, 726, 810, 823).
Each of these studies has low power and are confounded by
factors that may lead to lower 25OHD levels and the outcome in question, including race/ethnicity, maternal overweight/obesity, lower socioeconomic status, poor nutrition,
etc. For example, maternal overweight/obesity is a significant risk factor for preterm delivery, C-sections, low birth
weight, preeclampsia/pregnancy-induced hypertension,
vaginal infections, and other adverse obstetrical outcomes
(542). But maternal overweight/obesity also causes low
25OHD by binding the fat-soluble vitamin D into the
maternal fat stores, and by additional associations with
reduced vitamin D intake, less time spent outdoors, etc.
Consequently, the studies reporting associations between
vitamin D intake or 25OHD levels and obstetrical outcomes may really be demonstrating residual confounding
from the link between obesity and these outcomes, and
also need to consider that the results of the existing randomized trials did not find these outcomes in their primary analyses (183, 184, 367, 399, 455, 710, 779, 966,
1013). Larger randomized trials that compare truly vitamin D-deficient to sufficient mothers are needed to properly test the hypothesis, and eliminate the confounding
caused by maternal overweight and obesity.
3. Summary
Several animal models (severe vitamin D deficiency and absence of VDR or Cyp27b1) have demonstrated improved to
near-normalized mineral homeostasis and intestinal calcium absorption during pregnancy, suggesting that calcitriol is not required for the adaptations that are invoked
during pregnancy, or that other physiological mechanisms
are able to compensate for its absence. Clinical data are not
as extensive, but the results of available clinical trials do not
show a clear benefit of high-dose vitamin D supplementation on maternal mineral or skeletal homeostasis, or obstetrical and fetal outcomes. Most of the clinical trials did not
enroll women who were vitamin D deficient, so the ability
to detect any benefit was likely lost.
H. Calcitonin Deficiency
1. Animal data
Early attempts to create experimental models of calcitonin
deficiency did not appreciate that there are extrathyroidal
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Overall, these studies have largely examined women who,
prior to the intervention, had 25OHD values well above the
20 nM threshold that has been shown to result in normal
intestinal calcium absorption. Only Brooke’s study (and
possibly Marya’s two studies, although 25OHD levels were
not measured) compared true vitamin D deficiency to a
vitamin D-replete state, and an increase in maternal serum
calcium was observed. No obstetrical outcome differences
were reported, but it is unclear that the authors of that
report were looking for any. It may take a study of that
extreme to determine if there are differences in obstetrical
outcomes, but ethical considerations may prevent it being
carried out in the modern day. Among the modern studies,
Dawodu’s began with vitamin D-deficient women but at the
end of pregnancy the mean 25OHD level was in the insufficient range at 40 nM (229). In that arm of the study, 79%
of women had a 25OHD value ⬍50 nM, so it contained
many vitamin D-deficient women, but still no significant
maternal or fetal/neonatal differences were seen apart from
an increase in serum 25OHD.
ulate intestinal calcium absorption and potentially induce
osteoclast-mediated bone resorption.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
In contrast to these surgical models, Ctcgrp null mice represent true calcitonin deficiency because the gene encoding
calcitonin and calcitonin gene-related peptide has been ablated, but they are also confounded by loss of CGRP-␣
(394). At the end of pregnancy there were no differences
from WT sisters in BMC of the whole body, lumbar spine,
or hindlimb, suggesting that loss of calcitonin does not impair the ability of the mother to gain bone mass during
pregnancy (992, 994). These mice received standard 1%
calcium intake and have not been studied on a calciumrestricted diet.
Overall, the surgical models suggested that an intact thyroid
gland may protect the maternal skeleton from loss of bone
mineral during pregnancy and that this effect is attributable
to calcitonin, assuming that parathyroid and thyroid function remained normal. However, Ctcgrp null mice did not
display excess bone loss during pregnancy.
2. Human data
Increased serum calcitonin has been proposed to protect the
skeletons of women from excessive resorption during pregnancy, but this concept has not been directly tested. Totally
thyroidectomized women have placenta and breasts as
sources of calcitonin production during pregnancy, so they
are not truly calcitonin deficient. No women with genetic
loss of calcitonin or its receptor have been identified or
studied during pregnancy.
Nevertheless, several studies have looked at the long-term
effects of total thyroidectomy on bone density and risk of
fractures in both men and women, with some studies suggesting an increased risk and others finding none (326, 338,
422, 630, 659). Studies from the last decade are confounded
by the common practice to treat with suppressive doses of
484
thyroid hormone to reduce the risk of cancer recurrence,
but even in those studies bone loss has not been consistently
found (476, 543). None of these studies looked at the effects
of pregnancy, during which the women may not have been
calcitonin deficient anyway.
It is notable that with modern calcitonin assays, the basal
calcitonin level is unchanged before and after total thyroidectomy in patients without medullary thyroid cancer; it is
only the calcium-stimulated or pentagastrin-stimulated calcitonin that is lost (513). This suggests that extrathyroidal
calcitonin sources are functional in nonpregnant, nonlactating women.
3. Summary
Thyroidectomy to create partial calcitonin deficiency during pregnancy led to bone loss at term compared with shamoperated animals; however, no effect was seen in pregnant
mice lacking the calcitonin gene. There are no comparable
human data for the surgical or genetic models of calcitonin
deficiency during pregnancy.
I. Low or High Calcium Intake
1. Animal data
As noted earlier (sect. II, A1, A2, and D), a calcium-restricted diet provokes marked hypocalcemia and secondary
hyperparathyroidism in pregnant rats; it also leads to compensatory secondary hyperparathyroidism and skeletal resorption in the fetuses (492). In pregnant ewes it causes
hypocalcemia and bone resorption, but the birth weights of
offspring are unaffected (detailed analysis of the fetal bones
was not done) (69). Conversely, high calcium intake prevents hypocalcemia and secondary hyperparathyroidism,
and enables most of the calcium transported to the fetuses
to come from the maternal diet rather than her skeleton. It
also reduces the likelihood of net loss of calcium from the
skeleton and may enable a net gain. Rats consuming a 1.6%
and 1.4% calcium diet had a higher femoral calcium content at the end of pregnancy compared with rats that consumed 0.5% calcium (719, 818).
2. Human data
Pregnancy is normally a state of absorptive hypercalciuria
with suppressed PTH, which implies that for most women
calcium is absorbed in excess of maternal and fetal requirements. But as noted earlier (sect. II, A1, A2, and D), PTH
does not fall and may rise above normal in women with low
dietary intakes of calcium or high intake of phytate (which
blocks calcium absorption). However, in some women with
chronically low calcium intakes, the efficiency of intestinal
calcium absorption may be greater than normal, as suggested by a study in which most women with a dietary
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sites of calcitonin synthesis during pregnancy, including the
mammary glands and placenta. In pregnant goats or rats,
calcitonin deficiency was created by a complete thyroparathyroidectomy followed by parathyroid gland autotransplantation and treatment with exogenous thyroid hormone
(55, 58, 163, 551, 900). Serum calcitonin, TSH, PTH, and
ionized calcium were not measured, so it is uncertain
whether a calcitonin-deficient, euthyroid, euparathyroid
state was achieved. In three studies the animals were killed
the day before expected delivery (55, 58, 163), whereas two
other studies reporting a pregnancy-related effect must be
excluded because the animals were killed after 3 wk of
lactation (551, 900) (see sect. VH). Among the three pregnancy studies, the ash weight and calcium content were
5–10% lower in thyroidectomized compared with shamoperated animals at the end of pregnancy; these differences
were statistically significant in goat metacarpals and metatarsals (55, 58), but not in rat femora (163). The spine is the
potential site of greatest bone loss during pregnancy, but it
was not examined in these studies.
CHRISTOPHER S. KOVACS
In contrast to low calcium intake, excessively high intake
will create similar effects as primary hyperparathyroidism
in pregnancy: increased net absorption of calcium, maternal
hypercalcemia, increased maternal to fetal transfer of calcium, and suppression of the fetal parathyroids (100, 483,
767). Neonatal hypoparathyroidism has resulted from
women consuming 3– 6 g elemental calcium daily to treat
nausea of pregnancy (100, 767).
3. Summary
Extremes of low and high calcium intake should both be
avoided in pregnancy due to adverse effects that each can
have on the mother and the fetus. Low calcium intake
causes secondary hyperparathyroidism in mother and fetus
and resorption of the maternal and fetal skeletons with
consequent fragility. Conversely, high calcium intake leads
to increased flow of calcium across the placenta, suppression of the fetal parathyroids, and a predisposition to neonatal hypoparathyroidism with hypocalcemia.
J. Hypercalcemia of Malignancy
1. Animal data
No animal models have been studied during pregnancy.
2. Human data
There are over a dozen published cases of hypercalcemia of
malignancy during pregnancy, which is usually due to
PTHrP overproduction (4, 211, 325, 424, 428, 608, 614,
634, 898, 945). This is usually but not always a terminal
condition, so the first decision is whether to terminate the
pregnancy to enable chemotherapy to be administered, defer such treatment until the baby is born, or (as has also
been reported, Ref. 614) to proceed with chemotherapy
during pregnancy regardless of its potential teratogenic effects. In about half of case reports, the baby’s outcome is
not mentioned, but the cord blood calcium is likely to be
high and followed by neonatal hypocalcemia and tetany.
Treatment options include debulking or curative surgery,
hydration, diuresis, and possibly calcitonin or bisphosphonates. There are potential teratogenic effects of calcitonin
and bisphosphonates (492), but they have been used during
pregnancy to treat this condition.
3. Summary
Hypercalcemia of malignancy causes severe and potentially
terminal maternal hypercalcemia; if the baby survives, it is
at high risk for neonatal hypocalcemia.
K. Fibroblast Growth Factor 23-Related
Disorders
1. Animal data
Pregnancies are unremarkable in Phex/Hyp⫹/⫺ mice, a
model of XLH that leads to FGF23 excess (240, 581, 679).
Despite very high levels of FGF23 in pregnant Phex⫹/⫺
females (581, 679), which normally downregulate calcitriol
synthesis and increase its catabolism, maternal serum calcitriol increases to the expected high levels of pregnancy
(581, 679), and likely contributes to pregnancy-related increases in intestinal calcium and phosphorus absorption.
Despite the maternal hypophosphatemia, the fetuses display normal serum mineral and calciotropic hormone concentrations, lengths, placental phosphorus transport, skeletal development, and mineralization (581).
Since phosphorus is actively transported across the placenta, maternal hyperphosphatemia can be expected to increase the flow of phosphorus and, thereby, potentially affect fetal mineralization. Hyperphosphatemic disorders due
to absence of FGF23 have not been studied during pregnancy because Fgf23 null mice die by several weeks of age
(848), whereas Klotho null mice have marked hypogonadism and die by 9 –10 wk of age (516). Experimental renal
failure in rats has shown that maternal hyperphosphatemia
does not impair skeletal development or mineralization
(765, 766); however, there is a modest reduction in fetal
weight and length that has been attributed to decreased
food intake in uremic mothers (664, 765).
2. Human data
Isolated case reports have confirmed that hypophosphatemia persists during pregnancy in women with XLH
(447, 745), but the lack of adverse outcomes from untreated
pregnancies has made it uncertain whether the hypophosphatemia needs to be treated. Nevertheless, the general
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intake of less than 420 mg were in a positive calcium balance in all three trimesters (830). A lower calcium intake is
more likely to induce bone loss during pregnancy (10) and
has been associated with increased risk of osteoporosis developing during pregnancy (501). Whether the mother obtains the needed mineral from her diet or skeleton may be of
no consequence to the fetus, although a randomized trial
found that 2 g of supplemental calcium versus placebo improved the BMC of babies whose mothers were in the lowest quintile of dietary calcium intake (⬍600 mg/day) (488).
Significant maternal hypocalcemia impairs the delivery of
calcium to the fetuses, who may develop secondary hyperparathyroidism, skeletal demineralization, and fractures, as
has occurred in cases of poorly treated maternal hypoparathyroidism during pregnancy (492). The lowest quintile of
maternal calcium intake is also associated with increased
risk of preeclampsia, whereas calcium supplementation reduces that risk (see sect. IIC).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
principle is to maintain calcitriol and phosphorus supplementation throughout pregnancy to ensure adequate delivery of phosphorus to the fetus (538).
3. Summary
Hypophosphatemic and hyperphosphatemic disorders in
the pregnant mother have the potential to adversely affect
the fetus. There are insufficient human data to know for
certain, but the limited animal data are reassuring that fetal
mineral and bone metabolism may be unaffected by extremes of low and high serum phosphorus in the mother.
IV. SKELETAL AND MINERAL PHYSIOLOGY
DURING LACTATION AND POSTWEANING RECOVERY
In their widely quoted seminal text The Parathyroid Glands
and Metabolic Bone Disease (15), Albright and Reifenstein
used data from several sources (77, 407, 836) to estimate
that maternal losses of calcium are fourfold higher during 9
mo of lactation than in pregnancy, or ⬃80 g in milk versus
20 g in the fetal skeleton. This means an output of more
than 300 mg of calcium in milk each day. However, the
authors misread source data that showed closer to 30 g of
calcium in a term fetus (77), used an overestimate of milk
production (407), and lacked any skeletal calcium content
data at 9 mo. Modern studies, referred to earlier in the
overall introduction, have shown that the average full-term
fetus has 30 g of calcium and that another 30 g (⬃100
mg/day) is added by 9 mo. Consequently, the calcium required by the neonate during 9 mo of lactation equals that
required by a fetus during all of pregnancy and does not
exceed it. However, as explained in the following paragraphs, maternal losses of calcium during 9 mo of lactation
are about double that of pregnancy.
Other older studies similarly overestimated average daily
loss of calcium into milk due to overgenerous estimates of
milk volumes. In a large study of 200 women who expressed milk manually for 24 h, the volume ranged from 0.8
to 1.8 liters for a mean daily loss of 400 mg calcium (582,
486
As noted in the overall introduction, more recent studies
have relied on weighing the baby before and after feeds,
whereas analyses of milk calcium content at different stages
of lactation revealed similar results to older studies. An
average daily output of 780 ml milk (20, 138, 376, 653)
with an average calcium content of 260 mg/l during the first
6 mo of lactation (41) results in a more realistic average
calcium loss of 200 –210 mg/day (774), from which the
baby is expected to accrete ⬃100 mg daily.
These are average amounts, and it is recognized that individual daily losses can vary considerably. Losses have been
much higher in the more extreme examples cited above, and
in women nursing twins who generally produce about double the amount of milk of women who nurse singletons
(233, 792). The composition of milk also varies within and
between feedings (536, 654), between an individual’s
breasts (654), and between mothers and different ethnic
groups (536). The calcium content of milk is higher at 3 mo
than at 6 mo postpartum (459, 536, 856, 957), but the
volume of milk per feed is higher at 6 mo (856). Consequently, daily maternal loss of calcium could be greater at 6
mo and beyond, compared with the first 3 mo of lactation
(856). However, the number of feeds is usually fewer after 6
mo, thereby leading to an overall decline in daily calcium
losses.
Maternal milk output also increases in proportion to litter
number and weight in lactating animals, thereby maintaining a similar weight of pups regardless of their number. In
mice, for example, the weight of individual pups at 12 days
of age shows ⬍10% variation from a litter of 4 versus a
litter of 12. But the combined weight of a litter of 12 is three
times that of a litter of 4, confirming that a larger litter
means a greater maternal output of milk and calcium (87).
A similar constancy of neonatal pup weight has been seen in
pigs whose litter sizes range from 5 to 12 at 8 wk of age (87).
Ewes suckling twins produce about double the amount of
milk of ewes nursing singletons (970).
To meet the mineral requirements of lactation, maternal
adaptations might include increased intestinal absorption
of calcium, renal conservation of calcium, and increased
skeletal resorption of calcium. Studies reviewed in this section reveal that the main adaptation is a temporary demineralization of the skeleton, which appears to meet the cal-
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There are no published reports on pregnancies in women
with hyperphosphatemic disorders caused by deficiency of
FGF23 or its co-receptor. Large case series of pregnancies in
women on dialysis have shown increased obstetrical risks of
gestational hypertension, preeclampsia, eclampsia, and maternal mortality, and increased adverse fetal outcomes including premature birth, intrauterine growth restriction,
low birth weight, stillbirth, and neonatal mortality (139,
594, 656). These outcomes may relate more to the maternal
renal failure than the hyperphosphatemia per se. No data
have been reported about cord blood chemistries or skeletal
development and mineralization in the fetuses or neonates
of these hyperphosphatemic mothers.
584). Individual women were identified who had sustained
production of up to 3 liters of milk per day during 6 –12 mo
of lactation (419, 583, 838); analysis of their milk revealed
daily calcium losses of 500-1,200 mg (419, 838). However,
manual expression of milk can yield much greater volumes
than a suckling baby demands, thereby overestimating milk
production. Further bias was introduced by studying
women known to produce large volumes of milk, some of
whom were employed as wet nurses.
CHRISTOPHER S. KOVACS
Total Ca
(mmol/l)
2.7
Ionized Ca2+
(mmol/l)
2.1
1.6
0.9
Phosphorus
(mmol/l)
1.7
A. Changes in Mineral Ions and Calciotropic
Hormones
0.9
PTH
(pmol/l)
5.0
Progressive changes in serum calcium, phosphorus, and
calciotropic hormone levels during human lactation are
schematically depicted in FIGURE 2. Important differences among human, rat, and mouse lactation are listed
in TABLE 2.
0.0
Calcitriol
(pmol/l)
300
1. Calcium and phosphorus
A) ANIMAL DATA. The serum calcium of lactating rats has been
quite variable in published reports, and not clearly explained by the calcium content of the diet: hypercalcemia on
1.5 or 1.2% calcium (86, 318); normocalcemia on 1.6%
(568), 1% (991), 0.5% (114), 0.4% calcium (91, 318, 569),
and an unspecified diet (337); low blood calcium on 1.2,
0.9, 0.8, and 0.4% calcium (76, 90, 320, 321, 568, 718,
920, 927, 989); and marked hypocalcemia on 0.1, 0.04,
and 0.01% calcium (32, 320, 321, 568, 991). The ionized
calcium has been low on a 1.6% calcium diet (568), high on
a 1.2% calcium diet (318), low on a 0.8% calcium diet
(989), normal (318) and low on a 0.4% calcium diet (90,
568, 569), and low on a 0.1% calcium diet (32, 568).
0.0
Calcitonin
(pmol/l)
20.0
0.0
PTHrP
(pmol/l)
5.0
0.0
Estradiol
(nmol/l)
100.0
0.0
Prolactin
(ng/ml)
150.0
0.0
Lactation Weaning
PostWeaning
FIGURE 2. Schematic depiction of longitudinal changes in calcium,
phosphorus, and calciotropic hormone levels during lactation and
post-weaning skeletal recovery in women. Normal adult values are
indicated by the shaded areas. PTH does not decline in women with
low calcium or high phytate intakes and may even rise above normal.
Calcidiol (25OHD) values are not depicted; most longitudinal studies
indicate that the levels are unchanged by lactation, but may vary due
to seasonal variation in sunlight exposure and changes in vitamin D
intake. PTHrP and prolactin surge with each suckling episode, and
this is represented by upward spikes. FGF23 values cannot be plotted due to lack of data. Very limited data suggest that calcitriol and
PTH may increase during post-weaning, and the lines are dashed to
reflect the uncertainty. The data from which this summary figure has
been derived are cited in section IVA.
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cium requirements of milk production. Two processes,
osteoclast-mediated bone resorption and osteocytic osteolysis, are responsible for mobilizing skeletal calcium. Conservation of calcium by the kidneys is also evident (in contrast to pregnancy), but intestinal calcium absorption falls
to normal in lactating women from the elevated values of
pregnancy (it remains elevated in lactating rodents). PTH
and calcitriol do not appear to be the main regulators of
these processes; instead, secretion of PTHrP by breast tissue
and systemically low estradiol levels are two of the key
factors that stimulate bone resorption, while PTHrP also
stimulates renal calcium conservation. So it is evident that
the maternal adaptations during lactation differ from those
that are invoked during pregnancy, which in turn means
different consequences for normal women, and for women
who have disorders of bone and mineral metabolism.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
Table 2. Key differences in mineral physiology of human and rodent lactation
Rat
Mouse
Normal
Normal to slightly increased
Normal to slightly increased
Normal to increased
Normal to increased
Low to low-normal*
Normal
Increased
Increased
No data
Low
Normal
Decreased
5–10%
Low
Low
Low
Variable
Normal
Increased
Increased
Increased
Increased
No data
? Low
Increased
Decreased
25–35%
Normal
Normal
Normal
Variable
Normal
Low to normal
Increased
Increased
Increased
No data
? Low
Increased
Decreased
25–35%
*Women with low calcium or high phytate intakes have normal or increased PTH.
Differences in rat strains, litter sizes, and whether the samples were drawn fasted or not likely contribute to the variation in results. Greater demands for milk production (such
as larger litter number and combined weight of all pups)
provoke a lower maternal serum calcium (90, 320, 567,
708). Abrupt weaning causes the serum calcium to rebound
into the hypercalcemic range for several days (76, 86, 396,
718). This is likely due to sudden loss of the outflow of
calcium into milk while increased bone resorption and intestinal calcium absorption persist (see sect. IV, B and E).
An increase in serum calcium after abrupt weaning occurred even when dietary intake of calcium was negligible
on a 0.02% calcium diet (396), which confirms that increased skeletal resorption is a driver of the post-weaning
rebound in calcium.
Serum calcium declined a greater amount during lactation
in vitamin D-deficient rats (91), indicating that vitamin D
deficiency impairs the ability of the mother to maintain her
serum calcium during lactation. This contrasts with pregnancy in which the same vitamin D-deficient rats achieved a
significant increase in serum calcium (915). In the first 3
days after weaning, serum calcium rebounded twofold
higher to near-normal values in severely vitamin D-deficient
rats before declining significantly to the prepregnancy value
(915). This is also consistent with persistent upregulation of
intestinal calcium absorption and bone resorption for some
days after the outflow into milk has ceased.
In multiple studies from the author’s laboratory wherein
WT Black Swiss or C57BL/6 mice consumed a standard 1%
calcium diet, there was no change in the ionized calcium or
the serum calcium during lactation regardless of whether
the samples were drawn nonfasting or fasting (296, 330,
477, 478, 580, 992, 994). The ionized calcium was also
488
measured every other day in the same mice from the time of
mating, and no change occurred during pregnancy or lactation (827, 992). These findings suggest that a normal
mouse may be more capable of maintaining her serum calcium in the normal range than a rat during reproductive
cycles. However, CD1 mice maintained on a 1% calcium
diet showed a modest but statistically significant decline in
serum calcium during lactation (34). Consequently, there
may be strain differences in the ability of mice to maintain
normal serum calcium during lactation. More marked hypocalcemia was provoked in CD1 mice on a 0.01% calcium
diet (37).
In lactating ewes serum calcium rose after delivery and declined as lactation progressed, with a low-calcium diet causing a steeper decline in serum calcium (69). Deer maintained
an increased albumin-corrected serum calcium during lactation (170). Serum calcium remained normal in lactating
goats (55).
Serum phosphorus has also shown widely variable responses in lactating rats, with increases above normal (320,
568, 718), normal values (76, 114, 337, 568), and significant decreases (86, 319). Phosphorus rose during the first
several days after abrupt weaning, simultaneous with the
spike in serum calcium (86, 718). It either remained normal
or declined modestly in lactating mice (477, 478, 580),
declined in lactating goats (55), and increased above normal
in deer (170).
Serum magnesium is unaltered or modestly reduced in lactating rats (86, 132), and unchanged in mice (580) and
goats (55). Magnesium also increases abruptly after forced
weaning in rats (86).
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Serum calcium
Albumin-corrected calcium
Ionized calcium
Phosphorus
Magnesium
PTH
Calcitriol
Calcitonin
PTHrP
FGF23
Estradiol
Intestinal calcium absorption
Urinary calcium excretion
Trabecular bone losses
Human
CHRISTOPHER S. KOVACS
B) HUMAN DATA.
Numerous studies have shown that serum phosphorus increases during lactation, with mean values exceeding the
upper limit of normal in some studies (33, 156, 157, 164,
207, 221, 294, 453, 454, 468, 470, 497, 558, 632, 721,
757, 805, 871). Phosphorus rose higher in women nursing
twins in one study (646) but not in another (347). Renal
tubular reabsorption of phosphorus also increases (156,
157, 206, 207, 468, 470, 558). Given that intestinal absorption of phosphorus is likely normal (sect. IVC), this increase
in serum phosphorus in breastfeeding women likely results
from the effects of increased skeletal resorption (sect. IVE)
combined with relatively decreased renal phosphorus excretion (sect. IVD).
Serum magnesium is normal or modestly increased during
lactation (33, 164, 207, 221, 294, 348, 505, 721, 871), with
no consistent difference between women nursing twins and
singletons (347).
C) SUMMARY.
Serum calcium, ionized calcium, and phosphorus are usually normal in lactating mice, but these values
may be increased, normal, or decreased in lactating rats,
likely due to variable effects of diet, litter size, rat strain, and
whether samples were drawn fasting or not. Milk production imposes a high rate of efflux of calcium from the rodent
circulation, such that the serum calcium can be low during
suckling but rebound above normal with forced weaning. In
breastfeeding women, the ionized and albumin-adjusted
calcium are normal to slightly increased, while serum phosphorus increases and may exceed the normal range.
2. PTH
A) ANIMAL DATA.
In most studies of lactating rats PTH has
increased across a wide range of diets containing 0.4 –1.4%
calcium (32, 90, 254, 318, 320, 337, 627, 807, 920); however, PTH remained unchanged in lactating rats on 1.6, 0.4,
and 0.1% calcium in one study (568), and on an unspecified
diet (337). A low-calcium diet (320, 321) and nursing larger
litters (320, 708) cause higher PTH concentrations,
whereas if only three pups are nursed PTH is normal (320).
After weaning, PTH falls within 6 h and becomes normal by
24 – 48 h (321).
In contrast to the studies in rats, longitudinal studies of
Black Swiss and C57BL/6 mice consuming a 1% calcium
diet have found that PTH is suppressed during lactation
from prepregnancy values, and similar to low values of
pregnancy (330, 477, 478, 994). A 2% calcium diet suppresses PTH further (330, 478), whereas fasting overnight
leads to nonsuppressed PTH (580). Conversely in lactating
CD1 mice consuming a 1% calcium diet, the serum PTH
was no different than in virgin mice, whereas a 0.01% calcium diet caused a marked rise in PTH (34).
These findings suggest that PTH is needed to support the
delivery of calcium during lactation, such as by stimulating
bone resorption, Cyp27b1 expression and activity, and renal calcium conservation. Low dietary calcium intake and
larger litter sizes provoke higher PTH to stimulate these
processes, whereas high calcium intake and smaller litter
sizes prevent the need for PTH to increase. Rats may be
more dependent on PTH than mice, given that lactating rats
have been consistently found to have elevated PTH despite
even high calcium intake, while lactating mice may have
suppressed PTH unless fasted. The role that PTH plays in
regulating mineral homeostasis during lactation, as revealed through studies of parathyroidectomized rats and
Pth null mice, is discussed in more detail in sections IV,
C–E, and VD.
B) HUMAN DATA.
Lactation was originally thought to represent a state of secondary hyperparathyroidism (15), but
although some early-generation PTH assay results appeared to confirm this hypothesis (757), most found normal
levels (219, 348, 385, 578). Modern intact PTH assays have
generally revealed that PTH is suppressed toward the lower
end of the normal range and may become undetectable
during lactation (9, 157, 206, 207, 251, 294, 349, 454, 497,
505, 558, 871, 1025). This suppression is not seen with
COOH-terminal or mid-molecule assays (221, 871).
Women nursing twins had increased PTH in one study
(347) while another found no difference (646).
In contrast to these studies, others have reported increased
PTH during lactation in women from regions of Africa and
Asia in which low calcium, high phytate, and low vitamin D
intakes are more prevalent (168, 228, 439, 601, 805). Such
a difference has also been seen when African American and
Caucasian women, all from North America, have been
compared (156).
The influence of PTH in regulating mineral metabolism during lactation is further discussed in subsequent sections that
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Multiple cross-sectional and longitudinal
studies have consistently shown that the serum calcium,
whether adjusted for albumin or not, is normal or slightly
increased in breastfeeding women (9, 156, 157, 164, 168,
207, 221, 348, 349, 385, 453, 454, 468, 470, 558, 641,
721, 757, 764, 805, 871); one exception is a study that
found a decrease in the albumin-adjusted serum calcium
(632). The ionized calcium has similarly been shown to be
either increased slightly (221, 251, 470, 497, 757) or unchanged (157, 294, 453, 558, 721, 805, 871) in lactating
women compared with themselves or with controls. Mothers nursing twins had higher serum calcium than mothers
nursing singletons in one study (347) but not in another
report (646). In studies in which serum calcium and ionized
calcium were modestly but significantly increased, mean
serum calcium remained within the normal range. However, substantial hypercalcemia can occur during lactation
and resolve with weaning (see sect. V, D and F) (549).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
address the synthesis of calcitriol (sect. IIA4) and the adaptations that occur in the intestines (sect. IVB), kidneys (sect.
IVC) and bone (sect. IVD). PTH’s role is also illuminated by
data on the effects of hyperparathyroidism (sect. VB) and
hypoparathyroidism (sect. VD) in breastfeeding women.
PTH rises to normal (206, 558) or above normal (207, 470,
632, 871) during the post-weaning interval. This elevation
corresponds to the time when bone mineral is restored to
the skeleton (see sect. IVG) (27, 410).
3. PTHrP
A) ANIMAL DATA. Few measurements of plasma PTHrP have
been made in mice due to the lack of rodent-specific assays
and the large samples sizes required for the human assays.
Nevertheless, PTHrP is increased in the circulation of lactating mice (37, 530, 953, 956, 989, 994). The source is
largely mammary tissue, in which PTHrP mRNA and protein become substantially upregulated during lactation
(738, 992, 994). The fall in progesterone and estradiol after
delivery, and surge in prolactin, are thought to accelerate
PTHrP production (737, 906, 916, 940, 956). Suckling induces expression of PTHrP mRNA and protein within rat
mammary tissue (906, 1004); this effect is partly mediated
by prolactin and blocked by bromocriptine (906), whereas
oxytocin has no effect (906). In the goat, prolactin also
stimulates PTHrP, while treatment with bromocriptine reduces the PTHrP content of milk (744). Studies of cultured
rat mammary epithelial cells found that PTHrP production
was increased by low progesterone but not responsive to
prolactin or estradiol (940). The PTHrP content of milk is
higher at the end of lactation in rats, by which time prolactin has been normal for days, which suggests that prolactin
is not required for sustained PTHrP synthesis and secretion
during lactation (129).
Loss of calcitonin in Ctcgrp null mice resulted in upregulation of PTHrP mRNA and protein expression within mammary tissue (992, 994), but whether this was a direct effect
of loss of calcitonin signaling within mammary tissue, or
secondary to other systemic changes in those mice (see sect.
490
Local factors are important for stimulating PTHrP, since
milking one goat mammary gland increases the PTHrP concentration in milk from that gland but not the contralateral
gland (916).
Higher PTHrP concentrations in the venous outflow of goat
mammary glands was the first confirmation that PTHrP
reaches the maternal circulation from this source (744). A
suckling-induced phosphaturia and increase in nephrogenous cAMP, which persists in parathyroidectomized,
lactating rats, appears to be a physiological response to
systemic release of PTHrP (1004). Similarly in cows, a
milking-induced phosphaturia blocked by a PTH/PTHrP
receptor antagonist implicated PTHrP as the culprit (56).
Definitive confirmation that PTHrP reaches the maternal
circulation from mammary tissue came from a mouse
model in which the Pthrp gene was deleted from mammary tissue at the onset of lactation, and this reduced the
plasma PTHrP concentration (953). Moreover, in these
mice lacking mammary-derived PTHrP, bone resorption
was decreased and less bone was lost by the end of lactation
(953). Conversely, Ctcgrp null mice had increased mammary expression of PTHrP and lost twice as much bone
mineral content during lactation as their WT sisters (994).
Collectively, these findings confirm that through its expression of PTHrP, mammary tissue plays a central role in regulating bone resorption during lactation (see sects. IV, E
and F, and V, D and F). In addition to affecting skeletal
metabolism, mammary-derived PTHrP also appears to locally regulate the fluid and mineral content of milk, as discussed in section IVB.
B) HUMAN DATA.
PTHrP was originally cloned from small
amounts expressed by tumors causing humoral hypercalcemia of malignancy, and shown to circulate in picomolar
amounts in the blood of affected patients. But it later became apparent that 1,000 –10,000 times the concentration
of the elusive protein was readily available in milk, whether
produced by breastfeeding women or obtained from the
corner store (134, 208, 473, 681, 742, 812). Milk was
tested in part because it had been known for some time that
hypoparathyroid and aparathyroid women normalize mineral homeostasis or even become hypercalcemic while
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C) SUMMARY. PTH is generally suppressed in lactating mice
unless the samples are drawn fasting, whereas PTH is almost invariably elevated in lactating rats regardless of the
calcium content of the diet. In largely Caucasian women
from North America and Europe who are consuming adequate calcium, PTH is typically suppressed during lactation, so the original hypothesis of hyperparathyroidism in
lactation has not been substantiated. However, PTH is elevated in women from certain regions of Asia and Africa, as
well as in African American women from North America,
so lactation does represent a state of physiological secondary hyperparathyroidism in some women. A rise in PTH
during lactation is attributable to lower calcium and higher
phytate intakes, as well as probable ethnic differences.
VH), is unknown. Serotonin increases during lactation in
mice (101) and may stimulate mammary gland PTHrP,
since increased dietary intake of a serotonin precursor
raised PTHrP mRNA and protein expression in the mammary glands, and also increased plasma PTHrP significantly
(530). Conversely, deletion of tryptophan hydroxylase-1 in
mice results in global serotonin deficiency, and reduced
PTHrP expression in mammary tissue during lactation
(380). This was reversed in a dose-dependent fashion by a
serotonin receptor agonist and worsened by a serotonin
receptor antagonist (380).
CHRISTOPHER S. KOVACS
breastfeeding, which suggested the presence of a PTH-like
factor during lactation (see sect. VD).
In section IIA3B, the inherent problems with measuring
PTHrP in serum as opposed to plasma, and limitations of
the available assays, apply to published studies of lactating
women. Despite these problems, and with few exceptions
(473), most studies have found the circulating PTHrP1– 86
or PTHrP1–34 level to be significantly increased in lactating
women vs. nonpregnant women or bottle-feeding controls
(251, 349, 497, 558, 863). An assay directed against a midregion sequence (PTHrP63–77) also found PTHrP to be elevated in the blood of lactating women (130).
PTHrP declines significantly during the post-weaning interval (558). Exactly when it disappears from the maternal
circulation have not been established, but the variable response of hypoparathyroid women to weaning indicates
that it may be gone by weaning or persist for up to many
months (see sect. VD).
C) SUMMARY. Lactating mammary tissue upregulates expression of PTHrP, some of which is secreted into the maternal
circulation to alter mineral and skeletal homeostasis. In a
real sense the breasts become accessory parathyroids by
producing substantial amounts of PTHrP. As discussed in
sections IV, B–F, release of PTHrP into the maternal circulation has systemic effects to alter milk composition, intestinal mineral absorption, renal mineral handling, and skeletal resorption. The most convincing evidence comes from
aparathyroid or hypoparathyroid women who release
PTHrP from the breasts and normalize mineral homeostasis
during lactation (see sect. VD) (148 –150, 213, 785) and
pseudohyperparathyroid women who become hypercalcemic while breastfeeding (see sect. VF).
25OHD is likely not altered during lactation, as suggested
by studies of rats on three different calcium diets (568). But
in two other studies from one lab the 25OHD level in lactating rats was significantly lower than in control rats (114,
115).
B) HUMAN DATA.
Free and total calcitriol falls to normal during postpartum (206, 439, 578, 746, 809, 987) and remains
normal throughout lactation and postweaning (156, 157,
206, 207, 348, 385, 470, 505, 632, 764, 805, 871, 987).
One study found that extended lactation (⬎6 mo) was associated with higher calcitriol (348), another report found
that calcitriol increased during the postweaning interval of
bone recovery (871), and a third report found that calcitriol
was 10% higher during lactation and that this persisted
during the post-weaning interval (454). Women nursing
twins had higher calcitriol levels than women nursing singletons in one study (347) but not in another (646).
25OHD levels do not appear to be altered by up to 12 mo of
breastfeeding in most studies (33, 156, 157, 165–167, 470,
505, 558, 764, 780, 805, 862, 871). This is consistent with
milk normally containing very low amounts of vitamin D
and 25OHD (see sects. IVB and VG).
4. Calcitriol
The decline to normal concentrations of calcitriol may result from pregnancy-related factors being lost at parturition, such as high levels of estradiol and placental lactogen.
PTHrP reaches peak levels during lactation and likely stimulates Cyp27b1, but there is some evidence that it may be
less potent than PTH in stimulating Cyp27b1 (308, 413,
414, 494, 988).
A) ANIMAL DATA. Serum calcitriol increases twofold or more
in lactating rats (90, 92, 93, 114, 718, 1021), and higher
levels are achieved with larger litters or more intense lacta-
C) SUMMARY. Calcitriol remains elevated in lactating rats and
mice, whereas in breastfeeding women the level promptly
declines to nonpregnant values. These differences between
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Circulating PTHrP increases after suckling (251, 557, 558);
together with its very high content in milk, this confirms
that the breasts must be the source. PTHrP may not be
elevated in the first 3 days postpartum before lactation is
fully established (151). PTHrP immunoreactivity rises
steadily in breast milk over the first few days postpartum,
and subsequently declines as lactation wanes (129, 208,
251). PTHrP concentrations correlate positively with ionized calcium and negatively with PTH of lactating women
(251, 497). Increased plasma PTHrP correlates with a
greater loss of bone mineral density during lactation (863).
Furthermore, there have been several cases of excess production of PTHrP by the breasts during lactation that have
caused hypercalcemia (pseudohyperparathyroidism) (see
sect. VF).
tion (90, 567). The fall in serum and ionized calcium and
rise in PTH, observed in most studies of lactating rats, likely
contribute to the increase in calcitriol. This increase is also
influenced by the diet, rising higher with a 0.1% calcium
diet and being prevented by a 1.6% calcium diet (568). In
that study PTH was no different between lactating and
nonlactating rats despite the three different diets, indicating
that the changes in calcitriol were independent of changes in
PTH (568). Another set of analyses also indicated that PTH
is not a significant predictor of the calcitriol level in lactating rats (90, 567). But PTH must account for some of the
increase in calcitriol during lactation since two studies
found that serum calcitriol in lactating parathyroidectomized rats was only half the concentration of lactating intact rats, although the achieved level was at least double
that of nonlactating rats (569, 718). In normal rats calcitriol
falls below normal by 2 days after weaning, simultaneous
with a rise in calcium and phosphorus, before increasing to
normal values by 7 days after weaning (718).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
rodents and women are consistent with indications that
rodents require increases in both intestinal calcium absorption and skeletal resorption to meet the mineral requirements of lactation, whereas women require only increases
in skeletal resorption (see sect. IV, C and E).
5. Calcitonin
Calcitonin has been shown to inhibit lactation by acting on
suckling-induced prolactin release by pituitary lactotrophs
(177, 680, 756, 919). Calcitonin is also expressed by pituitary gonadotrophs (755), wherein its targeted overexpression leads to hypoprolactinemia (1014). This leads to consideration of a physiological negative-feedback loop during
lactation in which calcitonin inhibits the release of prolactin
by the pituitary, thereby reducing milk production, releasing the inhibition of ovarian function, and inhibiting PTHrP
release by mammary tissue.
C) SUMMARY. Calcitonin may be normal or increased in lactating rodents and breastfeeding women. Although largely
considered a vestigial hormone, there is convincing evidence from animal models that calcitonin protects against
excess skeletal resorption during lactation (sects. IVE and
VH). It surges to high levels at weaning, which may point to
a functional role in inducing osteoclast apoptosis, or it may
simply be responding to the post-weaning spike in serum
calcium. Calcitonin can also inhibit prolactin and lactation
in women and animal models when administered at pharmacological doses.
6. FGF23
A) ANIMAL DATA. There are no published data of circulating
FGF23 concentrations in lactating animals. The physiological importance of FGF23 is uncertain given the variable
changes in serum phosphorus during lactation in rodents.
The effect of excess FGF23 on serum minerals and milk
composition is discussed in sections IVB and VJ.
B) HUMAN DATA.
No measurements of FGF23 in breastfeeding women have been reported. The relative hyperphosphatemia of lactation could conceivably cause a compensatory increase in FGF23. The influence of excess FGF23 on
milk composition is discussed in sections IVB and VJ.
C) SUMMARY.
Calcitonin surges within 24 h after abrupt weaning in rats,
at a time when osteoclasts are undergoing widespread apoptosis (627), so calcitonin may be one of the signals that
contributes to the sudden downregulation of osteoclastmediated bone resorption. Alternatively, it may simply be
responding to the post-weaning spike in serum calcium.
B) HUMAN DATA. Few studies have measured calcitonin in
breastfeeding women. Available data show high levels
throughout lactation (221, 878) but also normal values between 6 wk and 12 mo postpartum (347, 385, 505, 632,
764). There was no difference in serum calcium among
these studies that could explain the variable calcitonin values. Women nursing twins had higher serum calcitonin than
women nursing singletons, but mean values were normal
(347).
There are insufficient data to know whether
serum FGF23 concentrations are altered in lactating rodents or humans.
7. Sex steroids and other hormones
A) ANIMAL DATA.
Lactation induces a surge in prolactin and a
fall in estradiol and progesterone in the rat, mouse, and
ewe; the fall in progesterone and estradiol are triggers of
lactogenesis (655).
The breast is an important extrathyroidal source of calcitonin. It is secreted into breast milk at 45 times its concentration in blood, such that during lactation, totally thyroidectomized women and women with intact thyroids have the
same mean calcitonin concentration (131).
In mice, serum estradiol is usually near the detection limit of
available assays. Although it has been shown to be low in
lactating mice in one study (34), in most studies serum
estradiol is not significantly different from prepregnancy,
pregnancy, or virgin measurements (627, 956, 992, 1026).
It is unclear whether the lack of suppressed levels during
lactation is because estradiol is not low or because the assays are not sensitive enough to detect differences. Moreover, lactating mice go through estrus cycles and can become pregnant while lactating, so estradiol levels may not
be sufficiently low in lactating mice to cause bone resorption.
The effect of calcitonin to inhibit prolactin in rodents, and
similar findings in human studies (155, 431), led to a com-
Prolactin levels surge during early lactation as it exerts its
role in initiating milk production; dopaminergic agents in-
492
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A) ANIMAL DATA. Similar to serum calcium and PTH, serum
calcitonin levels in lactating rats have been quite variable,
including low values on a 1.4 and 1.5% calcium (86, 627);
high levels on 1.2% and 0.9% calcium (76, 926) and an
unspecified diet (201); and normal values on an unspecified
diet (337). Calcitonin levels are higher in fed versus fasted
lactating rats (201). In ewes, calcitonin drops to nonpregnant levels at delivery, rises early in lactation, and declines
to normal as lactation progresses (312). Deer show increased calcitonin during lactation which rises further during post-weaning before it declines (170). No measurements have been published in lactating mice.
mon warning in prescribing information that calcitonin
should not be used in breastfeeding women because of its
potential to inhibit lactation.
CHRISTOPHER S. KOVACS
hibit prolactin and stop milk production. Prolactin and prolactin receptor null mice cannot be studied because they are
infertile, but loss of one allele of the prolactin receptor
causes impaired lactation (465). Prolactin has been proposed to directly stimulate osteoblasts and osteoclasts during lactation, but inhibiting prolactin with bromocriptine
achieved inconsistent results (888). Moreover, inhibiting
prolactin does not necessarily test a direct role of prolactin
on bone, since loss of prolactin will inhibit milk production,
reduce ovarian suppression, and reduce PTHrP production
by mammary tissue.
IGF-I did not change in lactating mice compared with agematched virgins, but approximately doubled by the third
week of post-lactation recovery (101). As noted above, serotonin increased during lactation and may stimulate
PTHrP production; there was a further increase during
post-weaning recovery (101).
B) HUMAN DATA.
Human lactation is also characterized by
increased prolactin, and reduced estradiol and progesterone. Delivery of the placenta is responsible for the fall in
progesterone and estradiol, which in turn trigger lactogenesis (617, 655). Failure to drain the breasts of milk (via
suckling or pumping) leads to milk stasis, apoptosis of
mammary cells, and cessation of lactation.
Estradiol is suppressed to menopausal levels during early
lactation (157, 409, 505, 695, 764), especially when basal
levels of prolactin are elevated (409, 695). Low estradiol
may persist throughout lactation or recover to normal values after several months. It likely contributes to bone resorption during lactation, as discussed in section IVE. Prolactin declines as the postpartum days pass but continues to
spike upwards with each suckling episode (409, 505, 655,
695). Any effect of low estradiol may be lessened during
prolonged lactation in women whose menses resume.
Oxytocin spikes in the maternal circulation within a few
minutes of the baby being put to the breast (230, 655).
C) SUMMARY. Continuously low estradiol, and intermittently
high prolactin and oxytocin levels, characterize the hormonal milieu of lactation. Low estradiol contributes to skeletal resorption, but the extent to which prolactin and oxytocin have direct or indirect effects to regulate skeletal metabolism during lactation is uncertain. Lactation also causes
changes in luteinizing and follicle stimulating hormone,
B. Calcium Pumping and Secretion in
Mammary Tissue
1. Animal data
The process by which calcium enters mammary epithelial
cells and is eventually secreted into milk is incompletely
understood (FIGURE 3). Calcium appears to enter the basolateral membranes of mammary epithelial cells via stretchactivated and other calcium channels. A low concentration
of calcium is maintained within the cytoplasm by PMCA1
actively pumping calcium into the Golgi apparatus, wherein
calcium becomes bound to proteins (casein and ␣-lactalbumin) or complexed to phosphate and citrate. Calcium is also
bound to carrier proteins such as calbindin-D9k within the
cytoplasm (442) and transported to the apical membrane.
Calcium is extruded from the Golgi apparatus into milk
through transepithelial secretion (617, 652), a process that
accounts for ⬃30% of calcium transport into milk. About
70% of calcium entry into milk results from plasma membrane calcium ATPase isoform 2 (PMCA2) pumping calcium across the apical membranes directly into milk (753,
954).
The calcium and fluid content of milk are tightly regulated.
Identified regulatory factors include suckling, the calcium
receptor, PTHrP, prolactin, calcitriol, and others (442, 655,
952, 953). Lactating mammary epithelial cells also express
numerous genes and proteins that are involved in calcium
homeostasis elsewhere in the organism, including the calcium receptor, PTHrP, calcitonin, the calcitonin receptor,
Cyp27b1, VDR, and calbindin-D9k; however, TRPV5 and
TRPV6 are not expressed (938, 952, 1026).
PTHrP plays a key role in the embryonic and adolescent
development of the mammary glands (99, 258, 389, 999),
so its later expression by lactating mammary tissue and
breast cancers is understandable. The intense expression of
PTHrP in lactating mammary tissue, and its secretion into
milk at high concentrations, have prompted investigations
to determine whether PTHrP regulates the calcium content
of milk. Early studies showed that the PTHrP concentration
in milk was positively correlated with calcium content of
milk from cows (539, 681) and rats (989), but not in all
studies from rats (738, 1004). One study found that with
time since suckling, PTHrP content of milk decreased while
the calcium content increased (1004). Treatment of lactating goats with bromocriptine reduced the milk content of
both PTHrP and calcium (744). PTHrP also has vasodilatory effects on mammary vessels, through which it may
regulate mammary blood flow (907, 908). PTHrP’s expression in mammary tissue is increased by low estradiol, low
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Oxytocin is required to cause contraction of myoepithelial
cells within mammary tissue, thereby causing milk ejection.
Oxytocin has also been proposed to regulate osteoblasts
and osteoclasts during lactation (565, 895), but this has not
been studied. Oxytocin null mice are unable to lactate because lack of milk ejection causes apoptosis of mammary
cells (663).
progesterone, testosterone, inhibins, and activins. Whether
these play direct or indirect roles in regulating maternal
skeletal metabolism during lactation is uncertain.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
Basolateral
surface
Ca2+
ADP
ATP
Ca2+
Ca2+
Ca2+
PMCA1
Ca2+
Ca2+
Ca2+
Mammary
epithelial cell
Apical
surface
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
~2.2 mM
[Ca2+] in blood
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
<1 mM
[Ca2+] in cytoplasm
Ca2+
Ca2+
Ca2+
~3 mM
[Ca2+] in milk
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
2+
Ca2+ Ca
2+
Ca
Calbindin-D9k Ca2+
Ca2+
Ca2+
Ca2+
+
PMCA2
Ca2+
Ca2+
Ca2+
ADP
Ca2+
Calcitonin
?
Ca2+
?
Ca2+
–
Into blood
PTHrP
Into milk
progesterone, low dietary calcium, systemic hypocalcemia,
high prolactin, and suckling (737, 906, 910, 916, 940, 952,
956, 1003, 1004). Each of these stimulatory factors supports a role for PTHrP in regulating mammary gland and
mineral physiology during lactation. On the other hand, an
early study failed to detect a change in milk calcium content
when lactating mice were passively immunized with antiPTHrP antibody (620).
The role of PTHrP has been further explored through the
use of gene deletion models in mice. Selective deletion of
Pthrp from mammary epithelial cells at the onset of lactation resulted in reduced milk calcium content (953). However, this may have been an indirect effect because the supply of calcium to mammary tissue was also reduced, as
indicated by reduced bone turnover markers and less bone
resorbed by the end of lactation (953). Conversely, significant upregulation of PTHrP mRNA and protein occurred
within mammary epithelial cells of Ctcgrp null mice (which
lack calcitonin), and the milk calcium content was significantly doubled at day 14 of lactation (994), and nonsignificantly increased at day 7 of lactation (992). Again, this may
have been an indirect effect because in these mice the supply
of calcium to mammary tissue was significantly increased,
as shown by increased bone turnover markers and a doubling of net bone lost by the end of lactation (992, 994).
494
ATP
Ca2+
Further studies that examined the effect of calcimimetic
agents, and selective deletion of the calcium receptor, have
clarified the role of PTHrP within mammary tissue. It is the
calcium receptor, expressed by mammary epithelial cells,
which appears to directly regulate production of PTHrP,
and the fluid and calcium content of milk (36, 591, 952).
While a low calcium diet increases mammary production of
PTHrP, this effect is blocked by a calcimimetic drug, which
activates the calcium receptor to downregulate PTHrP
(952). Ablation of the calcium receptor globally, or selectively within mammary epithelial cells, upregulates mammary gland PTHrP expression and reduces calcium transport into milk (36, 591). Moreover, selective ablation of the
calcium receptor from mammary epithelial cells raises the
plasma PTHrP level, induces hypercalcemia, and causes increased bone resorption and net loss of bone by the end of
lactation (591). But despite systemic hypercalcemia and increased bone resorption, the milk calcium content remains
low because of loss of the calcium receptor’s actions to
promote calcium entry into milk (591).
The calcium receptor also upregulates expression of
PMCA2, expressed on the apical plasma membranes of
mammary epithelial cells, to stimulate calcium secretion
into milk (952, 954). The importance of PMCA2 has been
revealed by a spontaneous loss of function mutation of
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Ca2+
FIGURE 3. Calcium transport across mammary epithelial cells into milk. The basolateral
(left) and apical (right) basement membranes
of a mammary epithelial cell are depicted.
Calcium enters the cell through channels that
have not been defined; TRPV6 and TRPV5
are not expressed. About 20 –30% of calcium destined for secretion into milk is
pumped into the Golgi apparatus via PMCA1,
wherein it is packaged into secretory granules containing proteins (casein and ␣-lactalbumin) and complexes of calcium with phosphate and citrate. These granules are extruded from the Golgi apparatus into milk
through transepithelial secretion at the apical
membrane. About 70 – 80% of calcium entering the cell becomes bound to carrier proteins such as calbindin-D9k and is shuttled to
the apical membrane in the transcellular
pathway, from where PMCA2 actively pumps
the calcium into milk. Calcium ions binding to
the calcium receptor on the basolateral
membrane inhibit PTHrP and stimulate
PMCA2 to pump calcium into milk. Calcitonin
may also influence these processes, perhaps
through regulation by the calcium receptor
(which regulates calcitonin in C-cells of the
thyroid), since absence of calcitonin causes
upregulation of PTHrP within mammary epithelial cells, and milk calcium concentration is
also increased. PTHrP is released into milk at
higher concentrations than it is released into
the maternal circulation.
CHRISTOPHER S. KOVACS
Pmca2 in deafwaddler mice, which produce milk of low
calcium content (753, 954). Deletion of the calcium receptor from mammary epithelial cells did not affect expression
of PMCA2, thereby confirming that it is loss of the calcium
receptor function that specifically leads to the low calcium
content of milk (591), perhaps by reduced activity but not
expression of PMCA2.
Putting these observations together, it appears that mammary epithelial cells utilize the calcium receptor to sense the
availability of calcium for milk production. The calcium
receptor will promote calcium secretion into milk when the
supply is adequate, and stimulate production of PTHrP
A
This model implies a negative feedback loop that will enable
milk production to decrease or cease if the serum calcium
becomes dangerously low for the mother (955). However, it
is not a fail-safe loop because hypocalcemia leading to tetany and death can occur during lactation in rats and mice
that nurse large litters, and in dairy cows (milk fever).
Blocking the effect of PTHrP to resorb bone through use of
a bisphosphonate or osteoprotegerin (OPG) treatment in
lactating mice did not cause a compensatory increase in
PTHrP (37, 956), but this might be explained in part because the serum calcium did not decrease. In a separate
study, a fall in serum calcium and an increase in calcitriol
were observed in bisphosphonate-treated rats which may
imply increased PTHrP activity (115), but PTHrP was not
B
Increased maternal serum calcium
Reduced maternal serum calcium
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
H2O
Calcium and H2O
PTHrP
(milk)
+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
H2O
Calcium and H2O
PTHrP
(milk)
+
Ca2+
Ca2+
Ca2+
Ca2+
–
Ca2+
PTHrP
Ca2+
–
PTHrP
PTHrP
(maternal plasma)
PTHrP
(maternal plasma)
FIGURE 4. The role of PTHrP and calcium receptor (CaSR) within the lactating breast. The calcium receptor
(represented schematically) is expressed by lactating mammary epithelial cells. It monitors the systemic
concentration of calcium to control PTHrP synthesis and, thereby, the supply of calcium to the breast. An
increase in serum calcium or administration of a calcimimetic inhibits PTHrP expression (A), whereas a
decrease in serum calcium or ablation of the calcium receptor from mammary epithelial cells stimulates PTHrP
expression (B). The calcium receptor also directly regulates the calcium and fluid composition of milk independent of PTHrP. Administration of a calcimimetic stimulates calcium and water transport into the breast, while
ablation of the calcium receptor results in low milk calcium despite increased PTHrP and systemic hypercalcemia. PTHrP produced by mammary epithelial cells enters the maternal circulation to stimulate maternal
bone resorption and renal calcium conservation. It also enters milk at 1,000- to 10,000-fold higher concentrations, from where it may influence neonatal accrual of calcium.
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Studies in goats have revealed that the calcium receptor and
PTHrP may play opposing roles with respect to mammary
epithelial cell survival. Activation of the calcium receptor by
calcium or a calcimimetic drug inhibited proliferation and
induced apoptosis of mammary epithelial cells, whereas
overexpression of PTHrP had the opposite effect to inhibit
apoptosis and promote proliferation (552).
when the calcium supply is insufficient (FIGURE 4). In this
model, PTHrP’s role is to maintain systemic delivery of
calcium to the mammary epithelial cells by resorbing calcium from the skeleton and reabsorbing calcium from the
kidney tubules. Thereby, PTHrP plays an indirect but key
role in determining the calcium content of milk.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
measured. Moreover, several additional physiological observations suggest that the mammary gland calcium receptor has
quite limited ability to prevent systemic hypocalcemia. In severely vitamin D-deficient rats, which have a serum calcium
50% of normal, the calcium content of milk was unchanged
compared with normocalcemic, vitamin D-sufficient mothers
(91). In cows, the calcium content of milk is unaffected by low,
normal, or high dietary calcium content, or low to high milk
output (204).
Other work has established that serotonin stimulates not
only rat mammary gland expression of PTHrP, but milk
PTHrP content, plasma PTHrP, systemic bone resorption,
and milk calcium content (530). These findings confirm an
important physiological role for serotonin in regulating
mammary gland physiology during lactation, but also imply that increased expression of PTHrP causes increased
milk calcium content. However, expression of PMCA2
more than doubled in mammary tissue in these studies
(530), and that can be expected to increase milk calcium
independent of PTHrP. It is unclear whether the increase in
PMCA2 resulted from increased serotonin signaling or the
increase in PTHrP expression.
Although Cyp27b1 and VDR are expressed in mammary
epithelial cells and increase their expression 20- and 50fold, respectively, during late pregnancy and lactation
(1026), their relative roles are uncertain and the data are
conflicting. In Vdr null mice, the milk calcium content was
no different than in WT, although the mice were studied on
a high-calcium diet that maintained normocalcemia (1026).
Vdr null mice did display accelerated glandular development and early casein expression during pregnancy, increased milk output, and delayed involution of the mammary tissue after weaning (1026). Conversely, Cyp27b1
null mice were also studied on the same rescue diet but
remained hypocalcemic, and produced milk with reduced
calcium content (442). Mammary gland expression of
PTHrP, PMCA2 and calbindin-D9k was also significantly
reduced in Cyp27b1 nulls (442). It is unclear whether the
reduced milk calcium content resulted from systemic hypocalcemia or the loss of calcitriol within mammary tissue.
If it is the loss of calcitriol, the lack of alteration in milk
496
Phosphorus is also subjected to regulated pumping and secretion into breast milk, although less is known about the
regulatory factors involved. The FGF23 target NaPi2b is
coexpressed with VDR in mammary epithelial cells of the
goat and mouse (417, 631, 643), and NaPi2b expression
decreased in response to lower dietary phosphorus intake
(643). Expression of Klotho and FGF receptors by lactating
mammary tissue has evidently not been studied. Systemic
hypophosphatemia in Phex/Hyp mice did not alter the
phosphorus or calcium content of milk (240), but this differs from findings in women (see below).
PTH likely plays a supportive role in milk production by
helping to maintain the maternal serum calcium near the
normal range, and this may explain why PTH is often elevated in normal lactating rats. In Ctcgrp null mice that had
elevated mammary expression of PTHrP and increased milk
calcium content, serum PTH was also increased above normal and may have contributed to the milk calcium level
(992, 994). Milk calcium content was normal in parathyroidectomized rats, but the study was confounded by the
serum calcium remaining in the normal range on a 1.2%
calcium diet (319).
2. Human data
Fewer studies of calciotropic factors affecting milk content
have been done in women. The PTHrP concentration of
milk (245, 812, 941) and in the maternal circulation (245)
correlates positively with total milk calcium content. A randomized trial found no effect of calcium supplementation
on milk PTHrP content, but there may be a diurnal variation with more PTHrP in milk obtained in the morning
compared with the afternoon (208). Diets that are high
(206, 452, 484, 723) or low (728 –731) in calcium, or high
(60) or low (731) in vitamin D, do not affect milk calcium
content.
The vitamin D content of milk is normally quite low, and
this is why breastfeeding is a risk factor for vitamin D deficiency and rickets in neonates and infants. It is a curiosity as
to why the vitamin D content is so low. It is not possible for
humans to develop vitamin D toxicity from sunlight exposure due to limited substrate produced in skin each day, but
it is possible to become vitamin D toxic from overingestion
of vitamin D from supplements and vitamin D-fortified
foods. Therefore, a teleological argument is that neonatal
physiology was designed to obtain sufficient vitamin D
from sunlight exposure, with milk content of vitamin D
kept low to prevent excess intake by the baby, and also to
prevent excess loss of 25OHD from the mother.
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Notably, the effect of the calcium receptor to inhibit mammary gland production of PTHrP is reversed in certain malignant breast cancers, such that altered G protein coupling
causes the calcium receptor to stimulate rather than inhibit
the production of PTHrP (592). This may explain why a
positive feedback loop results when certain breast cancers
produce PTHrP to resorb bone, and the released calcium
acts through the calcium receptor to stimulate more PTHrP
rather than inhibiting it. Altered G protein coupling is also
a potential explanation for why lactation may lead to
PTHrP-mediated hypercalcemia in some women (see sect.
VF).
calcium in Vdr null mice may mean that this effect of calcitriol is not mediated by VDR. Additional studies in severely vitamin D-deficient mice and rats also found that the
calcium content of milk was normal (19, 119).
CHRISTOPHER S. KOVACS
Two cases of women with hypophosphatemia due to XLH
found that the phosphorus content of milk was reduced to
about half the normal value (447, 745). The reduced serum
phosphorus in these women may explain the low phosphorus content of milk, without requiring a direct role of
FGF23 to regulate the phosphorus content of milk.
3. Summary
The increased intestinal calcium absorption contributes to
the rebound hypercalcemia after abrupt weaning (396,
718), which also persists in severely vitamin D-deficient rats
(915). However, rebound hypercalcemia may have a
greater contribution from increased skeletal resorption,
which also does not require calcitriol or VDR (see sects. IVE
and VG).
C. Intestinal Mineral Absorption
1. Animal data
Lactating rodents maintain an increased rate of intestinal
calcium absorption accompanied by high serum calcitriol,
compared with nonpregnant values (93, 114, 360, 718).
Duodenal expression of calbindin-D9k, PMCA1, and VDR
are higher in lactating compared with virgin rats (949,
1021). Lactating mice similarly maintain increased circulating levels of calcitriol and presumably have increased intestinal calcium absorption as well. These findings indicate
that increased intestinal calcium absorption and increased
skeletal resorption are both invoked to meet the calcium
demands imposed by a rodent’s relatively large litters, and a
short (3 wk) duration of lactation.
On the other hand, although reducing either the dietary
intake of calcium or skeletal resorption during lactation will
cause maternal hypocalcemia, neither manipulation reduces the calcium content of milk. It is only when both are
reduced, such as a calcium-restricted diet in mice also
treated with OPG to block bone resorption, that more profound maternal hypocalcemia and reduced milk calcium
content result (see also sect. IVE). These findings indicate
that the rodent balances input from both skeletal resorption
and increased intestinal absorption of calcium, and that
either route of delivery can make up for the other during
lactation. It is only when both are impaired that systemic
hypocalcemia and reduced milk calcium content will result.
As with studies in pregnancy, factors other than calcitriol
may stimulate intestinal calcium absorption during lacta-
Estradiol has been proposed to contribute to the stimulation of intestinal calcium absorption during pregnancy because its levels are high, but estradiol is unlikely to be a
factor during lactation because its levels are reduced. Moreover, intestinal calcium absorption was unaffected by ovariectomy on the second day after delivery (32).
Intestinal phosphorus and magnesium absorption are both
significantly increased during lactation in rats (113, 114).
Intestinal phosphorus absorption remains high despite severe vitamin D deficiency (93), confirming that it is independent of calcitriol. During post-weaning recovery, intestinal calcium and phosphorus absorption fall to virgin values in rats (93, 360).
2. Human data
Multiple studies have demonstrated that intestinal calcium
absorption is normal (equivalent to nonpregnant values)
during lactation, reduced from the doubled rate that occurs
during pregnancy (324, 372, 453, 467– 469, 764, 873).
This fall in the rate coincides with calcitriol also declining to
normal (sect. IVA) and supports that calcitriol contributes
to the increased efficiency of calcium absorption during
pregnancy.
Even when lactating and control women were randomized
to receive 1 g calcium or placebo to take daily, no difference
in fractional absorption of calcium was evident across the
groups (453). A small increase in intestinal calcium absorption occurs in women whose menses have resumed while
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The calcium receptor appears to directly control the calcium content of milk by inhibiting PTHrP and stimulating
PMCA2. There is also evidence that PMCA2 may be locally
regulated by PTHrP, serotonin, and calcitriol. PTHrP is
expressed by mammary epithelial cells wherein it plays a
supportive role in regulating the calcium content of milk,
largely by stimulating systemic bone resorption and renal
tubular conservation of calcium. The calcium receptor may
inhibit PTHrP release to prevent maternal hypocalcemia,
but this effect must be modest since lactation-induced hypocalcemia occurs in rodents and cows, and extremes of
low and high dietary calcium intake do not alter milk calcium content in women. XLH in women results in milk with
low phosphorus content.
tion, since severely vitamin D-deficient rats increase duodenal calcium absorption to a value equal to that of vitamin
D-sufficient rats; they also raise their serum calcium significantly but not to normal (93, 360). When these severely
vitamin D-deficient rats were also parathyroidectomized
and transferred to a high-calcium diet, an increased rate of
intestinal calcium absorption was maintained despite absence of both calcitriol and PTH, and it was no different
from the rate achieved in intact, vitamin D-sufficient rats
(93). Moreover, ketoconazole treatment reduced serum calcitriol by half in lactating rats, but this had no effect on the
efficiency of intestinal calcium absorption (92), confirming
that calcitriol is not necessary for an increased rate of absorption to be achieved during lactation. Intestinal calcium
absorption has not been measured in lactating Vdr null and
Cyp27b1 null mice.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
they are still lactating (453), which supports a role for
higher estradiol levels boosting calcium absorption.
Women often increase dietary or supplemental intake of
calcium while breastfeeding, and this will increase the total
amount of calcium absorbed, even though the efficiency of
absorption is not altered (453). However, randomized trials
and cohort studies have found that this increases urine calcium excretion without affecting milk calcium or the
amount of bone resorbed during lactation (206, 452, 484,
723, 729, 730) (see sects. IVE and VI).
A post-weaning 20% increase in intestinal absorption of
calcium has been observed in one study (453), whereas
another found a nonsignificant 9% increase (764). These
values are well below the doubling that is achieved during
pregnancy but may still facilitate restoration of the skeleton
after lactation.
3. Summary
Intestinal absorption of calcium and phosphorus was increased during pregnancy, and these high rates continue in
rodents throughout lactation. This is likely mediated in part
by high levels of calcitriol, but its persistence despite severe
vitamin D deficiency indicates that calcitriol-independent
mechanisms also stimulate intestinal calcium absorption
during lactation.
In contrast, intestinal calcium absorption falls to nonpregnant values during lactation in women, accompanied by a
fall in calcitriol. High or low calcium intakes, and high
vitamin D intakes, do not seem to alter this rate in lactating
women. A modest increase in intestinal calcium absorption
may occur during post-weaning recovery.
D. Reduced Renal Excretion of Calcium
1. Animal data
Renal conservation of calcium occurs during lactation in
the lactating rat and mouse, with urine calcium concentrations falling to low levels even when a high-calcium diet is
consumed (34, 291, 330, 477, 580, 994). Rendering rats
severely vitamin D-deficient did not impair the ability of the
kidneys to conserve calcium compared with vitamin D-replete rats (93). Similarly, absence of calcitriol, PTH, or calcitonin did not alter urine calcium excretion in the respective mouse models (330, 478, 994).
498
In rats, the persistence of elevated PTH during lactation (see
sect. IVA2) likely complements the actions of PTHrP to
conserve calcium and excrete phosphorus.
2. Human data
The glomerular filtration rate declines during lactation
from the increased rate of pregnancy, the tubular maximum
for calcium increases, while fractional excretion of calcium
(especially on 24 h collections) falls and may reach hypocalciuric values (18, 168, 207, 221, 304, 439, 454, 467, 468,
470, 632, 757, 764). This is more readily seen in longitudinal studies in which lactating women were compared with
themselves at earlier time points, and has also been demonstrated by the urinary response to an oral calcium load in
pregnant, lactating, and control women (805). The increase
in tubular reabsorption of calcium is attributable to PTHrP.
Fractional excretion of calcium did not appear to be reduced in two recent cross-sectional studies from the same
authors; however, the results were confounded by the lactating women consuming 60 and 80% more calcium than
the unrelated controls (156, 157).
Urine phosphorus excretion may be normal or increased in
24-h urine collections due to the increased filtered load of
phosphorus and the phosphaturic actions of PTHrP (206,
207, 439, 454, 468, 470, 757), whereas morning spot
urines corrected for creatinine may show decreased values
(168). Multiple studies have calculated a significant increase in tubular maximum for phosphate (18, 156, 157,
206, 324, 468, 470, 558), which suggests that the kidneys
are actively conserving phosphorus despite the phosphaturic actions of PTHrP and overt phosphaturia. This may
imply the presence of an anti-phosphaturic factor during
lactation or low levels of FGF23.
The relative hypocalciuria and renal calcium conservation
persists during the postweaning interval in some studies
(207, 470, 558), whereas the tubular maximum for phosphorus declines to normal (206, 207, 470, 558).
3. Summary
Urine calcium excretion decreases and urine phosphorus
excretion may increase during lactation. These actions conserve calcium to provide it to milk while excreting unneeded
phosphorus generated from skeletal resorption and intestinal phosphorus absorption. An increase in the renal tubular
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The failure of intestinal calcium absorption to increase during lactation does not imply inadequacy of vitamin D intake. Clinical trials of high-dose vitamin D (4,000 – 6,400
IU daily) resulted in a very high mean 25OHD level of 160
nM (64 ng/ml), but there was no effect on breast milk calcium content (60, 402, 965).
This relative hypocalciuria is consistently accompanied by
phosphaturia in mice (330, 477, 478, 580, 994), which is
likely a demonstration of the physiological actions of
PTHrP to conserve calcium and excrete phosphorus. A
suckling-induced phosphaturia attributable to PTHrP has
also been demonstrated in rats, goats, cows, and sheep (56,
226, 907, 1003).
CHRISTOPHER S. KOVACS
maximum for phosphorus suggests the presence of an antiphosphaturic factor (or low FGF23) despite the increased
urine phosphorus excretion.
E. Increased Skeletal Resorption and
Osteocytic Osteolysis During Lactation
1. Animal data
One of the earliest demonstrations that the maternal skeleton
provides mineral during lactation involved fixing radioisotopes of calcium and strontium into maternal bone during
pregnancy. When the mice later lactated, isotopes appeared in
milk and the bodies of cross-fostered pups, with the amount
and timing of release of radioactivity suggesting that the last
calcium fixed into bone during pregnancy is the first to be
removed during lactation (706).
Objective evidence of bone resorption during lactation, and
variations in the extent of it among skeletal sites, has come
from measurements of bone turnover markers, histomorphometric and electron microscopy studies, ash weight,
bone mineral content by DXA, material properties of bone,
and bone structure by microCT.
Bone turnover markers are increased during lactation, with
bone resorption markers generally showing proportionately greater increases than in bone formation markers (35,
101, 330, 477, 478, 580, 956, 994). These alterations in
bone turnover markers can be prevented by treatment with
a bisphosphonate, OPG, and high-dose estradiol treatment
(37, 956).
Histomorphometric studies have shown that osteoclast-mediated bone resorption is increased primarily in trabecular
compartments during lactation in rats (271, 408, 629, 920,
972), beagles (300, 626), and mice (34, 194, 956). Increases
in osteoblast number, osteoblast surface, osteoid thickness,
osteoclast number, and resorptive surfaces are noted, with
the increases being more marked in the resorptive parameters (34, 194, 626, 956). The resorption is particularly
marked within the trabecular compartments of the vertebrae and the ends of the long bones, resulting in reduced
mineralized tissue volumes, thinning of trabeculae, and decreased trabecular number (34, 194, 626, 956). These histomorphometric changes could be completely prevented by
treatment with a bisphosphonate or OPG, and blunted by
Visible enlargement of osteocyte lacunae in certain human
pathological states was first described by Rigal and Vignal
in 1881 (763). This was reaffirmed by von Recklinghausen’s observations in 1910 (962), who proposed that osteocytes digest their surrounding bone matrix when stressed by
such conditions as severe osteomalacia and rickets.
Belanger and co-workers (67, 68) rediscovered this concept
in the 1960s, named it osteocytic osteolysis, and carried out
a detailed series of experiments that confirmed objective
loss of mineral and protein content from the enlarged osteocytic lacunae. Furthermore, osteocytic osteolysis was
shown to be inhibited by interventions known to suppress
bone resorption (calcitonin or a high-calcium diet), and
exacerbated by factors known to stimulate bone resorption
in rodents (low-calcium diet, parathyroid extract, secondary hyperparathyroidism, pregnancy) and humans (hyperparathyroidism and Paget’s disease) (67, 68). Belanger (67)
also recognized that the combined surface area of osteocyte
lacunae is ⬃10 times the trabecular bone surface in humans,
which thereby represents a significant storehouse of mineral
to be resorbed when needed.
Unfortunately, the concept that osteocytes can function like
osteoclasts was disbelieved by many investigators and
largely overlooked for decades. More recently, the Bonewald lab has revisited this concept and confirmed with modern techniques that osteocytes express osteoclast-related
genes and enzymes, and resorb the mineral and proteinaceous matrix that fills their lacunae (733, 734). Moreover,
they showed that this process occurs during lactation in
mice (733, 734, 998), and when it was blocked by conditional ablation of the PTH/PTHrP receptor from osteocytes, the amount of mineral lost during lactation was 50%
of normal (733). This finding may at first glance be an
indication that osteocytic osteolysis contributes ⬃50% of
the mineral that is resorbed from the skeleton during lactation, with the balance achieved by osteoclast-mediated resorption of trabeculae (FIGURE 5). However, loss of PTH
signaling in osteocytes also affects nuclear factor kappa-〉
ligand (RANKL) production and the number and activity of
osteoclasts, so osteoclast-mediated bone resorption may
have been reduced as well.
The objective loss of bone mass and mineral content from
the maternal skeleton has also been demonstrated by bone
ash weight measurements, analysis of the calcium content
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Multiple lines of evidence have demonstrated that the maternal skeleton is significantly resorbed during lactation to
provide calcium and other minerals to milk. Osteoclastmediated bone resorption is upregulated to resorb mainly
trabecular bone and endocortical surfaces, while osteocytic
osteolysis is upregulated to resorb mineral from cortical and
trabecular bone. Since lactation is a state of rapid bone loss,
bone turnover is uncoupled in favor of resorption.
fivefold physiological levels of estradiol (37, 115, 956). But
osteoclast-mediated bone resorption is not the only mechanism by which bone is resorbed to release calcium during
lactation. More recent histomorphometric and electron microscopy assessments have shown that osteocytic osteolysis
also occurs during lactation, in both trabecular and cortical
bone (904, 998). Because cortical bone makes up more than
90% of the skeleton, there is the potential for substantial
mineral to be mobilized through osteocytic osteolysis.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
of the ash, and radiological assessment of mineral content
by DXA. Lactating rats and mice normally resorb ⬃25–
35% of bone mineral, primarily from trabecular-rich vertebrae, to a lesser extent from trabecular bone of the femora
and tibiae, and much less from purely cortical bone (34, 35,
101, 176, 271, 296, 320, 330, 337, 392, 408, 477, 478,
486, 518, 580, 628, 629, 708, 740, 772, 920, 972, 991,
994). Ewes resorb bone preferentially from the vertebrae
and pelvis, resulting in reduced ash weight, while the limbs
and digits are relatively spared (69). The African green
monkey, which may resemble the human condition more
closely, loses ⬃20% of bone mineral density of the lumbar
spine during 20 wk of lactation (393). The greater losses of
mineral content from trabecular bone demonstrate the ability of osteoclasts to resorb mineral from bone that has the
greatest surface area. The proportionately smaller losses of
mineral from cortical bone may be due to osteocytic osteolysis.
In rats and mice, the material properties of bone are adversely impacted by the resorption of bone during lactation.
The strength, stiffness, and toughness of vertebrae, tibiae,
and femora are reduced while ductility is increased (489,
518, 580, 708, 709, 947).
MicroCT measurements of the lumbar vertebrae of lactating mice have revealed 30 –50% reductions in trabecular
bone volumes, 20% lower trabecular thickness, trabecular
perforations, reductions in tissue density, and progression
to more rodlike than platelike structures (34, 35, 566). The
tibiae and femora show similar changes in trabecular bone,
while cortical bone displays reductions in cortical thickness,
cross-sectional area, and tissue mineral density, and an increase in cortical porosity and endosteal perimeter (35, 101,
566, 580). However, another microCT study from the same
investigators found no significant change in cortical parameters in the femora except for an increase in tissue density (34),
500
while a peripheral QCT (pQCT) study found that lactation
increased tibial mid-shaft cortical width, area, periosteal circumference, and cross-sectional moment of inertia in frontal,
sagittal, and torsional planes (772). The latter two studies
suggest that the weight-bearing limbs have a compensatory
improvement in bone volumes and strength during lactation
that may offset the potential loss of strength induced by resorption of trabecular microarchitecture.
That resorption of bone during lactation is needed to support milk production has been confirmed by finding that a
low-calcium diet initiated at delivery causes greater skeletal
losses that can exceed 43% of trabecular bone mineral content in rats and mice (37, 271, 320, 350, 355, 708, 991).
Furthermore, nursing larger numbers of pups, which means
increased milk production, causes greater resorption of
bone in rats (320, 708). Bone strength assessments have
demonstrated that a low-calcium diet or nursing more pups
each leads to weaker bone at the end of lactation compared
with a normal-calcium diet or fewer pups (708). MicroCT
studies have confirmed that calcium restriction results in
greater reductions in bone volumes, trabecular number and
thickness, and tissue density (37). In ewes, a low-calcium
diet exacerbates the decline in ash weight (69). Treating
lactating rats with a bisphosphonate causes maternal hypocalcemia that is not seen in control rats (115), confirming
that skeletal resorption of mineral is required to maintain
maternal serum calcium in the setting of milk production.
However, this effect was not seen in one study of lactating
mice (956).
Conversely, a high-calcium diet may blunt but not prevent
bone loss during lactation, confirming that it is hormonally
programmed independent of maternal serum calcium or
dietary calcium intake. When lactating rats were studied on
diets ranging from 1.2 to 0.3% calcium, there was no
change in resorption of skeletal calcium (271, 318),
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FIGURE 5. Osteocytic osteolysis and osteoclast-mediated bone resorption. A: quiescent bone with an
osteocyte surrounded by its lacuna and canaliculi (gray halo and tentacles). B: lactation with an osteoclast
resorbing bone (resorption pit) while an osteocyte resorbs mineral from its lacuna and pericanalicular spaces
(surrounding white regions). C: post-weaning phase, during which osteoblasts restore bone in areas previously
resorbed by osteoclasts (hatched resorption pit), and osteocytes remineralize their lacuna and pericanalicular
spaces (surrounding black regions). Evidence from osteocyte-specific ablation of the PTH/PTHrP receptor in
mice suggests that bone resorption and osteocytic osteolysis may each account for ⬃50% of the mineral lost
from the skeleton during lactation. [From Kovacs and Ralston (501). Copyright 2015, with kind permission
from Springer Science ⫹ Business Media.]
CHRISTOPHER S. KOVACS
whereas when lactating mice were studied on a 2 versus 1%
calcium diet there was definite blunting of mineral content
loss (478). In lactating ewes, a high-calcium diet also
blunted the decline in ash weight (69). Bone loss was completely blocked with OPG treatment in mice, but even then
milk production remained normal, likely from upregulated
intestinal calcium absorption (37). It took the combined
effects of OPG treatment and a 0.01% calcium diet to disrupt lactation, resulting in maternal hypocalcemia and
deaths in 41% of the mothers by day 12 of lactation (37).
Lactational losses of bone mass were not affected by ovariectomy, adrenalectomy, or immediate pregnancy in rats
(32, 118). When ovariectomized, sham-operated, and intact lactating rats were each stressed by a 0.1% calcium
diet, there was no difference in the reduction of femoral ash
weight among the groups (32). Ovariectomy to create estradiol deficiency leads to modest and slow bone loss in
rodents, and not to the rapid loss that occurs during lactation (22, 34, 260). Conversely, treatment with estradiol to
achieve fivefold higher levels than normal during lactation
blunted bone loss and caused a small decline in milk calcium (956).
Several older studies tested whether calcitonin deficiency,
created through thyroidectomy followed by thyroid hormone replacement, causes greater loss of bone in lactating
goats and rats. The results were contradictory, with evidence of increased loss versus no difference between thyroidectomized animals and sham-operated controls (58,
392, 551, 900). These models were confounded by extrathyroidal production of calcitonin in the mammary
glands (131, 938) and pituitary (755), which was not appreciated at the time. A more recent study examined global
calcitonin and CGRP-␣ deficiency in Ctcgrp null mice and
found that bone loss increased twofold, accompanied by
Collectively these data show that PTH, calcitriol, VDR, low
or high estradiol, and adrenal hormones are not needed for
the normal mobilization of skeletal calcium during lactation, but loss of calcitonin can lead to more severe losses of
bone mass during lactation. Since ovariectomy in lactating
rodents does not increase the amount of bone lost, this
implies that estradiol is already low in lactating rodents or
that low estradiol is not a relevant stimulus for bone loss
during lactation. The comparatively slow bone loss after
ovariectomy alone indicates that low estradiol cannot account for the rapidity and extent of bone loss that occurs
during lactation. From earlier observations in some of the
surgical and vitamin D deficiency models, Brommage and
DeLuca (118) correctly proposed in 1985 that the putative
hypercalcemia of malignancy factor (PTHrP) might regulate bone resorption during lactation.
PTHrP and low estradiol have subsequently been shown to
play significant roles in increasing skeletal resorption during lactation. Conditional ablation of Pthrp from mammary tissue resulted in reduced bone turnover markers and
less bone loss during lactation (953). Conversely, ablation
of the calcium receptor from mammary epithelial cells resulted in reduced calcium content of milk, increased mammary gland and circulating PTHrP, markedly increased
bone resorption, and greater bone loss compared with normal (591). As noted previously, pharmacological treatment
with estradiol reduced bone loss during lactation but did
not obliterate it (956). The combined effects of ovariectomy
and continuous PTHrP infusions administered through a
mini-pump led to more bone loss in the lumbar spine and
femora than with either treatment alone in nonlactating
mice (34). However, the magnitude of bone loss in this
model (ovariectomy ⫹ continuous PTHrP infusion) was
less than what occurs during lactation (34), which could be
an indication that PTHrP and estradiol deficiency do not
completely explain lactational bone resorption. However,
the combination of ovariectomy with a continuous PTHrP
infusion provided no “drain” for calcium to escape the
mouse (there was no milk production), so there was no net
loss of calcium. Instead, systemic hypercalcemia resulted,
which likely had a dampening effect on further bone loss
(34).
Another recent study found that FGF21 circulates at high
levels in lactating mice (101). This is a counterregulatory
factor that stimulates gluconeogenesis and fatty acid oxidation during substrate deficiency, and a member of a subfamily that includes FGF23 (724). Intriguingly, Fgf21 null mice
do not resorb bone during lactation, as shown by microCT
of the proximal tibiae, histomorphometric analysis of femora, and a lack of increase in bone resorptive markers (101).
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The classic calciotropic hormones do not appear to be required for increased osteoclast-mediated bone resorption
and osteocytic osteolysis to occur during lactation. Parathyroidectomy in rats did not blunt the lactational fall in skeletal mineral content (319, 395), while lactating Pth null
mice lost the same bone mineral content from whole body,
spine, and hindlimb as their WT sisters (478). Vitamin Ddeficient and vitamin D-replete rats each resorbed a similar
amount of calcium from the femora in two separate studies
(362, 598). In one of these cross-sectional studies, the authors concluded that vitamin D-deficient rats lost twice as
much mineral compared with unmated rats, but compared
with their respective peak values at the end of pregnancy,
vitamin D-deficient and vitamin D-replete rats lost a similar
amount (598). Similarly, Vdr null mice and their WT sisters
lost the same amount of BMC from whole body, lumbar
spine, and hindlimb (296, 489). In a preliminary report, the
magnitude of bone loss during lactation in Cyp27b1 null
females is equivalent to that of their WT sisters (330).
histomorphometric evidence of increased osteoclast number and activity, and reduced osteoblast parameters (194,
992, 994) (see sect. VH).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
above normal due to the increased bone-specific fraction
(769, 1002). These values confirm that bone turnover is
significantly increased during lactation in women.
Finally, increased weight bearing has been theorized to reduce skeletal losses during lactation. This was assessed by
DXA and pQCT at multiple skeletal sites in rats forced to
stand erect to reach their food and water from time of
mating through the end of pregnancy, and then switched to
cages of normal height, compared with rats housed in cages
of normal height (772). Skeletal losses in the lumbar spine,
femora, tibiae, and whole body were unaffected by increased weight-bearing, except for a borderline statistically
significant and very small relative improvement in mineralization and strength parameters of the tibial diaphysis
(772).
One of the earliest longitudinal studies to assess skeletal
changes during lactation used a 241Am source and found
that the femoral shaft BMC declined 2.2% over the first 100
days of lactation (40). Since that time, multiple longitudinal
studies (observational studies and clinical trials) have been
carried using SPA, DPA, or DXA. A consistent decline in
BMD or BMC has been reported, with mean values ranging
from 3 to 10.0% after 3– 6 mo of lactation. The greatest
(5–10%) losses occur in the lumbar spine, with more modest (0 –5%) losses at less-trabecular-rich sites (hip, femur
and distal radius), and the smallest (0 –2%) changes at
purely cortical sites such as the whole body (9, 18, 109, 123,
124, 140, 165–168, 180, 193, 206, 251, 256, 371, 403–
405, 409, 412, 452, 457, 468, 470, 484, 505, 526, 533–
535, 560, 572, 574, 609, 621, 633, 635, 705, 723, 729,
764, 855, 857, 859, 1009). Collectively, these studies suggest that 6 mo of exclusive lactation will result in a median
loss of ⬃6 – 8% of BMD from the lumbar spine, with half or
less those amounts lost from the appendicular skeleton.
2. Human data
The available data from breastfeeding women confirm that
hormonally programmed resorption of the maternal skeleton occurs, similar to what has been demonstrated in rodents, sheep, goats, and primates. Careful metabolic studies
have shown that women are in a markedly negative calcium
balance while breastfeeding, especially during the interval
of greatest milk production, and despite any supplemental
calcium intake (253, 419).
That the maternal skeleton contributes mineral to breast
milk has been inadvertently confirmed by Techa River residents in Russia, who released 90Sr into breast milk years
after their exposure from ingestion of contaminated river
water (924). Observational data and mathematical models
predict that the amounts of 90Sr, 45Ca, 131I, and other isotopes in breast milk will be highest when maternal exposure
occurs in late pregnancy or while lactating, confirming that
dietary intake remains a significant contributor to breast
milk (1, 366, 851, 924).
There are no histomorphometric data from lactating women; instead, serial measurement of bone turnover markers,
bone density, and bone structure by high-resolution pQCT
(HR-pQCT) has been carried out.
Bone resorption markers (NTX, CTX, tartrate-resistant
acid phosphatase, deoxypyridinoline/creatinine, hydroxyproline/creatinine) are elevated severalfold during lactation,
above the levels attained in the third trimester and in controls (9, 123, 124, 156, 157, 206, 207, 251, 454, 468, 470,
572, 695, 764, 805, 859, 1002, 1009). Bone formation
markers (P1NP, bone-specific alkaline phosphatase, osteocalcin) have been normal in a few studies (207, 769), but
generally are also high during lactation, and increased over
third trimester values or controls (9, 123, 124, 156, 157,
206, 251, 409, 454, 468, 470, 572, 695, 764, 805, 859,
1002, 1009). Total alkaline phosphatase loses the placental
fraction at delivery and falls markedly, but may remain
502
It is important to emphasize that these are mean changes
from the cohorts of each study; responses of individual
women to lactation can vary from a small gain to a 20%
decline in the lumbar spine BMD (405, 705). Some women
start pregnancy with normal BMD but reach an osteoporotic level (⫺2.5 SD) at the spine or hip during lactation
(705). Some observational studies have included postpartum controls who do not breastfeed; these women do not
lose lumbar spine BMD but may show small (0 –2%) but
statistically significant gains in BMD over the postpartum
interval, suggesting a recovery from small losses incurred
during pregnancy (9, 140, 371, 412, 451, 505, 572, 633).
Women who breastfeed for more prolonged periods, such
as a year or more, may experience even greater bone loss
(379, 857, 860). However, this should be mitigated by the
infant consuming solid foods by 6 mo of age and a reduction in the amount of milk produced. On the other hand, a
professional “wet nurse” can have high volumes of milk
output that are sustained for long intervals (419, 583, 838),
so ongoing bone loss seems inevitable. However, no bone
density data have been reported for such women.
HR-pQCT has been used in very few studies to date, and the
only sites that can be assessed by this technology are peripheral appendicular sites such as the radius and distal femur,
sites that lose much less mineral content than the lumbar
spine. These studies have confirmed 0 –2% reductions in
trabecular thickness, and cortical thickness and volume,
with the losses being greater in those who lactate longer (84,
109). Trabecular number and volumetric BMD appeared to
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The mechanism that leads to the failure to resorb bone is
unknown. It may be due to altered energy metabolism or
some interaction with PTHrP, which was not measured.
CHRISTOPHER S. KOVACS
increase, which may be an artifact from trabecularization of
cortical bone (84, 109).
Peripheral ultrasound is not a useful technique to assess
bone loss during lactation. Although DXA and HR-pQCT
have confirmed that bone mass declines significantly during
lactation, ultrasound of the os calcis or midtibial shaft
showed no changes (533, 917, 1015).
Two small studies by the same investigators in Spain reported contradictory results when lactating adolescents and
adults were compared. The first reported that adolescents
and adults lost a similar amount of BMD during lactation
but had recovered it fully by 9 mo postpartum (159). The
second study reported that adolescent lumbar spine BMD
increased by 9% at 3 mo and 15% by 12 mo postpartum,
compared with adult women who lost only 2% of lumbar
spine BMD at 3 mo and achieved a net increase of 4% by 12
mo postpartum (798). The second study implies that adolescent accrual of bone mass is not impaired by simultaneous lactation, but the marked differences between the two
studies are unexplained. Lactation in adolescents has been
an ongoing concern with regard to poor dietary intake of
calcium, and potential interference in reaching peak bone
mass (see sect. IVG).
The studies in adolescents indicate that a higher calcium
intake prevents bone resorption in the radius during lactation, a site that normally shows proportionately little resorption during lactation. Several blinded, randomized in-
Conversely, low calcium intakes (⬍300 mg/day) do not
appear to increase maternal bone loss or markers of bone
resorption during lactation, nor do they alter breast milk
calcium content (728 –731). These findings are consistent
with most of the milk calcium content programmed to come
from resorption of the maternal skeleton, such that calcium
intakes ranging from low to high do not affect these parameters. However, greater intensity (number of feeds per day)
and exclusivity (all of baby’s nutrition comes from milk) of
lactation, which are indicators of increased breast milk output, lead to greater loss of maternal bone mass (535).
Intervening to correct calcium intake in women who habitually consume low calcium may be detrimental. A randomized intervention administered 1,500 mg calcium or placebo during pregnancy but not postpartum to Gambian
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Few studies have looked at lactating adolescents. A 15%
decrease in radial BMC over 16 wk of lactation was found
in teenaged mothers whose calcium intake was below the
recommended amount, whereas lactating adults showed no
change in radial BMC; the lumbar spine was not assessed
(166, 167). A follow-up study of lactating adolescents
found that a calcium intake of 900 mg daily led to a 10%
loss of radial BMC over 16 wk compared with no loss when
1,600 mg calcium was consumed; lactating adults who consumed 1,500 mg calcium daily also lost no radial BMD
(164). A more recent study of lactating adolescents (mean
age 16 yr) found no significant changes in BMD of the
lumbar spine, femoral neck, and total hip by 6 mo of lactation with a calcium intake of 1,200 mg daily (590). Another
study of lactating adolescents (mean age 17) found that
randomization to a supplement containing 500 mg calcium
and 200 IU vitamin D resulted in a higher lumbar spine
BMD by 20 wk of lactation compared with placebo; however, women receiving the supplement had significantly reduced their breastfeeding frequency and intensity, and
twice as many of them had resumed menses, compared with
the placebo group (250). These differences mean that the
women in the treatment arm would have lost less bone due
to reduced breast milk output and recovery from low estradiol, and not necessarily as a direct result of the supplement.
terventional studies have shown that the lumbar spine and
hip are preferentially resorbed during lactation such that
taking a 1 g calcium supplement in addition to usual intake
will not reduce the amount of bone lost. One study compared 1,800 to 800 mg calcium intake daily and the lumbar
spine declined ⬃4% over 6 mo of lactation with no difference between the groups (452). A second compared with
2,400 to 1,200 mg calcium daily, and the lumbar spine,
radius, and ulna declined ⬃6% in both groups (206). A
third study compared 1,400 to ⬍300 mg calcium, and the
intervention caused an increase in urinary calcium excretion but neither group lost radial BMD or experienced a
change in markers of bone resorption during up to 18 mo of
lactation (the spine was not assessed) (729, 730). A fourth
also used a 1 g supplement but did not measure dietary
calcium intake; the women lost ⬃4% of lumbar spine BMD
with no difference between the groups (723). In two observational cohort studies in which the lumbar spine declined
4% during 3 mo of lactation (535) and 6% during 6 mo of
lactation (484), the relative losses were not affected by maternal calcium intake. One of these cohort studies found
that the skeletal losses were inversely proportionate to
breast milk output and, thereby, maternal calcium losses
(535), whereas the other noted a significant correlation to
duration of lactation and time to resumption of menses
(484). A randomized study using ultrasound of the os calcis
compared 2,400 with 1,200 mg calcium and noted a 15%
reduction in urinary NTX, but no change in apparent bone
loss after 1 mo of lactation (post hoc analyses suggested that
higher compliers had a significant increase in SOS of the
heel) (274). Another randomized study compared calcium
intakes of 1,850 to 850 mg, and although PTH and calcitriol were lower in the calcium-supplemented women,
there was no effect of calcium supplementation on bone
turnover markers during 6 mo of lactation (454). Overall,
the results of these randomized interventions and cohort
studies indicate that increased skeletal resorption seems to
be programmed during lactation and, unlike rodents, not
suppressible by high calcium intakes.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
women with habitual intakes of ⬃350 mg calcium. There
was no effect on bone density at any skeletal site at the end
of pregnancy, but during 12 mo of lactation, the women
who had received the calcium supplement during pregnancy
more than doubled their losses in BMD of the lumbar spine,
total hip, and distal radius and had greater increases in bone
turnover markers (439). A followup study showed that
these effects persisted long term, including through a subsequent pregnancy and lactation cycle (441). These results
suggest that Gambian women are beneficially adapted to
their low calcium intakes, while use of a calcium supplement during pregnancy disrupts this adaptation to create an
adverse response when the supplement is subsequently
withheld during lactation.
Deficiency of estradiol contributes to bone loss during lactation, but the extent to which it does so is uncertain. Some
analyses have suggested that low estradiol, and a longer
duration of lactational amenorrhea, predict the speed and
magnitude of bone loss during lactation (140, 301, 409,
451, 484, 723, 857, 863, 1025). Earlier resumption of menses or use of an oral contraceptive are associated with reduced skeletal losses, while bone turnover markers normalize after recovery of menses and bone loss at the lumbar
spine slows or begins to reverse (140, 451, 484, 723, 764,
863). On the other hand, in another study there was no
difference in calciotropic hormones, bone turnover markers, bone density, and intensity of lactation between amenorrheic and eumenorrheic women during lactation, suggesting that resumption of menses does not predict reduced
bone loss during lactation (572). Bone density has also con-
It is difficult to analyze the independent effects of low estradiol on bone turnover during lactation. More intense lactation causes more breast milk output and bone loss, but
more intense lactation is also associated with lower estradiol and prolonged amenorrhea. The impact of isolated low
estradiol is that it causes 1–2% annual losses of BMD in
recently menopausal women (331), but the older ages of
these women may not reflect what happens to reproductive
age women with low estradiol.
In this context the effects of GnRH analog-induced estradiol deficiency in reproductive-age women are illuminating. This treatment induces marked estradiol deficiency,
which can be beneficial to treat endometriosis, uterine
leiomyomata, and premenstrual syndrome. However, its
effects differ from what is observed during lactation
(TABLE 3). Six months of acute estradiol deficiency causes
2– 4% reductions in BMD of the spine with no losses at
cortical sites (288, 415, 640, 657, 684, 696, 758, 762,
781, 891, 942). This is accompanied by increased serum
calcium and phosphorus (265, 288, 640, 657, 781), increased fractional excretion of calcium (265, 288, 640,
657, 781, 891, 942), and low PTH and calcitriol (265,
657, 781). In contrast, 6 mo of lactation typically causes
greater loss of BMD from both trabecular and cortical
sites, low PTH but normal calcitriol, and reduced fractional excretion of calcium.
In summary, clinical data are consistent with low estradiol playing a permissive role in bone loss during lactation, but with the more excessive bone loss and other
changes in calcium metabolism likely contributed to by
high circulating levels of PTHrP (FIGURE 6). This would
explain the increased bone turnover markers, accelerated
bone loss, and reduced urinary calcium excretion, while
the normal calcitriol and intestinal calcium absorption
may be explained by PTHrP’s apparent reduced efficacy
at stimulating these relative to PTH. Consistent with this,
higher plasma PTHrP predicted greater loss of BMD at
Table 3. Comparison of the effects of 6 months of lactation versus 6 months of GnRH agonist therapy
Serum calcium
Serum phosphorus
PTH
Calcitriol
24-h urine calcium
Urinary Ca/Cr
Bone resorption markers
aBMD changes (DXA)
Recovery of aBMD at 1 yr
504
Lactation
GnRH Agonist
Increased
Increased
Decreased
Normal
Decreased
Decreased
Increased
5–10% at trabecular-rich sites; less at cortical
Complete in most
Increased
Increased
Decreased
Decreased
Increased
Increased
Increased
2–4% at trabecular-rich sites
Incomplete in most
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Weight-bearing exercise has been proposed to reduce the
amount of bone resorbed during lactation. A small randomized trial of 20 lactating women found a small benefit on
lumbar spine BMD (4.8 vs. 7.0% loss in the usual activity
group), but no effect on whole body or total hip BMD
(574). However, a subsequent study by the same investigators found no beneficial effect of exercise on any skeletal site
(193). A cohort study comparing exercising to sedentary
women also showed no impact of exercise on lactational
BMD losses (560).
tinued to decline in women who breastfed for an extended
period after their menses resumed (301, 857).
CHRISTOPHER S. KOVACS
FIGURE 6. Schematic depiction of the effects of acute,
isolated estradiol deficiency from GnRH analog therapy
versus lactation. Acute estradiol deficiency increases
skeletal resorption and the serum calcium; PTH becomes suppressed and renal calcium losses increase.
During lactation, PTHrP (secreted by the breast) and low
estradiol increase skeletal resorption and raise serum
calcium, but the resorbed calcium is directed into breast
milk. Although PTH is suppressed during lactation, renal
calcium conservation occurs, likely stimulated by PTHrP.
[Adapted from Kovacs and Konenberg (499). Copyright
1997 The Endocrine Society. Permission conveyed
through Copyright Clearance Center, Inc.]
3. Summary
Bone turnover is markedly increased during lactation,
but uncoupled to cause net resorption. Mean losses of
25–35% occur in the lumbar spine during 3 wk of lactation in rodents, while 5–10% losses at the lumbar spine
are induced by 6 mo of breastfeeding, with smaller losses
at other skeletal sites. Bone loss results from a combination of osteoclast-mediated bone resorption and osteocytic osteolysis; how much each contributes to the decline in BMD during lactation is uncertain. The very
modest to zero change in BMD at cortical sites in lactating women may mean that osteocytic osteolysis is less
important in humans compared with osteoclast-mediated
bone resorption. Bone loss during lactation is driven by
the combined effects of low estradiol and increased circulating PTHrP. Animal data support that both of these
factors are important in regulating skeletal homeostasis
during lactation. Conversely in women, the more modest
effects of isolated low estradiol, ongoing bone loss despite resumption of menses or use of an oral contraceptive, and the effects of lactational release of PTHrP to
normalize hypoparathyroidism (see sect. VD) and induce
pseudohyperparathyroidism (see sect. VF) may all point
to PTHrP having a greater effect on regulating skeletal
metabolism during lactation.
F. Breast-Brain-Bone Circuit Controlling
Bone Metabolism During Lactation
The preceding animal and human data are consistent
with an important physiological interaction and crosstalk among breast, brain, and bone during lactation. The
breast may be the central driver of this interaction. The
summary model (FIGURE 7), which also draws on data
discussed in sections IV and V, is as follows.
High prolactin and suckling-induced reflex arcs each act
on the GnRH pulse center in the hypothalamus to suppress the pituitary gonadotropins [luteinizing hormone
(LH) and follicle stimulating hormone (FSH)] and, in
turn, ovarian function. This leads to low estradiol levels
in early lactation that may persist or normalize despite
ongoing lactation. Low estradiol upregulates RANKL
and downregulates OPG in osteoblasts; consequently,
differentiation, recruitment, and function of osteoclasts
are stimulated, thereby resulting in increased bone resorption. Suckling, prolactin, and low estradiol also
stimulate mammary epithelial cells to produce PTHrP.
While most of the PTHrP is released into milk, some of it
is released into the maternal bloodstream, both continuously and with additional surges induced by suckling.
Increased PTHrP synergizes with the effects of low estradiol to stimulate osteoclast-mediated bone resorption
and osteocytic osteolysis. The calcium receptor may
modulate the release of PTHrP from breast tissue somewhat to reduce the likelihood that milk production produces systemic hypocalcemia; however, it is clear from
some clinical cases that mammary tissue PTHrP production may be autonomous.
That mammary tissue plays a central role in regulating
skeletal physiology during lactation has been made most
clear by the finding that mammary-specific ablation of
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the lumbar spine and femoral neck in breastfeeding
women, after adjusting for low estradiol, PTH, and intensity of breastfeeding (863). Higher plasma PTHrP in
turn was predicted by more intense lactation, higher prolactin, and lower estradiol (863). Some studies of men
and nonlactating women have found that hyperprolactinemia due to pituitary adenomas is associated with
elevated PTHrP, and that increased PTHrP predicts a
higher serum calcium, and lower PTH and lumbar spine
BMD (497, 880).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
PTHrP reduces bone turnover and loss, while mammaryspecific ablation of the calcium receptor leads to markedly increased mammary expression of PTHrP, higher
systemic PTHrP levels, increased bone turnover, and
greater net bone loss (591, 953). Suckling induces production and release of PTHrP, whereas milk stasis causes
the entire process to shut down.
Lactating mammary epithelial cells also produce high
concentrations of calcitonin, which may act locally to
reduce the calcium content of milk or inhibit PTHrP, as
suggested by Ctcgrp null mice (see sect. VH). Calcitonin
also has systemic actions to suppress osteoclast-mediated
bone resorption and osteocytic osteolysis in bone. Furthermore, calcitonin may inhibit the pituitary lac-
506
totrophs and reduce the release of prolactin, which in
turn would lessen ovarian suppression and inhibit production of PTHrP. A conditional deletion of calcitonin
from mammary tissue is needed to determine its role
during lactation.
Additional players in the cross-talk among breast, brain,
and bone include oxytocin and calcitonin, and there may
be others. In addition to its critical role in stimulating
milk ejection, oxytocin may affect the differentiation and
function of osteoblasts and osteoclasts. Serotonin may
stimulate the production of PTHrP and have other direct and indirect effects on bone metabolism during
lactation.
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FIGURE 7. Breast-brain-bone circuit controls lactation. Suckling and prolactin (PRL) both inhibit the hypothalamic gonadotropin-releasing hormone (GnRH) pulse center, which in turn suppresses the gonadotropins
[luteinizing hormone (LH) and follicle-stimulating hormone (FSH)], leading to low levels of the ovarian sex
steroids [estradiol (E2) and progesterone (PROG)]. Prolactin may also have direct effects on its receptor in bone
cells. PTHrP production and release from the breast are stimulated by suckling, prolactin, low estradiol, and
the calcium receptor. PTHrP enters the bloodstream and combines with systemically low estradiol levels to
markedly upregulate bone resorption and (at least in rodents) osteocytic osteolysis. Increased bone resorption
releases calcium and phosphate into the bloodstream, which then reaches the breast ducts and is actively
pumped into the breast milk. PTHrP also passes into milk at high concentrations, but whether swallowed
PTHrP plays a role in regulating calcium physiology of the neonate is uncertain. In addition to stimulating milk
ejection, oxytocin (OT) may directly affect osteoblast and osteoclast function (dashed line). Calcitonin (CT) may
inhibit skeletal responsiveness to PTHrP and low estradiol given that mice lacking calcitonin lose twice the amount
of bone during lactation as normal mice. Not depicted is that calcitonin may also act on the pituitary to suppress
prolactin release, and within breast tissue to reduce PTHrP expression and lower the milk calcium content (see
text). [Adapted from Kovacs (493). Copyright 2005, with kind permission from Springer Science ⫹ Business
Media.]
CHRISTOPHER S. KOVACS
G. Bone Formation and Skeletal Recovery
Post-Weaning
1. Animal data
After the pups are weaned, the maternal skeleton undergoes
a rapid phase of remineralization. Bone turnover continues
to be increased over nonpregnant values, but it is now uncoupled in the opposite direction from lactation, favoring
net bone gain.
The extent of skeletal recovery has been documented in
several ways.
Serial studies using DXA, and cross-sectional studies using
skeletal ash weight, indicate that rodents restore skeletal
mineral content within 2– 4 wk after weaning (35, 362,
994). Black Swiss and C57BL/6 mice regain their prepregnancy BMC in whole body, lumbar spine, and hindlimb
within 14 days of weaning (296, 477, 478, 580, 992, 994),
whereas CD1 mice regain their prepregnancy BMD by 28
days after weaning, but remain below the values for agematched virgin mice (35, 37). The most remarkable change
occurs in Ctcgrp null mice, which lose 55% of trabecular
(lumbar spine) BMC and 30% of cortical (whole body and
hindlimb) BMC during lactation, but restore this within 18
days of weaning, taking just 4 days longer than their WT
sisters that experienced half the losses (992, 994).
Histomorphometry has revealed increased osteoid seams
covering 50 –70% of bone surfaces, while dynamic histomorphometry has shown widely spaced tetracycline labels
(107, 194, 628, 947). The combination of increased osteoid
surface and widened seams corresponds to a markedly in-
Microradiographs, scanning electron microscopy, and microCT have been used to assess recovery of microarchitecture, which have revealed normalization at some sites, and
permanent alterations at others. The vertebrae fully recover
their microarchitecture, including bone volumes, trabecular
number and thickness, mineralization, stiffness, and reversion from a rodlike back to a platelike structure (35, 566).
The femora and tibiae significantly improve trabecular
number and thickness, bone volumes, mineralization, cortical thickness, porosity, and stiffness (35, 106, 107, 355,
566, 628, 947, 994). In some studies, the values in tibiae
and femora become equivalent to age-matched virgins (35,
628), whereas in other studies there were permanent reductions in these parameters compared with virgin mice or
prepregnancy values (566, 628). Recovery is full or better
when the end-of-pregnancy value is the baseline measurement (107). There are also region-specific differences in the
degree of recovery, since in rats the proximal and distal
femora regained the mineral content of nulliparous controls
while the femoral midshaft did not completely recover
(355), and there was a permanent reduction in the trabecular content of the femora (355, 628).
Intriguingly, in some studies the cross-sectional diameters,
cortical perimeters, and volumes of the tibiae or femora
were significantly greater at post-weaning compared with
prepregnancy, or post-weaning compared with agematched controls (106, 947, 994). Such changes in the macro-architecture of bone, especially the cortical diameter,
will increase the cross-sectional and polar moments of inertia, and, thereby, the breaking strength in bending and
torsion (FIGURE 8). This may contribute to maintenance of
bone strengths of the tibiae and femora despite any failure
to fully recover the trabecular microarchitecture (477).
Other biomechanical testing has shown vertebral and femoral strength and stiffness parameters to improve significantly in rats by 8 wk after weaning, and to equal the values
of nulliparous controls (947).
The rapidity and relative completeness of this post-weaning
phase of bone recovery has prompted numerous approaches to try to identify the factors that stimulate bone
formation and post-weaning recovery. Severely vitamin Ddeficient rats improve bone mass and architecture after lac-
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When weaning is forced by the sudden removal of pups
before the natural end of lactation, within 24 – 48 h there is
widespread apoptosis of osteoclasts that prompts a fall in
osteoclast number and activity below prepregnant values, a
marked decrease in RANKL and RANK expression, and a
substantial increase in osteoblast precursors, osteoblast
number, osteoid surface, and bone formation rate (35, 107,
194, 627). Transient hypercalcemia can occur over the first
several days due to continued increased levels of bone resorption and intestinal calcium absorption despite loss of
milk output (35, 396, 718), during which time PTH and
calcitriol fall and calcitonin surges (35, 627, 718). Bone
resorption markers decline rapidly while bone formation
markers increase (35, 477, 478, 580, 956, 992, 994). Osteocytic osteolysis also ceases, but now osteocytes express
osteoblast-specific genes, tetracycline-labeled bands become evident in their lacunae, and the matrix is restored to
its prior mineral content (FIGURE 5) (733, 734). This anabolic activity of osteoblasts and osteocytes is sustained for
several weeks, as a result of which bone strength, mineralization, and microarchitecture improve and may reach
prepregnancy values or better.
creased bone formation rate. Bone volumes, trabecular
thickness, and mineral content are recovered within 2– 4 wk
of weaning in the mouse and 4 – 8 wk of weaning in the rat
(107, 194, 628, 947). Detailed histomorphometric assessment of vertebrae and cortical bone of femora at 8 wk after
weaning in rats showed that bone formation rates and mineralizing surfaces on trabecular, periosteal, and endosteal
surfaces had declined to age-matched nulliparous values,
while bone mass, cortical thickness, and cortical area had
increased to virgin values (947).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
A
pregnant. However, measurements of intestinal calcium absorption have not been done in mice during this interval.
B
Ro
Ro
Ri
Ri
tation, appearing to regain the amount that was lost during
lactation (628); however, an earlier study from the same
investigators suggested that there was no recovery of ash
weight or calcium content (362). Vdr null mice and
Cyp27b1 null mice display osteomalacia and reduced bone
mass before pregnancy, but after lactation they upregulate
bone formation markers and increase BMC substantially to
values 40 –50% higher than prior to pregnancy (296, 330).
Pth null mice have low bone turnover prior to pregnancy,
but upregulate bone formation markers normally during
post-weaning, and increase BMC after lactation to values
20% higher than prepregnancy (478). Ctcgrp null mice lose
55% of skeletal mineral content during lactation but fully
regain it post-weaning (194, 992, 994). Osteoblast-specific
ablation of Pthrp results in an osteoporotic phenotype in
adult mice, but these obPthrp null mice lactate normally
and have full recovery of bone mass afterward (477). Collectively these studies indicate that PTH, osteoblast-derived
PTHrP, vitamin D, VDR, calcitriol, and calcitonin are not
required full remineralization of the maternal skeleton to be
achieved after lactation (194, 296, 477, 478, 992, 994).
Adequate calcium is required, since a low-calcium diet prevented skeletal recovery in rats, whereas normalizing the
diet 3 wk later allowed normal recovery to occur (355). An
increased rate of mineral absorption is evidently not required since both intestinal calcium and phosphorus absorption are normal during post-weaning recovery in rats
(93, 360). The marked increase in bone mass of Vdr nulls
and Cyp27b1 nulls (296, 330) may imply that intestinal
calcium absorption is increased, since these mice have a
reduced, rachitic bone structure on the same diet when non-
508
In rats that are not permitted to lactate, normalization of
BMD and skeletal microarchitecture (as assessed by histomorphometry) has been observed within a week of parturition (408). This is evidence of skeletal recovery from losses
incurred during pregnancy. Conversely, no post-weaning
improvement resulted after lactational bone loss was completely blocked by treatment with OPG (37). This may simply mean that if no bone is lost during lactation, then there
is nothing to restore, and no signal is sent to upregulate
bone formation.
2. Human data
Women also undergo a substantial increase in bone mass
and mineralization after weaning, evidently reversing the
losses that transiently occur during lactation. There are no
histomorphometric studies or direct tests of bone strength
in women, as there are in the rodent models. Instead, skeletal recovery after lactation has largely been determined by
longitudinal assessment of bone mass and mineralization
during lactation and post-weaning by DXA at the total
body, lumbar spine, and hip. More recently, changes in
microarchitecture by HR-pQCT have been assessed at peripheral sites. Many dozens of studies have examined the
effect that lactation has on predicting future risk of low
bone density, osteoporosis, or fracture.
Analysis of women who inadvertently ingested isotopes
while living near the Techa River in Russia revealed that
women who were pregnant and lactated during the time of
exposure had a greater content of 90Sr in the maternal skeleton years after the exposure, compared with women living
in the region who were pregnant prior to the exposure or
had never been pregnant (923). This result is compatible
with increased uptake of isotope into the maternal skeleton
during post-weaning recovery.
The available DXA data suggest that lactational loss of
bone density is completely reversed by 12 mo after weaning
in most women (140, 168, 206, 379, 403– 405, 412, 452,
457, 470, 484, 505, 532, 572, 635, 705, 723, 729, 764,
856, 857, 860, 1009), whereas recovery has been incomplete at some skeletal sites when assessed at 6 mo or less
after weaning the baby (9, 123, 124, 168, 403– 405, 457,
484, 532, 633, 635, 1009). A small longitudinal study of 22
women found a marked loss of 8% in the distal radius that
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FIGURE 8. Post-recovery increase in cross-sectional diameter improves skeletal resistance to bending and torsion. A and B represent
hypothetical cross-sections of circular bone shafts that have the
same cortical area or bone mass. The ability to resist bending in a
hollow cylinder is related to the moment of inertia I ⫽ ½m(Ri2 ⫹ Ro2),
where m is the mass of the cylinder and Ri and Ro are measurements of the inner and outer radii, respectively. Ability to resist
torsional stress is related to the polar moment of inertia J ⫽
␲(Ro4 ⫺ Ri4)/32. Therefore, despite its thinner cortical shell, the
increased radius in B will result in significantly increased moments
of inertia, and resistance to bending or torsional stresses, compared with the thicker cortical shell in A. In this manner, an
increase in cross-sectional diameters of the long bones after
weaning will increase bone strength and may compensate for
resorbed trabeculae that have not been replaced. [From Kovacs
and Ralston (501). Copyright 2015, with kind permission from
Springer Science ⫹ Business Media.]
Theoretically, increased weight bearing during this anabolic phase might lead to a greater increment in bone mass.
In a preliminary report, rats forced to stand upright to reach
their food during lactation and 6 wk of post-weaning
showed significantly higher femoral BMD and a trend toward increased tibial bone volumes, compared with rats
housed in normal cages (829).
CHRISTOPHER S. KOVACS
was still reduced 5% by 12 mo after weaning (609), which
suggests that the radius is slower to recover BMD. Note that
these studies report the mean responses of a cohort; the
response of individual women will vary, such that some
women may not return to baseline after lactation, while
others may end up with a BMD even higher than prior to
pregnancy. Recovery is fast enough that women who
breastfeed for 6 mo or more and have a second pregnancy
within 18 mo do not have reduced BMD of the spine or hip
at the end of the second pregnancy (534, 860).
HR-pQCT of the radius and ultradistal femur reveal recovery of trabecular microarchitecture and cortical parameters
in women who lactate for shorter intervals, but incomplete
recovery in women who lactate for longer (84, 109). However, follow-up in these studies was for less than 6 mo after
lactation ended for women who lactated for a longer duration, which is not sufficient time for recovery or to determine if permanent changes in structure resulted. Similar to
studies in animals, some clinical studies have found that
the cross-sectional diameter of the femur increased after
lactation or post-weaning recovery, and that cortical
bone area is restored or increased (869, 986). An increase
in bone volumes will improve bone strength and may
compensate for any permanent loss of trabecular microarchitecture (FIGURE 8).
Hip structural analysis of data from DXA scans provides
direct measurements of femoral geometry and derived measures of femoral strength. A longitudinal study obtained
these measurements at 2 wk, 6 mo, and 12 mo postpartum
in lactating women, while similar timing of measurements
were carried out in nonpregnant, nonlactating women
(537). In lactating women there was an ⬃3% decrease in
cross-sectional area, a 1.7% decline in cortical thickness, a
2.1% decrease in section modulus (bending strength), and a
2.3% increase in buckling ratio (instability) by 6 mo of
If a permanent reduction in BMD or skeletal strength were
to occur from lactation, then lactation should be a strong
risk factor for low BMD or fracture in women of all ages.
However, over five dozen epidemiologic studies of pre-,
peri-, and postmenopausal women have found a neutral
effect (16, 38, 63, 158, 203, 214, 215, 290, 292, 299, 341,
356, 368, 379, 383, 397, 444, 445, 448, 463, 481, 506,
509, 541, 547, 611, 619, 625, 636, 648, 683, 700, 761,
828, 845, 846, 861, 864, 865, 869, 879, 934, 935, 944,
951, 969, 1020) or a protective effect (25, 27, 71, 83, 144,
169, 212, 244, 279, 327, 365, 416, 421, 482, 507, 700,
804, 833, 879, 986, 1018) of lactation on peak bone mass,
BMD, and fracture risk. This includes a study in which
extended duration of breastfeeding per child conferred a
progressively greater protection against hip fractures (421).
A study of 1,852 twins and their females relatives, including
83 twins who were discordant for pregnancy and lactation,
found no effect of breastfeeding history on BMD or BMC
between twins, but that parous women who had breastfed
had higher BMC and BMD than parous women who had
never breastfed (700). A study of 30 women who had had at
least six pregnancies, and breastfed each child for at least 6
mo, found no effect of lactation on BMD (379).
A previously cited NHANES study of 819 women ages
20 –25 yr found that women who had breastfed as adolescents had higher bone mass than those who had not breastfed, indicating a protective effect (169). This study is particularly informative because of the shorter interval of time
elapsed between lactation and measurement of BMD, compared with most of the dozens of studies that examined
women decades later. It also suggests that adolescent pregnancy does not adversely impact the achievement of peak
bone mass, as previously feared.
There are, of course, a few contrary studies that suggest
lactation predicts lower BMD (261, 336, 352, 472, 559,
686, 770, 946, 971, 973) or increases the risk of fracture
(97, 525, 559, 699). Smoking may cause breastfeeding to
have a negative effect on BMD that is not seen in nonsmokers who breastfed (448).
Fractures do occur rarely during lactation while bone mass
and strength are temporarily reduced, so these lactational
losses of bone structure are not always benign in the short
term (see sect. VA). Overall, it appears that any harm of
lactational bone loss is transient in most women, such that
lactation generally confers a long-term neutral or protective
effect on future risk of fracture. The fewer studies suggesting a long-term adverse effect may point to ethnic or other
differences among the cohorts that remain to be explained;
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A study from China took a different approach of doing a
baseline BMD reading in 40 women with habitually low
calcium intakes, who had either stopped lactating or were
still lactating but had recovered their menses. They were
randomized to receive 600 mg of calcium versus placebo,
and subgrouped by genotyping for a VDR polymorphism
(FokI) (1012). A second BMD was obtained a year later and
revealed a net increase in bone mass with additional benefits
attributable to calcium supplementation and the FF genotype. BMD of the lumbar spine increased by as little as
7.9% in the placebo group with ff genotype to as great as
17.4% in the FF genotype receiving calcium, while the femoral neck BMD increased 4.4% in the ff genotype on placebo versus 14.7% in FF genotype on calcium. This study
provides confirmation that a substantial increase can occur
in BMD post-weaning. The suggested additional benefits of
calcium supplementation and the VDR polymorphism require independent confirmation.
lactation. These changes reversed by ⬃6 mo after lactation
ceased, during which no changes were seen in the controls
(537).
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
for example, low calcium intake or vitamin D deficiency
may impair skeletal recovery post-lactation.
It is evident from the many longitudinal DXA studies that
women who lactate for shorter intervals recover sooner,
and this is also likely because they lost less bone.
A small but statistically significant benefit on bone mass
gained during post-weaning was conferred by randomization to a 1 g calcium supplementation versus placebo, despite no beneficial effect of the supplement during lactation
(452). No study has prospectively examined the potential
benefit of weight-bearing exercise to increase BMD gains
after weaning. However, in retrospective studies of premenopausal women in which breastfeeding conferred a
higher lumbar spine BMD, increased weight-bearing also
conferred a significant, independent benefit (327, 1018).
No other studies have examined factors that may stimulate
post-weaning skeletal recovery. As noted earlier, one study
found a modest increase in intestinal calcium absorption
during post-weaning (453), whereas another study found
no significant increase (764).
3. Summary
Extensive animal data and human data indicate that bone
turnover is also increased during the post-weaning phase,
but uncoupled in the reverse direction from lactation to
favor bone formation. The maternal skeleton undergoes
substantial improvements in bone mass, mineralization,
and strength. Rodents appear to fully regain mineralization
and strength within 2– 8 wk, whereas women likely achieve
this closer to 1 yr after weaning. In both the animal and
human studies, there may be incomplete recovery of the
trabecular microarchitecture of the femora and tibiae, the
effects of which may be offset by an increase in the crosssectional diameters of these bones. Although no formal
measurements of bone strength after weaning have been
510
The question arises as to whether or not the skeletal losses
invoked by lactation and the recovery post-weaning are the
same in a first compared with a second or third reproductive
cycle, or in younger versus older mothers. In areas where
the trabecular microarchitecture is not completely restored,
such as the tibia or femur, there may be less resorption of
bone in subsequent lactation cycles. Conversely, the trabecular microarchitecture is completely restored in the spine,
so subsequent lactation cycles can be expected to result in a
similar magnitude of resorption and recovery. Available
data from human studies are consistent with a similar degree of skeletal resorption occurring in all lactation episodes, and a similar degree of recovery occurring afterwards
regardless of maternal age. This includes observational
studies that included women of various reproductive ages
and parity, and the dozens of epidemiological studies that
have not found an association among parity, lifetime extent
of lactation, and risk of osteoporosis or fractures. However,
there have been no systematic comparisons in animal or
human studies of younger versus older mothers, or primiparas versus multiparas, so differences in the skeletal responses to lactation and recovery invoked by age or parity
cannot be ruled out.
V. DISORDERS OF BONE AND MINERAL
METABOLISM DURING LACTATION
A. Osteoporosis of Lactation
1. Animal data
Despite significant skeletal resorption during lactation that
is most marked in the lumbar spine, it is unusual for fractures to be found. This is likely because the rodent ambulates on four limbs, thereby not loading the spine in the
same orientation or to the same degree as in a bipedal human.
2. Human data
Multiple case reports and series have confirmed that, although rare, osteoporotic fractures can occur in breastfeeding women (501). Consistent with most bone loss occurring
in the axial spine, vertebral compression fractures have
been reported, sometimes with as many as 6 –10 such fractures evident at presentation in one individual (98, 501,
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Recovery of estradiol to normal during post-weaning likely
facilitates skeletal recovery but cannot explain it fully. Estradiol suppresses bone formation and resorption when administered as replacement therapy in peri- and postmenopausal women (305, 750); it is not a potent stimulator of
bone formation. Moreover, when reproductive-age women
experience temporary estradiol deficiency induced by
GnRH analog treatment, they lose a small amount of BMD
and (unlike after lactation) most do not restore it afterwards
(288, 415, 640, 657, 684, 696, 758, 762, 781, 891, 942).
Earlier resumption of menses has correlated with an earlier
apparent increase in bone mass after lactation (484, 764),
which suggests a benefit of higher estradiol. But this is confounded by the fact that resumption of menses is an indicator of less intense lactation and, thereby, less bone lost and
an earlier start to postlactation recovery. Other studies have
found no effect of resumption of menses on bone loss during lactation or recovery afterward (572).
done in women, the fact that more than five dozen epidemiological studies found that lactation confers a neutral or
protective effect against low BMD and fragility suggests
that recovery is effectively complete, without long-term adverse effects on bone strength. Some data are compatible
with the possibility that weight-bearing exercise and increased calcium intake during post-weaning may contribute
to an even greater BMD being achieved.
CHRISTOPHER S. KOVACS
677, 687). These fractures can be quite debilitating. The
literature is confusing because many cases are described as
“pregnancy-associated osteoporosis” despite the fractures
occurring several months into lactation.
On the other hand, review of the individual cases indicates
that in many women there are additional factors that contribute to skeletal fragility, including causes of low bone
mass or fragility that precede pregnancy, and bone loss that
likely occurs during pregnancy (such as with very low calcium intake). This leads to the consideration that if a
woman is known to have skeletal fragility or very low bone
mass prior to pregnancy or at delivery, it may be reasonable
to advise against breastfeeding in case the programmed
skeletal resorption proves to be too much for that woman’s
skeleton (501).
When fractures do occur, it may also be reasonable to advise that breastfeeding cease to stop further bone loss and
initiate the expected post-weaning skeletal recovery. Individual cases have reported spontaneous improvements in
bone density by 20 –70% (29, 433, 713, 811, 928), so pharmacological therapy may be reasonably withheld for 12–18
mo to determine the magnitude of spontaneous recovery
(501). An anti-remodeling agent such as a bisphosphonate
or denosumab might blunt the spontaneous bone formation
that is expected during the post-weaning interval.
As noted earlier, individual case reports have described use
of nasal calcitonin (263, 687, 885), bisphosphonates (43,
3. Summary
Fragility fractures of the spine and other sites rarely occur
during lactation and may result from the normal physiological resorption of the skeleton during lactation, combined
with effects of low bone mass or skeletal fragility that preceded pregnancy, and skeletal resorption that may have
occurred during pregnancy (501). A spontaneous and substantial improvement in bone mass occurs after weaning
even in women who have fractured, so pharmacological
therapy should probably be withheld for at least a year to
determine if it is really needed.
B. Primary Hyperparathyroidism
1. Animal data
Animal models of primary hyperparathyroidism have not
been studied during lactation, although studies in Casr⫹/⫺
mice are relevant (see sect. VC). As described earlier, rebound hypercalcemia occurs after delivery and again at
weaning in normal rodents; the increase in serum calcium
may be even greater in rodents that are hypercalcemic from
primary hyperparathyroidism.
2. Human data
Severe hypercalcemia, also termed a parathyroid crisis, has
occurred during the postpartum interval in women with
primary hyperparathyroidism who were not operated on
during pregnancy, and in some women who go on to breastfeed (54, 153, 186, 612, 662, 795). The sudden rise in
serum calcium likely results from several factors, including
abrupt loss of the placenta (a significant route of calcium
loss), the initiation of low estradiol and PTHrP-induced
skeletal resorption to support milk production, the effect of
low estradiol to increase skeletal sensitivity to excess PTH,
and physiological resorption induced by physical inactivity
and bedrest during the puerperium. Consequently, significant worsening of hypercalcemia has occurred after delivery and in women who go on to breastfeed. However, there
is variability in everything, and in at least one case the serum
calcium improved during lactation, likely because milk production drains calcium from the maternal circulation (511).
3. Summary
Primary hyperparathyroidism can worsen significantly
postpartum, with variable effects in women who breast-
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In some breastfeeding women, the physiological bone resorption induced by PTHrP and low estradiol may be a
sufficient explanation for reduced skeletal strength that predisposes to fragility fractures. As noted earlier, in some
individuals the lumbar spine BMD has been shown to drop
from normal to osteoporotic values during otherwise normal lactation. In some instances release of PTHrP by the
breasts may be more exuberant than normal, leading to
more marked resorption of bone. Three such breastfeeding
women presented with hypercalcemia, increased PTHrP,
and vertebral compression fractures (29, 751). The hypercalcemia and increased PTHrP resolved in all three women
after weaning (29, 751), but in one woman the plasma
PTHrP level remained elevated for at least 4 mo after lactation ceased (751). Three other cases of compression fractures during lactation also had hypercalcemia that resolved
after weaning, which is suspicious for elevated PTHrP as the
cause (928). PTHrP was undetectable in one case and appropriate for lactation in two others, but common problems
with sample collection and processing (detailed in sect.
IIA3B) may explain why high levels of PTHrP were not
found. It is also conceivable that relative sensitivity to the
skeletal-resorptive effects of PTHrP may differ among
women, thereby contributing to differences in the amount
of bone lost during lactation.
143, 178, 263, 438, 475, 671, 677, 685, 799, 885, 897),
strontium ranelate (897, 1016), and teriparatide (98, 178,
377, 527, 544, 885) to treat osteoporosis diagnosed during
pregnancy or lactation. In each of these uncontrolled cases,
the achieved BMD increase was assumed to be due to pharmacological therapy, but remained within the expected
range of increase that can occur spontaneously during postweaning recovery.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
feed. The clinician should be alert to this and consider
whether parathyroidectomy or medical therapy might be
needed during the postpartum interval.
C. Familial Hypocalciuric Hypercalcemia
1. Animal data
Treatment of mammary epithelial cells with a calcimimetic
drug that activates the calcium receptor results in increased
milk calcium content and reduced PTHrP content (36, 952).
Therefore, activating mutations of the calcium receptor,
which cause systemic hypocalcemia, may be expected to
result in milk with increased calcium but reduced PTHrP
content.
2. Human data
The available mouse data predict that women with FHH
who breastfeed will have increased PTHrP, more bone loss,
increased renal calcium excretion, but a lower calcium content of milk. However, there are no published case reports
describing changes in serum minerals, bone density, or milk
composition in these women.
3. Summary
FHH likely causes increased PTHrP-mediated bone loss and
reduced milk calcium content, but confirmatory human
data are lacking.
D. Hypoparathyroidism
1. Animal data
Lactation appears to improve mineral and skeletal homeostasis in rodents that lack PTH. This has been most clearly
shown in Pth null mice, which lactate normally on a stan-
512
Parathyroidectomy has been carried out during established
lactation in rats, resulting in sudden PTH deficiency that
was not present prior to pregnancy or lactation. As discussed in the following paragraphs, parathyroidectomy results in improved values compared with nonlactating, parathyroidectomized rats, but worsening of some parameters
compared with intact or sham-operated rats. The calcium
content of the diet appears to be an important confounding
variable.
In a series of experiments carried out by one team of investigators, lactating, parathyroidectomized rats consuming a
2% calcium diet had normal serum calcium and phosphorus that was also no different from values in lactating, intact
rats on the same diet (395). On this diet the femoral ash
weight declined ⬃40% during lactation in both intact and
parathyroidectomized rats, confirming that resorption of
bone during lactation does not require PTH and is not made
worse by its absence (395). Substitution of a 0.02% calcium
diet caused the serum calcium to fall to half normal in
lactating, parathyroidectomized rats, and 60% of them
died suddenly from presumed tetany or arrhythmias. In
contrast, none of the nonlactating parathyroidectomized
rats died, nor did any intact rats (395).
In other studies, parathyroidectomy in rats during lactation
caused a 50% fall in serum or ionized calcium and an increase in serum phosphorus when 0.4 and 1% calcium diets
were consumed (295, 569, 718). The magnitude of hyperphosphatemia in parathyroidectomized rats lessened as lactation progressed (295). Calcitriol increased in lactating,
parathyroidectomized rats to at least double the value of
nonlactating, parathyroidectomized rats and nonlactating,
sham-operated rats, but remained below the concentration
of lactating sham-operated rats (569, 718). Intestinal calcium absorption increased normally during lactation despite simultaneous parathyroidectomy and vitamin D deficiency (93). Milk calcium content was significantly higher
at day 6 of lactation and normal during the remainder of
lactation in parathyroidectomized rats, despite the serum
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Casr⫹/⫺ mice have life-long hypercalcemia and hypocalciuria and mimic the human condition of FHH (394). They
lactate normally, and their pups grow at the expected rate.
However, mammary tissue shows twofold increased PTHrP
expression while milk has twice the normal content of
PTHrP but modestly reduced calcium content (36). These
results imply that skeletal resorption increases to compensate for reduced entry of the calcium into milk. A
mammary-specific deletion of Casr confirmed this by
finding increased PTHrP in mammary tissue, plasma, and
milk; suppressed PTH; reduced milk calcium content;
reduced bone volumes and BMD; and increased urine
calcium excretion, compared with lactating controls
(591). These findings point to a central role of the CaSR
in mammary tissue to control skeletal resorption during
lactation, and the milk content of PTHrP and calcium.
dard 1% calcium diet, normalize serum calcium and phosphorus, and experience a normal loss of BMC at whole
body, lumbar spine, and hindlimb (478). After weaning,
they fully regain the mineral content lost during lactation,
reach a BMC that is 10 –15% higher than the prepregnancy
baseline value, and redevelop hypocalcemia and hyperphosphatemia. They are somewhat more prone to anesthetic-related deaths associated with serial DXA readings (133).
A 2% calcium diet blunted the lactational decline in BMC
but did not reduce the post-lactation gain in BMC (478).
Overall, the studies in Pth null mice indicate that loss of
PTH has no significant effect on lactational or post-weaning
mineral homeostasis. Calcitriol, PTHrP, and intestinal calcium absorption have not been measured in lactating Pth
null mice.
CHRISTOPHER S. KOVACS
calcium being 50% of normal (295). This confirms that
achieving a normal calcium content in milk does not require
PTH. Based on studies in mice, systemic hypocalcemia may
cause increased milk PTHrP content (36, 952).
2. Human data
Since the 1970s it has been appreciated that mineral and
skeletal metabolism substantially improves in hypoparathyroid women who are breastfeeding (30, 148, 161, 607, 790,
796, 811, 837, 890, 1008), and these observations contributed to the hypothesis that the lactating breast expresses a
PTH-like hormone. Occasionally women have been diagnosed to have hypoparathyroidism due to abrupt onset of
hypocalcemia when lactation ceases (72), which is also
compatible with loss of a calciotropic hormone produced
by the breasts.
That hypothesis proved to be correct when PTHrP was
identified and confirmed to be expressed at high levels in
lactating mammary tissue, the maternal circulation, and
milk. Furthermore, the animal data previously discussed
have confirmed the physiological role of PTHrP during lactation. One clinical case documented that hypoparathyroid
women can experience transient hypocalcemia in the first
day or two postpartum, presumably from the abrupt loss of
placental PTHrP (890). This hypocalcemia resolves as lactation, and expression of PTHrP in the breast, becomes
more fully established. However, most published cases of
hypoparathyroidism have not reported such a worsening
during the puerperium, but instead have noted that the
requirement for supplemental calcium and calcitriol drops
substantially as milk production is upregulated. Significant
iatrogenic hypercalcemia and vertebral compression fractures have occurred when attention has not been paid to
The reason for the improvement in mineral and skeletal
homeostasis is that PTHrP, released from lactating breast
tissue, stimulates bone turnover, renal tubular calcium conservation, and production of calcitriol by the kidneys (148,
607, 837). Calcitriol does not increase above normal, and
this may be because in some studies PTHrP appears less
potent than PTH in activating the PTH/PTHrP receptor and
stimulating Cyp27b1 (308, 413, 414, 494, 988). Another
potential reason is that the hormonal milieu of lactation,
including high prolactin and low estradiol, conceivably alters how Cyp27b1 responds to PTHrP during lactation.
Since the identification of PTHrP, many clinical reports
have deduced the presence of increased circulating PTHrP
but have not measured it (30, 890, 1008). However, a rise
and decline in plasma PTHrP has been shown to correspond
to the rise and decline in serum calcium, calcitriol, and bone
turnover markers (607, 811, 837). In all published cases,
the improvement in mineral homeostasis and decline afterwards correlates respectively with the increasing and lessening intensity of lactation. The less exclusively or intensively a hypoparathyroid woman breastfeeds, the more
likely it is that supplemental calcium and calcitriol are still
needed.
The ameliorating effect of breast-derived PTHrP wanes at
varying rates as lactation lessens and the baby is weaned. In
some women the calcium and calcitriol has to be reinstituted while breastfeeding was still ongoing, whereas in others it may not be required until days, weeks, or months after
lactation has ceased. In most cases the need to reinstitute or
increase the doses of calcium and calcitriol occurs within
days prior to or after weaning, but in one unpublished case
that the author was involved in, serum calcium remained
normal off all supplements for more than 1 yr post-weaning, before hypocalcemia abruptly recurred.
One clinical report documented a spontaneous 40% increase in lumbar spine BMD and 7.5% increase in femoral
neck BMD in a surgically hypoparathyroid woman after
lactation, confirming that substantial skeletal recovery is
possible after weaning without PTH (811).
3. Summary
Animal and human data are consistent with mammaryderived PTHrP stimulating bone turnover, renal calcium
conservation, and synthesis of calcitriol during lactation.
Rodents require both increased intestinal calcium absorption and skeletal resorption to meet the calcium require-
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Weight gain of the pups was normal when lactating, parathyroidectomized rats consumed a 2% calcium diet (395),
whereas weight gain was modestly reduced as early as 24 h
after parathyroidectomy when the mothers consumed 1 or
0.4% calcium diets (295, 569). This reduced weight gain
was not seen in pups nursed by Pth null mice compared with
WT mice; the ash weight and calcium content were no different at the end of 3 wk of lactation (133). Since the calcium content of milk is normal in parathyroidectomized
rats, other factor(s) must be contributing to reduced weight
gain in their pups. Since the parathyroidectomized mothers
are hypocalcemic on the diets associated with reduced pup
weight gain, maternal tetany may be preventing prolonged
suckling, or causing reduced milk volume. Another possibility is that the expected increased milk PTHrP content
(36, 952) is causing reduced weight gain, because milk content of PTHrP has been shown to be inversely related to the
rate of skeletal mineral accrual in nursed pups, and independent of milk calcium content (591). The physiological
role of PTHrP in milk may be to reduce or modulate skeletal
mineral accrual in the neonate (492).
monitoring the serum calcium and the anticipated requirement for the doses of calcium and calcitriol to be decreased
(148, 161, 790, 796, 811, 837, 1008). In some women
calcium and calcitriol both need to be stopped, whereas in
other women reduced doses may be all that is required.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
ments of lactation. A standard 1% calcium diet is sufficient
for lactating mice to normalize mineral homeostasis without PTH, whereas lactating rats appear to need a 2% calcium diet for normalization to occur without PTH. There
may be species differences that contribute to why mice and
rats do not have identical responses to absence of PTH.
E. Pseudohypoparathyroidism
1. Animal data
A mouse model of pseudohypoparathyroidism has not been
studied during lactation (322).
2. Human data
There are no animal or human data regarding mineral homeostasis and bone metabolism in animal models or
women with pseudohypoparathyroidism. It is expected that
lactation should lead to an overall improvement due to the
release of PTHrP from mammary tissue. Since pseudohypoparathyroidism leads largely to renal but not skeletal resistance to PTH, it is possible that lactation may lead to increased skeletal resorption compared with normal when the
effects of PTH and PTHrP are combined.
3. Summary
Pseudohypoparathyroidism can be anticipated to improve
during lactation, mimicking the clinical experience with hypoparathyroidism, but this has not been documented.
F. Pseudohyperparathyroidism
1. Animal data
Preceding sections have confirmed that lactating mammary
tissue produces PTHrP, and that suckling leads to increased
release of PTHrP and systemic effects on mineral homeostasis. However, there are no data on pseudohyperparathyroidism from lactating animals.
514
The physiological release of PTHrP from lactating breasts
alters mineral and skeletal homeostasis, thereby contributing to a small increase in serum calcium and phosphorus,
suppression of PTH, increased bone resorption, and reduced renal calcium excretion. But most women and their
clinicians are unaware of the presence of PTHrP or its effects, because these physiological changes are silent and
without consequences. As noted in section VD, the presence
of PTHrP becomes apparent in hypoparathyroid women
who normalize mineral and skeletal homeostasis, and will
become hypercalcemic if the doses of calcium and calcitriol
are not decreased or stopped.
Occasionally the effects of breast-derived PTHrP become
symptomatically obvious in otherwise normal breastfeeding women. PTHrP-mediated hypercalcemia is called pseudohyperparathyroidism because it mimics the effects of primary hyperparathyroidism but is not due to excess PTH. It
has developed during normal lactation (179, 549, 751,
847), in a woman who recently delivered a baby but was
unable to breastfeed because of a critical illness in the baby
(800), and even in nonlactating women who simply have
large breasts (435, 474, 603, 950). The mechanism is that
high levels of PTHrP cause excess skeletal resorption of
calcium and renal reabsorption of calcium; intestinal calcium absorption may also be increased if the achieved levels
of PTHrP are sufficient to cause high levels of calcitriol.
One woman developed hypercalcemia during each of two
pregnancies; it worsened and persisted while she breastfed
and resolved with weaning. During the second lactation
interval, high circulating levels of PTHrP were confirmed,
which normalized as the hypercalcemia resolved (549). A
second woman had lactation-induced hypercalcemia and
vertebral compression fractures, high PTHrP of 10.9 pg/ml,
low calcitriol, and undetectable PTH. The hypercalcemia
improved with weaning while the PTHrP level stayed elevated for several months before becoming undetectable
(751). In a third case, severe postpartum hypercalcemia
(4.85 mM) worsened over the first 3 days postpartum, accompanied by a very high plasma PTHrP (28.4 pM) with
undetectable PTH (800). The hypercalcemia persisted for
10 days despite treatment with intravenous pamidronate,
before subsiding to normal, accompanied by a fall in PTHrP
to undetectable, and a rise in PTH to normal. The authors
of that report incorrectly attributed placental PTHrP as the
explanation for her hypercalcemia (800). However, PTHrP
has a half-life of minutes in the circulation, and its placental
source was abruptly lost with the afterbirth; therefore, placental PTHrP cannot explain maternal hypercalcemia that
worsened over the first 3 days after delivery and persisted
for 10 days. The time course is consistent with release of
PTHrP from the breasts, which upregulates in response to
regulatory cues during late gestation and parturition, and
subsides when breastfeeding does not occur. A fourth case
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Women rely mainly on skeletal resorption to meet the calcium requirements of lactation. The available case reports
make very clear that lactation usually results in normalization or near-normalization of mineral and skeletal homeostasis in hypoparathyroid women. It is hazardous to blindly
maintain prepregnancy doses of calcitriol and calcium in
hypoparathyroid women who plan to breastfeed; the albumin-adjusted calcium or ionized calcium must be followed
so that appropriate reductions in the doses of these supplements can be made. As lactation lessens, and especially after
it ceases, the requirement for calcium and calcitriol can be
expected to revert to prepregnancy levels.
2. Human data
CHRISTOPHER S. KOVACS
involved a woman who developed hypercalcemia with suppressed PTH during two successive lactation episodes
(179). The hypercalcemia resolved and PTH rose to normal
with weaning each time; no measurements of PTHrP were
done. A fifth and much older case from 1981 (prior to the
discovery of PTHrP) also involved lactational hypercalcemia with low PTH; a bone biopsy revealed active skeletal
resorption suggestive of hyperparathyroidism (847). The
hypercalcemia resolved after weaning, and the authors correctly deduced that the breasts must be producing a PTHlike hormone.
Weaning the baby, combined with judicious use of breast
binders or dopaminergic medications that suppress prolactin (cabergoline, bromocriptine), should reverse the excess
production of PTHrP and consequent hypercalcemia. A bisphosphonate or denosumab may be needed to acutely shut
down the increased bone turnover. However, excess production of PTHrP can last for months or longer, which
explains why a few cases have even required bilateral mastectomies to correct the problem (435, 474, 603, 950).
3. Summary
Release of PTHrP from lactating breast tissue causes the
serum and ionized calcium to rise slightly in most women;
uncommonly, this has caused symptomatic hypercalcemia.
The prevalence of PTHrP-mediated hypercalcemia during
lactation may be underestimated since serum calcium is not
normally measured, and symptoms of hypercalcemia may
be misattributed to other aspects of life with a new baby.
When hypercalcemia does occur, it should resolve with
weaning, but occasionally surgical reduction in the amount
of breast tissue may be necessary.
G. Vitamin D Deficiency and Genetic Vitamin
D Resistance Syndromes
1. Animal data
The effect of extreme disturbances in maternal vitamin D
physiology during lactation and post-weaning recovery
have been investigated in Vdr null and Cyp27b1 null mice
as well as vitamin D-deficient mice and rats.
The same Vdr null mice have also been studied after being
raised on a 2% calcium diet from 3 wk of age (489), so
they did not have rickets prior to pregnancy. Micro-CT
studies, biomechanical tests, and femoral ash weight
were carried out during pregnancy and lactation. WT
mice gained trabecular bone volume and thickness during
pregnancy while the Vdr nulls did not, and this difference
persisted to day 5 of lactation but was gone by day 10
(489). By the end of lactation, WT and Vdr nulls resorbed
a similar amount of bone as determined by microCT and
ash weight studies, lost a similar amount of femoral bone
strength, and showed no significant differences between
the genotypes (489).
Milk calcium content was normal in Vdr null mice compared with WT (1026). But after weaning, Vdr nulls show
delayed involution and apoptosis of mammary epithelial
cells (1026). This suggests that calcitriol plays a role in
regulating involution after lactation.
In a preliminary report, Cyp27b1 null mice raised on a 2%
calcium diet from the time of weaning had reduced BMC
and microCT evidence of rickets prior to mating, gained
40% BMC during pregnancy, and lost a normal amount of
BMC during lactation (330). After weaning, they regained
what was lost during lactation and reached a higher BMC
value than prior to pregnancy (330). Serum calcium normalized during pregnancy but fell sharply during lactation
before recovering slowly to normal during post-weaning. In
contrast, phosphorus was low during lactation but normal
throughout post-weaning recovery.
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These cases emphasize the extreme of women developing
symptomatic hypercalcemia during lactation. This appears
to be uncommon; however, some cases may go undiagnosed
because hypercalcemia causes nonspecific constitutional
symptoms that will not be obviously different from normal
symptoms in a woman who is feeding a baby on demand
around the clock. Recall that the serum calcium and ionized
calcium have both been shown to rise during lactation in
longitudinal studies, so the prevalence of high serum calcium during lactation may be more common than what
these isolated cases would otherwise suggest.
In longitudinal studies wherein Vdr null mice were raised on
a standard 1% calcium diet to allow them to develop rickets, but switched to a 2% calcium diet prior mating to
maximize fertility, Vdr null mice increased BMC by 55%
during pregnancy, and lactated normally, losing a normal
amount of BMC compared with their WT sisters on the
same diet (296). Serum calcium and phosphorus remained
normal throughout lactation and post-weaning. Within 14
days after weaning, the Vdr null mice restored all that had
been lost to achieve a BMC that was 50% higher than their
prepregnant baseline but equal to the WT value. Histomorphometry during late pregnancy compared with prepregnancy showed that the pregnancy-related increase in BMC
was largely attributable to mineralization of osteoid (296).
The subsequent increase in BMC after weaning implies that
new bone formation has occurred; however, histomorphometric studies have not yet been carried out in this time
frame. Preliminary and ongoing studies in the author’s lab
have shown that the post-weaning increase in BMC is no
different between WT and Vdr null mice when both are
switched to a 1% calcium diet after delivery, confirming
that the high calcium content of the diet is not required for
skeletal recovery to occur after weaning.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
Vitamin D-deficient mice from the CD1 background, kept
on a 1.2% calcium diet, had normal serum calcium and
ionized calcium but lower serum phosphorus during lactation (19). Their pups grew at the same rate as pups from
vitamin D-replete mice (19). Milk from these mice showed
normal nutritional and calcium content, but there was a
15% lower lactose content (19). Conversely, vitamin D-deficient mice in the Swiss background had mild (20% lower)
hypocalcemia and normal phosphorus (79). Analysis of
milk from these mice, and from vitamin D-deficient rats,
showed reduced protein content; the calcium content was
not measured (79).
Intestinal absorption of calcium doubled during lactation
and declined to virgin values during the recovery phase in
rats consuming 0.47 to 1.2–1.7% calcium diets (93, 360).
Intestinal phosphorus absorption also doubled on the 1.2–
1.7% calcium diet (93). Serum calcium and phosphorus
were normal, and intestinal calcium absorption was no different between vitamin D-deficient and replete rats either
during lactation or post-weaning on the 1.2–1.7% calcium
diet (93). On the 0.47% calcium diet, vitamin D-deficient
rats had lower serum calcium and phosphorus, and
achieved a doubling of intestinal calcium absorption during
lactation; they were studied separately from vitamin D-replete rats and may have had a slightly lower peak efficiency
of intestinal calcium absorption (360). These results indicate that calcitriol is not required for a doubling of efficiency of intestinal calcium and phosphorus absorption to
occur during lactation; however, the lower (0.47%) calcium diet likely reduces passive absorption of calcium (360)
516
In one study, vitamin D-deficient rats produced only ⬃20%
of the volume of milk of vitamin D-replete rats, as determined by injecting the rats with oxytocin and then manually
expressing the milk. The nutritional content of the milk was
normal to enhanced, since it contained more protein, calcium, phosphorus, but somewhat less carbohydrate than
normal milk (119). Pups of vitamin D-deficient rats had
modestly reduced weight gain, but this was corrected by
giving the mothers fewer pups to nurse, confirming that the
mother may be producing milk of insufficient quantity to
meet the demands of larger litters (119). However, the
markedly reduced volume of expressed milk was out of
keeping with the modest reduction in pup weight gain, so
the experimental technique may have overestimated any
difference in milk volumes produced. Hypocalcemic vitamin D-deficient rats may, for example, differ from vitamin
D-replete rats in their response to exogenous oxytocin, but
not in their response to suckling.
Rat milk contains a very low concentration of vitamin D
and 25OHD, which together total ⬃3–12 IU/liter (190).
This is similar to the low vitamin D content of human milk.
Overall, the rodent studies indicate that disrupted vitamin
D physiology is more likely to cause hypocalcemia in rats
than in mice, regardless of dietary calcium content. Lactation otherwise proceeds normally despite maternal loss of
calcitriol, VDR, or vitamin D, with the amount of bone
resorbed being comparable to that of their respective WT or
vitamin D-sufficient controls. Post-weaning, skeletal recovery occurs at a normal rate in Vdr null mice and (in a
preliminary report) Cyp27b1 mice, whereas vitamin D-deficient rats have been found to have discrepant results of
both normal skeletal recovery and failure to recover. In
vitamin D-deficient mice and rats, and in Vdr null mice,
milk content of calcium is normal, but the volume of milk
produced was reduced in one study of vitamin D-deficient
rats. A reduction in milk volume could explain a reduction
in pup growth rate that was seen in some but not all studies.
2. Human data
Observational cohort studies (145, 731, 862, 893) and randomized interventional trials (13, 14, 60, 402, 453, 672,
780, 788, 789, 965) have not shown any effect of higher
25OHD concentrations or vitamin D supplementation to
alter maternal mineral or skeletal homeostasis in otherwise
healthy, lactating women across a broad range of vitamin D
intakes and 25OHD levels. Vitamin D supplementation
raises maternal 25OHD levels with a similar dose-response
effect as in nonpregnant or nonlactating women. Many of
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Severely vitamin D-deficient rats have also been studied
during lactation and post-weaning skeletal recovery. On
diets ranging from 0.47 to 1.7% calcium, lactating vitamin
D-deficient rats are consistently hypocalcemic (values 50%
of normal and usually lower than in pregnancy) with serum
phosphorus that ranges from normal to modestly reduced
(93, 146, 360, 362, 598, 628), whereas during post-weaning recovery, hypocalcemia lessened and phosphorus was
consistently normal (93, 360, 362, 628). Lactation proceeds normally, with vitamin D-deficient and vitamin D-replete rats each resorbing a similar amount of calcium from
the femora compared with the peak value of pregnancy
(362, 598, 628). Histomorphometry revealed that lactating
vitamin D-deficient rats have significantly widened osteoid
seams as well as increased osteoblast surface, osteoclast
number, and resorptive surface (146). After weaning, severely vitamin D-deficient Holtzman rats on a 0.47% calcium diet recovered lactational losses in mineralized bone
volumes and cortical width, thereby achieving values that
equaled or exceeded those prior to pregnancy (628). But in
an earlier study from the same investigators, there was no
recovery of ash weight or mineral content at 3 wk (362).
The discrepancy in post-weaning skeletal recovery between
these two studies is unexplained.
compared with the 1.2–1.7.% calcium diet (360). Both
studies indicate that the normal rate of intestinal mineral
absorption in virgin rats is sufficient to facilitate skeletal
recovery during post-weaning (93, 360).
CHRISTOPHER S. KOVACS
the randomized trials measured only the achieved 25OHD
level as the outcome of interest (13, 60, 402, 780, 788, 965).
Although milk vitamin D and 25OHD content are low,
there is a correlation between milk 25OHD and neonatal
25OHD after the first month of lactation, indicating that
despite its low content of vitamin D, breast milk is an important determinant of neonatal vitamin D stores (145,
540, 780). The estimated half-life of 25OHD in infants is
2–3 wk (717), similar to values in adults (59, 62, 189, 344,
449), which means that a higher cord blood 25OHD will
only influence neonatal levels over about the first 6 wk.
Randomized intervention studies indicate that typical maternal vitamin D doses of 400-1,000 IU/day do not consistently increase breast milk content of vitamin D or 25OHD,
whereas with maternal vitamin D doses of 2,000 – 4,000
IU/day, an increase in milk content of vitamin D and
25OHD and neonatal 25OHD can be demonstrated (13,
14, 402, 780). Additional randomized trials have shown
that even higher maternal vitamin D intake increases the
amount of vitamin D and 25OHD in milk (also called “antirachitic activity” of milk) (60, 672, 788, 965). A dose of
6,400 IU/day raises the milk vitamin D content sufficiently
so that the babies achieved 25OHD values of 115 nM (46
ng/ml), the same level reached by babies who received 300
IU of vitamin D directly in the form of oral drops (965). A
daily maternal dose of 5,000 IU/day raised maternal
25OHD to 400 nM (160 ng/ml) and neonatal 250HD to 98
nM (39 ng/ml), while a single maternal dose of 150,000 IU
had a similar effect (672).
These high levels of maternal and neonatal 25OHD have
been targeted without evidence that they confer a specific
benefit. It is relevant to recall that multiple stable isotopebased studies in children, adolescents, and adults have
shown that on an adequate calcium diet, intestinal calcium
absorption is already maximal with a 25OHD level above
⬃20 nM (7, 24, 26, 306, 650, 774). Moreover, intestinal
calcium absorption in the breastfed neonate and infant is
Moreover, in areas where severe vitamin D deficiency rickets is endemic, it has been effectively treated with breast
milk as the only form of nutrition in mothers who received
150,000 IU vitamin D every 3 mo, or ⬃1,800 IU/day (902,
903). These babies and their mothers were protected from
sun exposure and had negligible vitamin D in the diet, so a
maternal supplement was the main source. Starting
25OHD values were 6 nM (2 ng/ml) or lower in mothers
and babies, consistent with extreme vitamin D deficiency.
Achieved 25OHD values were ⬃50 nM (20 ng/ml) in the
mothers and 40 nM (16 ng/ml) in their babies, both of
which are above the 20 nM threshold that appears to maximize intestinal calcium absorption. The far higher breast
milk vitamin D content and infant 25OHD levels achieved
by giving a 5,000 or 6,400 IU supplement daily to the
mother greatly exceed what has been shown to treat rickets,
the severe manifestation of vitamin D deficiency. Therefore,
such high doses may be superfluous if no additional benefit
is provided to mineral or skeletal metabolism. The question
remains as to whether such high vitamin D intakes or
achieved 25OHD levels in breastfed babies confer any nonskeletal benefits (773).
Breast milk calcium content is unaffected by maternal
25OHD over a wide range from 25 nM (10 ng/ml) to 160
nM (64 ng/ml) (60, 731). This includes cohort studies that
have examined low maternal vitamin D intakes and
25OHD concentrations (731), and randomized interventions which found that maternal intake of 2,000 – 6,400 IU
vitamin D/day failed to change the calcium content of milk
compared with an intake of 400 IU/day (60, 402, 965), even
though the 6,400 IU dose raised maternal 25OHD to 160
nM (64 ng/ml) (965). On the other hand, several individual
cases from India revealed that milk calcium content was
lower in mothers presenting with overt vitamin D deficiency
with mean 25OHD values of 6 nM (2.5 ng/ml), hypocalcemia, hypophosphatemia, and markedly elevated PTH
(903). These results confirm that calcitriol likely does not
play a direct role in causing calcium to enter milk, but
extremes of vitamin D deficiency (25OHD closer to 6 nM)
will impair milk production. As noted earlier, calcium intake does not alter breast milk calcium content (206, 452,
484, 723). Instead, the calcium content of milk is largely
regulated by the calcium receptor and PTHrP, with the
supply being the maternal skeleton and a lesser contribution
from diet. In extreme vitamin D deficiency, there is skeletal
resistance to the resorptive actions of PTH (550, 577, 624,
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Milk normally contains little vitamin D or 25OHD,
⬃30 – 40 IU/liter in total, while calcitriol is usually very low
to undetectable (400, 410, 515, 545, 587, 748, 872, 939).
Consequently, maternal 25OHD should not decline significantly as a consequence of milk production, and this has
been confirmed by multiple studies (156, 157, 165–167,
470, 505, 558, 764, 805, 862, 871). Moreover, this means
that breast milk is normally not a good source of vitamin D
for the neonate or infant. These facts are often disbelieved
because marketed milk and other dairy products in the
United States and Canada contain ⬃10 times the concentration of vitamin D, i.e., 400 IU/liter or 100 IU/standard
serving (250 ml or cup). However, that is a synthetic vitamin D supplement, which is added to milk and dairy products after pasteurization. It is not put there by the cow or
goat.
boosted by the lactose content of milk, which increases
passive, paracellular absorption of calcium (479, 480).
Therefore, a 25OHD level of 100 nM is far above the value
at which intestinal calcium absorption maximizes, and is
unlikely to confer any additional benefit on intestinal calcium absorption or bone metabolism in the neonate or infant.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
783), which likely contributes to maternal hypocalcemia
and low breast milk calcium content.
The effect of vitamin D deficiency or insufficiency has not
been explicitly examined during the recovery phase from
lactation. This is when calcitriol may be especially important to ensure adequate delivery of mineral to the rebuilding
skeleton. One study suggested that the FokI polymorphism
in Chinese women interacted with calcium intake to determine the magnitude of BMD increase 1 yr after lactation
ended or menses resumed, but the study was too small (40
subjects) to make generalizations to larger populations and
other ethnicities, or to know if it confirms an effect of calcitriol to directly or indirectly regulate skeletal recovery.
H. Calcitonin Deficiency
1. Animal data
As noted earlier (sect. IIIH), the theory that calcitonin protects against excessive resorption of the skeleton during
pregnancy was originally tested by removing the thyroid
glands of goats and rats, autotransplanting the parathyroids, and providing thyroid hormone replacement. The
same approach was used for lactation.
3. Summary
In two studies such thyroidectomized rats had ⬃10% lower
femoral ash weight, calcium, and phosphorus content than
sham-operated rats after 3 wk of lactation (551, 900). Although there was no difference in basal serum calcium between groups during lactation (900), there was a greater
surge in serum calcium after gavage in thyroidectomized
compared with sham-operated rats (927), suggesting that
calcitonin modulates the postprandial calcemic response
during lactation. Intestinal calcium absorption was also reduced 20% in thyroidectomized rats (551). These were
small studies and described only at abstract length, with few
methodological details and some relevant data not disclosed (551, 900). Whether the surgically altered animals
were euparathyroid and euthyroid was not determined, and
that may have confounded the results.
The animal data indicate that resorption of bone and milk
calcium content may be unaffected by extremes of vitamin
D physiology, including absence of VDR, calcitriol, and
vitamin D. Post-weaning recovery of bone mass also occurs
despite absence of VDR, calcitriol, and vitamin D, although
data from vitamin D-deficient rats are inconsistent.
These results were refuted by a later study that used a larger
sample size of rats, and confirmed that serum thyroxin and
calcium were no different between thyroidectomized and
sham-operated rats during lactation. Both groups resorbed
bone, but there was no difference between them in femoral
ash weight or calcium content at the end of lactation (392).
Clinical data are largely similar, suggesting that maternal
vitamin D stores are not adversely impacted by lactation,
that milk calcium content is unaffected by extremes of severe vitamin D deficiency and excess, and that lactational
bone loss is likely also unaffected. Given the prevalence of
insufficient to low levels of 25OHD in the normal population, the epidemiological studies also suggest that postweaning recovery of bone mass is also likely not impaired.
Overall, there is no clear evidence that the requirement for
vitamin D increases during lactation to meet maternal
Similar experiments were carried out in lactating, thyroidectomized, thyroxin-replaced goats but without confirmation of thyroid or parathyroid status. The thyroidectomized
goats lost 9% more ash weight and calcium from metatarsals and metacarpals compared with sham-operated animals (55). The sample size was quite small, consisting of
only five thyroidectomized and four intact goats.
Hereditary absence of Cyp24a1 reduces calcitriol catabolism and has been shown to lead to marked maternal hypercalcemia during pregnancy accompanied by high calcitriol.
While breastfeeding, hypercalcemia was milder and serum
calcitriol was normal (820). This is consistent with
Cyp27b1 stimulation being reduced to nonpregnant levels
during lactation.
518
None of these studies in rats or goats examined the trabecular bone of the spine, which is the site that loses the most
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Vitamin D deficiency and insufficiency also have not been
explicitly examined in any of the cohort studies or large
epidemiological studies that looked at the effect of prior
lactation history on BMD or fracture risk. However, since
those studies largely found a neutral or even a protective
effect of lactation on long-term BMD and fracture risk, and
the majority of women in those studies are considered to be
vitamin D insufficient or deficient by some modern experts,
it seems probable that skeletal recovery after weaning is not
impaired by vitamin D insufficiency either. Direct studies of
the effect of vitamin D supplementation during post-weaning recovery are needed. In the absence of such data, it is
prudent to recommend the same intake of vitamin D as in
nonpregnant women.
needs. Since milk normally contains little vitamin D or
25OHD, a theoretical benefit of high-dose vitamin D supplementation is that all of a baby’s nutrition could then
come from breast milk, rather than requiring that breast-fed
babies alone be stigmatized to receive vitamin D supplements. Further study is needed of the effectiveness, safety,
and adherence to this route of delivery compared with giving vitamin D supplements directly to the baby. The high
doses used in some of these studies are not needed if the
neonatal goal is a 25OHD level of only 50 nM, as the
Institute of Medicine and pediatric societies have suggested
(430).
CHRISTOPHER S. KOVACS
mineral during lactation. Moreover, extrathyroidal sources
of calcitonin synthesis were not appreciated when these
models were created; lactating mammary tissue is a potent
source of calcitonin, and there is additional expression in
the pituitary.
Remarkably, the 55% loss of BMC during lactation was
completely recovered within 18 days of weaning (994). This
was accompanied by histomorphometric evidence of a
marked reduction in osteoclasts, and a surge in osteoblast
numbers and surface to the same values of their WT sisters
during the post-weaning recovery phase (194). Marked
downregulation of Sost and Dkk1 expression occurred
within bone but was reduced even further in Ctcgrp null
mice, which likely contributed to the upregulation in osteoblast number and function (194).
The Ctcgrp null model confirms that physiological levels of
calcitonin protect the rodent skeleton from excessive re-
Calcitonin acts on the calcitonin receptor, which is expressed by osteoclasts (660), lactating mammary epithelial
cells (432, 938), and pituitary (831), as well as numerous
other tissues during embryonic and fetal development
(437). Pharmacological doses of CGRP and amylin can activate the CTR, but at physiological doses they act on different receptors (787). It is not possible to study the effect of
global loss of the calcitonin receptor during lactation because Ctr null mice usually die at the embryonic stage (220,
529), a lethality that is not seen in Ctcgrp null mice. WT and
Ctr⫹/⫺ mice were no different in their responses to lactation
(580).
More recently a conditional knockout using a CMV promoter has enabled deletion of Ctr at a later stage in development (225). This results in ⬎90% but not 100% loss of
CTR expression in kidneys and osteoclasts; expression in
other tissues relevant to lactation, especially mammary tissue and pituitary, were not assessed. During lactation these
conditionally deleted Ctr null mice show a greater increase
in osteocyte lacunar size compared with WT, suggesting
that loss of calcitonin signaling leads to increased osteocytic
osteolysis (187). However, there were no significant differences in bone structure by microCT or histomorphometry
between Ctr nulls and WT (187). Moreover, prolactin was
significantly reduced, which is the opposite of what was
expected given that targeted overexpression of calcitonin in
the pituitary, and pharmacological treatment with calcitonin, both reduce prolactin. A lower serum prolactin also
indicates relative inhibition of lactation in these conditionally deleted Ctr nulls and, therefore, the potential for reduced bone loss as a consequence, but milk calcium content
was normal and no significant disturbance in pup growth
was noted.
Overall, the conditional knockout of Ctr incompletely resembles the lactational phenotype of Ctcgrp null mice. It
remains to be determined if these differences are due to
insufficient deletion of CTRs from relevant tissues during
lactation; loss of actions of other ligands that may be mediated by CTR; physiological effects of calcitonin that are
mediated by other receptors; or that loss of two ligands in
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The postulated physiological role of calcitonin to protect
the maternal skeleton during lactation was reexamined in
Ctcgrp null mice, which lack calcitonin and calcitonin generelated peptide-␣, but retain calcitonin gene-related peptide-〉 (394). This global calcitonin deficiency resulted in
lactating Ctcgrp null mice losing double the BMC as their
WT sisters from whole body, lumbar spine, and hindlimb,
with the losses reaching 55% of lumbar spine BMC (994).
Treatment with calcitonin through 3 wk of lactation prevented the excess bone loss, whereas CGRP-␣ had no effect,
confirming that loss of calcitonin led to the skeletal phenotype. Increased expression of PTHrP in mammary tissue
and increased circulating PTH likely combined to cause
increased bone resorption and exaggerated net bone loss in
Ctcgrp null mice (992, 994). Histomorphometric studies
showed that Ctcgrp nulls had a doubling of osteoclast number and resorptive surfaces, and a halving of osteoblast
number and osteoid surface (194). Intestinal calcium absorption was no different between lactating Ctcgrp nulls
and WT (994). A doubling of milk calcium content was
found that was nonsignificant in early lactation (994) but
statistically significant at mid-lactation (992). It remains
undetermined whether the primary response to loss of calcitonin is increased bone resorption that leads to increased
flux of calcium into mammary tissue and milk, or loss of
calcitonin in mammary tissue that increases calcium transport into milk and, thereby, a compensatory increase in
PTHrP and PTH. It is also possible that both pathways are
involved, and that loss of calcitonin signaling in the pituitary contributes to increased prolactin, which in turn stimulates PTHrP and inhibits ovarian function. Lactating
Ctcgrp null mice did not have higher prolactin levels compared with WT (994), while serum estradiol was at the
detection limit of the assay in both genotypes at all time
points (992). The postulated role of calcitonin to inhibit
prolactin is not supported by Ctcgrp null mice.
sorption during lactation, but it remains to be determined
how much of calcitonin’s actions are at the level of osteoclasts, mammary epithelial cells, and pituitary lactotrophs
(994). Moreover, the model is confounded by loss of
CGRP-␣, which may contribute to the phenotype of altered
mineral and skeletal homeostasis. A mouse model in which
CGRP-␣ only was deleted, apparently leaving calcitonin
expression intact, resulted in osteopenia and reduced bone
formation (801). These mice have not been studied during
lactation. A mouse model with selective deletion of calcitonin has not been created. It would be especially informative to selectively delete calcitonin from mammary epithelial cells at the onset of lactation.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
Ctcgrp nulls leads to effects that loss of CTR cannot reproduce. Since the breast appears to be a key controller of the
skeletal response to lactation, as explained in section IVF, if
CTR is not ablated in mammary tissue or if calcitonin’s
actions within mammary tissue are not mediated by CTR,
then that could explain the more modest phenotype of the
conditional Ctr knockout during lactation.
2. Human data
No clinical studies have specifically tested whether calcitonin deficiency leads to increased bone resorption during
lactation. No individuals with inactivating mutations of
calcitonin or its receptor have been identified. However, it
is intriguing to speculate that such women may be among
the extreme cases of more marked bone loss or multiple
vertebral compression fractures that have been seen during lactation (501). In one report a thyroidectomized
woman nursing twins experienced multiple vertebral
compression fractures and had marked bone loss confirmed by DXA; the authors speculated that calcitonin
deficiency was to blame (811). But thyroidectomized
women are not expected to be calcitonin deficient while
breastfeeding because calcitonin produced by breast tissue leads to normal circulating calcitonin levels (52, 131,
755).
As noted earlier, long-term followup of thyroidectomized
men and women has yielded conflicting results as to
whether or not there is increased risk of bone loss and
fractures (326, 338, 422, 630, 659). More recent studies are
confounded by the use of high doses of thyroid hormone to
suppress TSH and reduce the risk of recurrence of thyroid
cancer.
I. Low or High Calcium Intake
1. Animal data
The preceding sections have made clear that lactating rodents require abundant calcium from multiple sources, mediated by increases in intestinal calcium absorption, skeletal
resorption, and renal tubal calcium reabsorption. But
within some limits, the rodent is capable of extracting more
from the skeleton when the diet is deficient, or more from
the diet when the skeleton cannot be resorbed. Consequently, a calcium-restricted diet increases skeletal losses
and also can lead to hypocalcemia and sudden death from
tetany; conversely, a high-calcium diet reduces skeletal
losses. Similarly in ewes, a calcium-restricted diet causes a
lower serum calcium, increased resorption, and reduced
skeletal ash weight within the vertebrae and pelvis by the
end of lactation, with relative sparing of the long bones
(69). A high-calcium diet reduces the amount of skeletal
resorption. In these studies there was no impact on the
offspring unless the mother died of hypocalcemia, because
the milk calcium content was maintained. Similarly, blocking bone resorption by treating with OPG did not affect
milk calcium content unless the animal was also given a low
calcium diet, thereby blocking the delivery of needed calcium to mammary tissue (37). These results confirm that
rodents and sheep rely on both compartments (skeleton and
intestines) to get needed calcium, but can get by with one of
these compartments alone. However, if mobilization of calcium from both compartments is blocked, then milk cannot
be produced adequately and severe maternal hypocalcemia
is inevitable.
Low calcium intake in the post-weaning phase has been
shown to impair skeletal recovery in rats, but full recovery
was achieved when a normal calcium diet was administered
later (355).
3. Summary
2. Human data
Surgical models in rats and goats have provided evidence
that loss of thyroidal calcitonin leads to increased bone loss
during lactation compared with sham-operated animals;
however, these effects were not confirmed by a larger study.
More recent use of gene ablation techniques has shown that
global loss of calcitonin and CGRP-␣ leads to a doubling of
bone loss during lactation but full recovery afterward. This
confirms that calcitonin is needed in the short term to prevent excessive skeletal resorption, but not in the long term
520
The calcium content of milk appears to be largely derived
from skeletal resorption. Low calcium intake does not reduce breast milk calcium, nor does it lead to increased resorption of the maternal skeleton during lactation (440,
535, 728 –731). Conversely, high calcium intake similarly
fails to increase breast milk calcium or reduce skeletal resorption during lactation (206, 275, 440, 452, 484, 535,
723, 729, 730); its only effect may be to increase urinary
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There is some consistency to the evidence that calcitonin
inhibits bone resorption during lactation. Global loss of
calcitonin and CGRP-␣ leads to more marked bone loss
than the surgical models, which may be explainable by retention of extrathyroidal (especially mammary) sources of
calcitonin in the surgical models. Conditional but incomplete deletion of CTR leads to increased osteocytic osteolysis but does not fully reproduce the phenotype of the Ctcgrp
null.
since the skeleton recovers fully from these extreme losses of
bone. Conditional deletion of CTR did not fully reproduce
the effects of loss of calcitonin and CGRP-␣. No human
studies have tested whether calcitonin deficiency causes excess bone loss during lactation, but it may contribute to
some of the extreme cases of lactational bone loss and fractures that have been reported in the literature.
CHRISTOPHER S. KOVACS
calcium excretion. These data from randomized clinical trials and cohort studies indicate that it does not matter how
much calcium is consumed during lactation because maternal skeletal resorption is hormonally programmed to supply needed calcium. There is no evidence that women require a higher intake of calcium during lactation compared
with nonpregnant women.
There are no data from lactating women with hyperphosphatemic disorders, but it is conceivable that phosphorus
content of milk will be elevated.
3. Summary
3. Summary
Whereas rodents will increase or decrease skeletal resorption during lactation in inverse proportion to calcium intake, in breastfeeding women the magnitude of skeletal resorption appears to be independent of the extremes of low
and high calcium intake. Consequently, it is quite evident
that women do not require increased intakes of calcium
during lactation because there is no benefit on the skeletal
response or on the calcium content of milk. Maintaining
adequate calcium intake is probably more crucial during the
post-weaning phase when the skeleton is reversing the uncoupled state of bone turnover from net resorption to net
formation.
J. FGF23-Related Disorders
1. Animal data
Phex⫹/⫺ females remain hypophosphatemic and normocalcemic during lactation, nurse the same number of pups as
normal controls, and their pups gain weight normally
(240). Analysis of expressed milk from Phex⫹/⫺ females has
shown normal phosphorus, calcium, and protein content
(240).
Hyperphosphatemic disorders due to absence of FGF23
have not been studied during lactation because of the inability to obtain pregnancies in Fgf23 null or Klotho null mice.
The effects of experimental renal failure causing maternal
hyperphosphatemia have not been studied during lactation.
2. Human data
Serum phosphorus was low during pregnancy and immediately postpartum in a woman with XLH, but normalized
once lactation was fully established (447). This supports the
Although hypophosphatemic mice produce milk with normal mineral composition, XLH in women reduces the phosphorus content of milk by 50%, and inconsistently reduces
the calcium content. These changes will contribute to the
development of neonatal rickets. However, the phosphorus
content of milk can be normalized with oral phosphorus
supplementation.
VI. CONCLUSIONS
Pregnancy and lactation invoke novel regulatory systems in
women to meet the challenges for increased delivery of minerals (FIGURE 9).
A doubling of intestinal calcium and phosphorus absorption during pregnancy meets the fetal mineral demand. This
adaptation may be only partially explained by a severalfold
increase in calcitriol and may persist despite vitamin D deficiency and inherited disorders of vitamin D physiology.
Minimal skeletal calcium is normally resorbed during pregnancy, but this will increase significantly and lead to skeletal fragility if maternal calcium intake is very low, because
the placenta acts to maintain calcium delivery to the fetus
even if the mother is hypocalcemic. The maternal kidneys,
not the placenta, supply most of the increased calcitriol
output during pregnancy, but do not seem to aid calcium
conservation because absorptive hypercalciuria is commonly found. Spot and fasting urines will not detect this
hypercalciuria.
A marked uncoupling of bone turnover to favor skeletal
resorption is the main mechanism by which calcium is supplied to the breast milk, aided by renal calcium conservation
and (in women) independent of dietary calcium intake. The
lactational response is driven by breast-produced PTHrP in
the setting of low estradiol, while PTH, vitamin D, and
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No studies have examined calcium requirements during
post-weaning, which may be the more critical time for adequate calcium intake. However, a study of adolescents
recovering from lactation found that there was a substantial
increment in bone mass despite a habitual intake of ⬍500
mg calcium/day (78). Randomization to a 1 g calcium supplement conferred a small benefit in bone mass gain during
6 mo of recovery (452), which confirms that calcium intake
can have a positive impact on bone mass accrual during this
interval.
idea that skeletal resorption is responsible for the increase in
serum phosphorus that normally occurs during lactation.
However, despite normalization of serum phosphorus, the
phosphorus content in expressed milk was 50% of normal
in two cases, whereas the calcium content was modestly
reduced in one but normal in the other (447, 745). Oral
phosphorus supplementation normalized the milk composition (447). In both cases, the babies inherited XLH and
subsequently became hypophosphatemic with skeletal evidence of rickets, which was likely due to the combined
effects of the mutation and the low phosphorus content of
milk (447, 745). This contrasts with apparently normal
milk phosphorus content in the mouse model.
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
FIGURE 9. Comparison of the adaptive processes of calcium and bone homeostasis during
human pregnancy and lactation, compared with
normal (nonpregnant, nonlactating). The thickness of arrows indicates a relative increase or
decrease with respect to normal. [Adapted from
Kovacs and Kronenberg (499). Copyright 1997
The Endocrine Society. Permission conveyed
through Copyright Clearance Center, Inc.]
After weaning the baby, an uncoupling of bone turnover in
the reverse direction from lactation is initiated, thereby favoring net bone formation. Osteoblasts upregulate number
and function while (at least in rodents) osteocytes function
like osteoblasts to remineralize their lacunae. The maternal
skeleton rapidly restores itself such that by 6 –12 mo after
lactation, the bone density has usually returned to baseline
or better, even in women who suffered fragility fractures.
This is an otherwise unprecedented interval of recovery
since most causes of bone loss in adults, once the insult is
removed, result in slow and partial recovery of bone mass
and structure. It appears that weaning triggers a programmed, sustained interval of bone formation, but the
mechanisms that regulate this recovery remain to be elucidated.
In the long term, most studies show that parity and lactation pose no adverse risk of low bone mass or fractures, and
in fact a number of studies have suggested that parity and
lactation confer a protective effect. These results may imply
that the cyclical resorption and rebuilding of the maternal
522
skeleton leads to beneficial changes in bone structure and
strength that are not seen in women who never bear a child
or breastfeed.
There are important differences among the various animal
models and in how they compare to and inform about the
human condition (TABLES 1 and 2). These issues must be
considered whenever animal studies are used to model the
response of women to pregnancy or lactation.
Lastly, these adaptations during pregnancy and lactation
have important effects on preexisting disorders of bone and
mineral metabolism. The presenting symptoms, signs, diagnostic indices, and treatment thresholds may be altered.
This is best exemplified by the normalization in mineral
homeostasis that occurs in hypoparathyroid women during
lactation, but which has led to iatrogenic and life-threatening hypercalcemia when unappreciated and left unmonitored.
ACKNOWLEDGMENTS
I thank Dr. Henry M. Kronenberg for providing critical
feedback on the manuscript and Drs. Scott Miller, Mary
Wlodek, and John Wysolmerski for clarifying the calcium
content of the diet used in some of their studies.
Address for reprint requests and other correspondence: C.
Kovacs, Health Sciences Centre, 300 Prince Philip Dr., St.
John’s, NL A1B 3V6 Canada (e-mail [email protected]).
GRANTS
This work was supported by Canadian Institutes of Health
Research Grants 133413, 126469, and 84253 and by Re-
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calcitriol are not required. Osteoclast-mediated bone resorption and (at least in rodents) osteocytic osteolysis contribute to the loss of skeletal mineral content. A similar
magnitude of bone loss occurs during lactation in women
with very low or high calcium intakes. In some women the
normal skeletal resorption during lactation may be sufficient to cause fragility fractures, whereas for the majority of
women it is a silent process that they are never aware of.
There is normally very little vitamin D or 25OHD in milk,
which explains why breast-fed babies are at higher risk for
rickets than formula-fed babies. Very high intakes of vitamin D will increase the breast milk content of vitamin D,
but will not alter breast milk calcium content.
CHRISTOPHER S. KOVACS
search & Development Corporation of Newfoundland and
Labrador Grant 5404.1145.102.
19. Allen JC. Effect of vitamin D deficiency on mouse mammary gland and milk. J Nutr
114: 42– 49, 1984.
DISCLOSURES
20. Allen JC, Keller RP, Archer P, Neville MC. Studies in human lactation: milk composition and daily secretion rates of macronutrients in the first year of lactation. Am J
Clin Nutr 54: 69 – 80, 1991.
No conflicts of interest, financial or otherwise, are declared
by the author.
21. Allen WM, Sansom BF. Parturient paresis (milk fever) and hypocalcemia (cows,
ewes, and goats). In: Current Veterinary Therapy: Food Animal Practice 2, edited by
Howard JL. Philadelphia, PA: Saunders, 1986, p. 311–320.
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