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Advanced Nutrition
Mineral Nutrition * Calcium
MargiAnne Isaia, MD MPH
MINERAL NUTRITION
Calcium – the most abundant mineral in the human body
Macro mineral – needed in amounts > 100 mg/day
Nutritionally essential mineral
- essentiality confirmed by biochemical mechanisms
Criteria for essentiality:
- is present in tissues of different animals at similar concentrations
- withdrawal produces similar physiological or structural abnormalities
regardless of species
- presence reverses or prevents abnormalities
- abnormalities are related to or a consequence of specific biochemical
changes that can be reversed by the essential element
MINERAL NUTRITION
Biologic roles of Calcium
Structural/mechanical: bone, teeth
99% of the total body Ca
The skeleton – obvious structural role
- important reservoir to maintain plasma Ca concentration
The bone Ca pool in adults turns every 8-12 years
- turnover does not occur in the teeth
Remodeling of the bone continues throughout life
Bone formation and bone resorption are balanced processes
Bone formation exceeds resorption during growth
If bone resorption exceeds bone formation – osteoporosis
Osteoblasts: receptors for PTH, 1,25(OH)2 Vitamin D, estrogen, Pg E2
Osteoclasts: receptors for Calcitonin (CT) and variety of cytokynes
Bone resorption – enhanced by PTH and inhibited by CT
MINERAL NUTRITION
The Bone Minerals
Distribution (%)
Tissue
Calcium
Phosphate
Magnesium
Skeleton
99
85
55
Soft tissue
1
15
45
ECF*
< 0.2
< 0.1
<1
Total (g)**
1000
600
25
ECF* extra cellular fluid
Total (g)** for an 70 kg male
MINERAL NUTRITION
Plasma levels are physiologically controlled
Physiochemical states (% of total)
State
Calcium
Phosphate
Magnesium
Free
(ionized)
50
55
55
Protein-bound
40
10
30
Complexed
10
35
15
Serum (total) *
9-10.5 mg/dl
or
2.25-2.75 mmol/L
3.0-4.5 mg/dl
or
0.97-1.45 mm0l/L
1.3-2.1 mEq/L
or
0.65-1.05mmol/L
Serum (total)* Adult levels
MINERAL NUTRITION
Biologic roles of Calcium
Catalytic: co-factor, co-enzyme for
- proteases
- blood clotting enzymes
These functions are not significantly affected by changes
in extracellular Ca2+ concentration
Signal transmitter: ionized Ca – the most common in all of biology
Binding to a large number of cell protein
with activation of their unique function
MINERAL NUTRITION
Examples of cell proteins binding or activated by Ca
Protein
Function
Calmodulin
Troponin C
Calretinin, retinin
Calneurin B
Protein kinase C
Phospholipase A2
Caldesmon
Parvalbumin
Calbindin
Calsequestrin
Modulator/regulator of several protein kinases
Modulator of muscle contraction
Activator of Guanyl cyclase
Phosphatase
Widely distributed protein kinase
Synthesis of arachidonic acid
Regulator of muscle contraction
Calcium storage
Calcium storage
Calcium storage
MINERAL NUTRITION
Extracellular and Intracellular Function
Extracellular fluid Calcium
- Forms: free ionized - approx 50%
protein bound, mostly to albumin, some to globulin
complexed to phosphate, citrate, etc
- Functions: source of calcium to skeleton and cells
blood clotting
intercellular adhesion
Intracellular Calcium
- Function: 2nd messenger, activates kinases to phosphorylate proteins;
involved in:
- muscle contraction
- neurotransmitter release
- Glycogen metabolism
- enzyme activation
- hormone release
- vision
- cellular differentiation
MINERAL NUTRITION
Ca = important extracellular “first” messenger
Key intracellular second messenger
Ionized Ca – the most common signal transduction element in cells,
because of its ability to bind to proteins reversibly
To effect a regulatory change, an internal or external stimulus (physical, electrical or chemical)
causes a change in Ca 2+ at a specific site in the cell, by:
- releasing a store of Ca 2+ from within
- causing Ca 2+ to enter the cell from outside.
Accumulation of Ca 2+ in the cytosol - followed by Phosphate precipitation
and cell death (Phosphate=vital in energy transfer)
The plasma membrane is important in maintaining Ca homeostasis
Calmodulin = intracellular Ca 2+ receptor protein that increases the total
capacity of Ca/Mg-ATP-ase pump
Ca 2+ flux across the plasma membrane:
influx pathways:
- potential-operated (voltage-dependent) channels
- receptors-operated channels
- Na+ channels (NCX)
efflux pathways: Na+/Ca 2+ exchange pathway maintained by Na pumps
PLASMA MEMBRANE AND CALCIUM HOMEOSTASIS
MINERAL NUTRITION
Ca Mechanism of Action
Stimulus g Receptor g Response
Receptors: G-protein-coupled receptors
tyrosine kinases receptors
Phospholipase C activated
PIP2 g
Phosphatidyl Inositol 4,5 –biPhosphate
IP3
+
Inositol triphosphate
DAG
Diacylglycerol
IP3 binds to R in ER or sarcoplasmic reticulum
it follows liberation of Ca 2+ from stores
hCa 2+ in cytosol g binds to Calmodulin g activates Kinases
DAG activates Protein kinase C which stimulates activity of Ca pump
Ca receptor protein pathways are universal in excitable and non-excitable cells.
Excitable cells(skeletal muscles, neurons) contain voltage-dependent Ca 2+ channels.
Entering Ca 2+ activates Ryanodine Receptors to release Ca 2+ from internal stores.
MINERAL NUTRITION
Mechanism of Action
Increased Ca 2+ in cytosol
binds to Calmodulin
Calmodulin activates Kinases
MINERAL NUTRITION
Calcium Homeostasis
Blood Calcium levels are constant:
physiologically maintained within a narrow range by:
- a system of controlling factors
- feed back mechanisms
Serum Calcium does not reflect nutritional status
Extracellular Calcium levels are detected by surface Ca 2+- sensing receptors (CaRs)
- CaRs are members of the super-family of G-protein-coupled receptors
- found in parathyroid, clear cells of thyroid, kidney, intestine, lung, brain, skin,
bone marrow, osteoblasts etc
- The CaR permits Ca 2+ to act as an extracellular 1st messenger
MINERAL NUTRITION
Calcium Homeostasis
When blood Calcium levels fall:
h Parathyroid hormone (PTH), and
h formation of 1,25-(OH)2 vitamin D
It results in:
h Calcium absorption
h renal tubular reabsorption of Calcium
h bone resorption
When blood Calcium levels increase:
i PTH
i formation of 1,25-(OH)2 vitamin D
h Calcitonin (hormone produced in thyroid, it lowers blood Ca)
It results in:
i Ca absorption
i renal reabsorption of Calcium
i bone resorption
The three tissues supporting Ca serum levels: gut, kidney and bone operate independently
of one another. Altered responsiveness of any of these can increase bone fragility
CALCIUM HOMEOSTASIS
CALCIUM HOMEOSTASIS
PTH/1,25(OH)2 D axis:
PTH stimulates Calcitriol synthesis
h renal 1 a 25 HO-ase activity
MINERAL NUTRITION
Calcium Homeostasis
Aging-suppressor gene Klotho involved in the renal control of Calcium,
Phosphate and Vitamin D metabolism
Klotho
- suppresses Phosphate re-absorption in renal proximal tubule
by directly binding to FGF receptors
- regulates Ca re-absorption in the distal convoluted tubule
by stabilizing TRPV5 Ca channel in plasma membrane
- decreases Calcitriol level
by inhibiting renal 1- a 25-hydroxylase activity
CALCIUM HOMEOSTASIS
FGF 23/Klotho axis
FGF 23 + Klotho actions:
- synergistic with PTH
(reduce tubular Phosphate reabsorption)
- antagonic with PTH
(inhibit Calcitriol synthesis)
MINERAL NUTRITION
Calcium absorption
From intestinal lumen, two distinct mechanisms of absorption
- their relative magnitude is determined by the amount of free Calcium available
for absorption
Transcellular:
active, saturable, only in duodenum, when Ca intake is low
Ca - enters the cell through voltage-insensitive (TRP) channels
- is pumped out of the cell via PMCA, primarily
- the rate limiting step is transport across the epithelial cell;
- greatly enhanced by carrier protein Calbindin
(Calbindin synthesis is totally dependent on Vitamin D)
Paracellular:
diffusional, nonsaturable,
in jejunum & ileum, and lesser extent in colon,
when dietary Ca is moderate or high
- transfer is linear function of Ca content of the chym
MINERAL NUTRITION
Calcium absorption
Factors affecting absorption:
background diet (nutrient-nutrient interaction), Calcium intake
(chemical form, solubility, pH),
vitamin D status, Ca nutritional status, serum Phosphorus level,
mucosal mass, intestinal transit time,
health status, stage of life, drug interactions, other
Increased absorption:
vitamin D adequacy, dietary enhancers, increased mucosal mass,
Ca deficiency, pregnancy, post-weaning status,
mucosal permeability, some minerals adequacy (Mg, K, Cu, B, Mn)
Decreased absorption:
vitamin D deficiency, decreased mucosal mass,
elderly (increased intestinal resistance to active vitamin D with age),
menopause, estrogen deficiency , decreased stomach acid,
rapid intestinal time, dietary inhibitors: oxalate, phytate
MINERAL NUTRITION
Food Sources and Bioavailability
Potential Calcium sources vary in gross Ca content and bioavailability
Bioavailability
-fraction of an ingested component that enters the blood circulation
and that can be used for physiological functions or storage.
-depends on absorption, distribution, metabolism, and excretion
Fractional Ca absorption from various dairy products is similar: approx. 30%.
Adjuvant added to food matrices
substantially alter bioavailability
Some plant constituents form indigestible salts with Ca giCa absorption
Oxalic Acid – the most potent inhibitor of Ca absorption
(high concentration in spinach, rhubarb)
Phytic Acid – modest inhibitor of Ca absorption
( the storage form of Phosphorus in seeds)
Fermentation, as occurs during bread making,
reduces Phytic Acid (Phytase present in yeast)
results in increased Ca absorption
Only concentrated sources of phytate (wheat bran ingested as extruded cereal
or dried beans) substantially reduce Ca absorption
MINERAL NUTRITION
Food Sources and Bioavailability
Plant rich in Ca Brassica genus:
- broccoli, kale, bok choy, cabbage, Mustard and Turnip greens
- Ca bioavailability is as good as that from milk
Brassica: an anomaly in the plant kingdom
oxalate not accumulated as a medium to detoxify excess Ca
to protect against cell death
Ca fortified food sources: fruit juices, fruit drinks, tofu, cereals
Calcium content of 8 fl oz of milk (240 ml)
compared to other food sources of Calcium
8 fl oz of mill = 1 cup yogurt = 1 ½ oz Cheddar cheese
= 1 ½ cups cooked kale
= 2 ¼ cups cooked broccoli
= 8 cups of cooked spinach
Mineral Nutrition
Comparing food sources of absorbable Calcium
FOOD
serving
size (g)
estimate CA
content (mg)
percentage
absorption (%)
Ca per serving
(mg)
Milk
Beans, pinto
Beans, red
Beans, white
Bok Choy
Broccoli
Cheddar cheese
Chinese mustard greens
Juice, Ca-fortified
Kale
Soymilk, Ca-fortified
Spinach
240
86
172
110
85
71
42
85
240
85
240
85
300
44.7
40.5
113
79
35
303
212
300
61
300
115
32.2
26.7
24.4
21.8
53.8
61.3
32.1
40.2
32.1
49.3
23.7
5.1
96.3
11.9
9.9
24.7
42.5
21.5
97.2
85.3
96.2
30.1
71.1
5.9
MINERAL NUTRITION
Nutrient Impact on Intestinal Ca Absorption and Renal Ca Excretion
Vitamin D
- most critical factor
- necessary for the active transport of Ca across the intestinal
mucosa
Protein
- protein is a major bulk constituent of bone
must be regularly supplied by the diet (low protein diets- elevated PTH;
protein intake associated with higher BMD)
- protein and Ca balance
- studies using purified protein:
1 mg rise in urinary Ca excretion for each 1 g of ingested protein
Sulfur containing AA - acid load- increase Ca excretion
Phosphorus in protein-rich foods has a hypocalciuric effect
- studies using whole food protein (meat, dairy):
no rise in urine Ca
- Kerstetter et al. 1998: high protein intake increases Ca absorption
MINERAL NUTRITION
Nutrient Impact on Intestinal Ca Absorption and Renal Ca Excretion
Phosphorus
- Bone mineral is predominantly Calcium Phosphate and
adequate dietary phosphate (Pi) is essential for bone
Effect of dietary Pi (Soda, additives, preservatives)
- iurinary Ca losses
-iCa absorption
Children who drink Soda instead of milk get depleted in Calcium
Ca supplements containing Phosphorus
(Tricalcium Phosphate, Dicalcium Phosphate)
have a diminishing effects on Ca absorption compared to
supplements without Phosphate
Caffeine
- short-term increase in urinary Calcium (diuretic effect?)
- daily consumption of caffeine equivalent to 2-3 cups of coffee
accelerated bone loss from the spine and total body in postmenopausal women
who consumed < 744 mg Ca/day
maybe small decrease in Ca absorption or confounding factor:
inverse association between milk intake and caffeine intake
MINERAL NUTRITION
Nutrient Impact on Intestinal Ca Absorption and Renal Ca Excretion
Sodium
- major determinant of urinary Ca is urinary Sodium
urinary Sodium reflects mainly dietary Sodium
excessive Sodium (NaCl) increases urinary Ca excretion
Sodium and Calcium share some of the same transport systems
in the proximal tubule:
- each 1000 mmol (2.3 g) increase of Sodium excreted
pulls out 0.6-1.0 mmol (20-40 mg) Ca
Herbal seasoning instead substantial use of salt reduces calciuria
Potassium
- for each 100 mg of Potassium ingested, 15 mg Ca is conserved
Calcium status is negatively impacted by an acid residue
ALKALINE RESIDUE from Mg & K RICH INTAKE INHIBITS BONE RESORPTION
MINERAL NUTRITION
Calcium Nutrition
Calcium not a typical nutrient
- critical biochemical roles
- inexhaustible reserve
- amount absorbed and retained depends on physiological state
Calcium requirements for bone health throughout life = not uniform
- changes in skeletal growth
- age-related changes in absorption and excretion
RCT: increased Ca intake results in:
increased Ca balance and increased bone gain during growth,
reduced bone loss in later years, reduced fracture incidence
Ca requirements based on maximal Calcium retention
- DRI: Adequate Intake (AI)
9-13 years & 14-18 years: 1300 mg
Adult: 1000 mg
Elderly: 1200 mg
MINERAL NUTRITION
Infancy
The rate of Ca deposition in relation to body size
higher than at any other period during life
Childhood and adolescence
Rate of growth slows between 2 and 8 years
Between 9 and 17 years, approx 45% of the adult skeleton is acquired,
the rate is not uniform
Maximal growth:
girls 12-14 years
boys 14-16 years
Regulators of the pubertal growth spurt and skeletal maturation:
- Insulin-like Growth Factor–1
- sex steroid hormones
Peak bone mass
= end of the phase of bone consolidation
= the maximum amount of bone accumulated
Girls, women,
90% of total body mineral content by age 16.9
99% of total body mineral content by age 22 years
ADOLESCENCE
The main determinant of bone density in adolescent girl is Ca intake.
Other lifestyle choices that affect peak bone mass:
- physical activity
- intake of other nutrients that affect Ca balance
- anorexia
- substance abuse
Beyond the timing of peak bone mass, lifestyle choices can affect the rate
of bone loss, but the window of opportunity to build bone has passed.
MINERAL NUTRITION
- total body bone mass- relatively constant over the reproductive years
Age-related bone loss
- varies with the individual
- most rapid during the first 3 years after menopause in women
The average adult loses bone at a rate of approx 1% year
Causes: declining Ca intakes, decreased efficiency of Ca conservation,
declining physical activity, decreased level of gonadal
hormones, decreased circulating levels of 1.25 (OH)2 D,
increased intestinal resistance to 1.25 (OH)2D
Results: - decreases in Ca absorption
- increases in urinary Ca
Ca intake required to prevent bone loss are sufficient to protect against the
risk of HTN ( 500-600 mg/day)
MINERAL NUTRITION
Pregnancy
During the third trimester 200mg/day of Ca – required for fetal growth
The mother’s Ca absorption increases beginning the second trimester
- to meet fetal demands
- to store Ca for the lactation period
Lactation
Ca transfer to breast milk varies with changes in volume
Breast milk concentration is relatively constant (280±26 mg/L)
- independent of the Ca content of the mother’s diet
Daily Calcium transfer from maternal serum to breast milk :
at 3 months following parturition 168 mg/d
at 6 months following parturition 280 mg/d
Increased Ca absorption at the end of pregnancy gradually disappears after childbirth
and during lactation period
Some renal conservation occurs, but maternal skeleton is depleted
at a rate of 1% per month
This loss - not prevented with Ca and Vitamin D supplementation
A post lactation anabolic phase allows recovery of bone density to pre lactation levels.
MINERAL NUTRITION
Adequacy of Calcium intake
Assessing a person’s usual Ca intake – many errors
- food frequency questionnaire
- diet recalls
- diet records
- duplicate plate analysis
Hidden Calcium taken in as food additives, water, fortified foods, components
of pharmaceutics
Upper tolerable limit, UI = 2500 mg/day
Adequate Intake (AI) for Calcium
Males
(mg/day)
Females (mg/day)
0-6 months
210
210
Infants
7-12 months
270
270
Children
1-3 years
500
500
Children
4-8 years
800
800
Children
9-13 years
1,300
1,300
Adolescents
14-18 years
1,300
1,300
Adults
19-50 years
1,000
1,000
Adults
51 years and
older
1,200
1,200
Pregnancy
18 years and
younger
-
1,300
Pregnancy
19 years and
older
-
1,000
Breastfeeding
18 years and
younger
-
1,300
Breastfeeding
19 years and
older
-
1,000
Life Stage
Age
Infants
MINERAL NUTRITION
MINERAL NUTRITION
Assessment of Calcium status
Total body bone mineral estimation
- dual energy X-ray absorptiometry (DEXA)
Interpretation of the results:
reserve = low - nutritional causes
- other: lack of adequate PA, weight loss
gonadal hormone deficiency,
medical diseases & their treatments
Serum Ca – total
- ionized
Low serum Ca – usually, means some abnormalities of PTH
- rarely, because of dietary Calcium deficiency
MINERAL NUTRITION
Calcium toxicity
Elevation of blood Calcium level = Hypercalcemia
Reasons: - overconsumption of Calcium
- elevation of urine Calcium excretion to the point that
either the kidneys calcify or renal stones develop
Hyper Ca : lax muscle tone, constipation, polyuria, nausea,
confusion, coma, death
Never occurs from ingestion of natural food sources
Results with ingestion of large quantities of Calcium as supplements
taken with absorbable alkali:
h urinary pH predisposes to Ca deposits in the kidneys
Milk alkali syndrome - in the treatment of Peptic Ulcers with large
quantities of milk, CaCO3 and NaHCO3
CALCIUM TOXICITY - NERVE CELL
MINERAL NUTRITION
Calcium toxicity
High Ca intakes contribute to kidney stone formation in susceptible persons.
Ca oxalate – the most common form of kidney stones in the US
Studies: high oxalate intake and reduced fluid consumption appear to be
more of a risk factor in the formation of kidney stones than Ca in
most individuals
Urinary oxalate excretion - more important risk factor for stones that
urinary Ca excretion
In general, the stone problem is helped by increasing Ca intake
a high-Ca diet: binds oxalate of dietary origin in the gut and
prevents its absorption,
thereby reducing urinary oxalate load
References:
5 ICVN, Loma Linda USA, 2008
Modern Nutrition in Health and Disease, Shils, 10th edition
www.pcrm.org
www. Pubmed.org
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