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Is post-menopausal osteoporosis a
calcium related disorder?
Alpa Kanji MBBS 4, King’s College London
Submission for Amulree Essay Prize
Word count: 5,638
January 2012
Alpa Kanji, King’s College London
Is post-menopausal osteoporosis a calcium related disorder?
Summary
Osteoporosis causes considerable morbidity and mortality due to an increase in bone
fragility which results in a higher incidence of fractures. Bone is a dynamic tissue
where the processes of bone resorption and formation are tightly coupled. Oestrogen
plays an important role in the interactions and functions of bone cells such that an
absence of this hormone can result in a reduced bone mass leading to osteoporosis.
PTH, secreted in response to chronic hypocalcaemia during aging, can also drive a
decrease in bone mass. Whilst osteoporosis may be related to hypocalcaemia, this is
by no means the only driver for disease development. This is also reflected in the fact
that calcium supplementation has been shown to attenuate losses in bone mineral
density, but does not completely stop bone loss. The challenge is to obtain a more
comprehensive picture of the factors driving the osteoporosis disease process which is
clearly complex and multifactorial.
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1. Osteoporosis is the commonest disease of bone
Osteoporosis is characterised by low bone mass and micro-architectural deterioration
of bone, leading to fragility and an increased risk of fracture (World Health
Organisation, 1994). Osteoporosis is by far the commonest disease of bone (Graham
et al., 2006). It has been estimated that over 200 million people worldwide have
osteoporosis and its prevalence is continuing to increase with the growing elderly
population (Reginster & Burlet, 2006). The socio-economic burden caused by this
disease on the national health systems of developed nations is significant. Currently,
osteoporosis and its related fractures are estimated to cost the UK National Health
Service £2.3 billion a year (National Osteoporosis Society, 2010).
The prevalence of osteoporosis and of its related fractures increases significantly with
age which may be partly attributed to a decline in bone mass coupled with the
increased incidence of falls amongst the elderly (Doherty et al., 2006). Osteoporosis
is also more common amongst women than men. Estimates suggest that in the UK
one in two women over 50 years of age will have a fracture compared to 1 in 5 men
(Staa et al., 2001). American physician Fuller Albright first described postmenopausal osteoporosis and suggested that the causative factor was oestrogen
deficiency. Later Riggs et al., proposed that there were two types of primary
osteoporosis; one associated with the post-menopausal stage (Riggs et al., 2002) and
another form associated with aging (Riggs et al., 1982).
Clinically, osteoporosis may initially be silent but can present with bone fragility
fractures, height loss, kyphosis and back pain due to vertebral osteoporosis (Graham
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et al., 2006). Fragility fractures commonly occur at the wrist (Colles’ fracture),
vertebrae and hip. These fractures can result in considerable morbidity, decreased
quality of life and are associated with an increased risk of mortality. The gold
standard for diagnosing osteoporosis is by assessing bone mineral density (BMD),
which is a quantitative measure of bone mass, usually at the proximal femur or
lumbar spine using dual energy X-ray absorptiometry (DXA).
In order to understand the aetiology and pathology of post-menopausal osteoporosis,
the normal physiology of bone including some of the factors driving bone remodelling
will be considered. It is important to attempt to unravel how changes in this process
may result in enhanced bone fragility and an increased incidence of fractures.
2. Bone is a dynamic tissue
Bone has multiple functions: it serves as an attachment site for muscles, thereby
permitting locomotion and it has a protective function as it encloses bone marrow and
vital organs. Bone also serves as a storage reservoir for calcium and phosphate and
plays a role in mineral homeostasis (Kumar & Clark, 2005).
2.1.Bone organization and composition
The human skeleton consists of 80% cortical bone, which is the dense, compact outer
part of bone, and 20% trabecular bone, which forms the inner meshwork (Rang et al.,
2005). Bone consists of 70% inorganic (mineral) matter by weight, 5-8% water with
organic matter constituting the remainder (Marcus et al., 2001). The inorganic
constituent of bone is mainly crystalline hydroxyapatite [Ca10 (PO4)6 (OH)2]. The
organic matrix of bone, known as osteoid, consists mostly of Type I collagen.
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Mineralization occurs by deposition of hydroxyapatite between the collagen fibrils,
which transforms it into hard bone matrix (Rang et al., 2005).
Bone metabolism is regulated by osteoblasts, osteoclasts and osteocytes. Osteoblasts
are responsible for bone formation but also play a critical role in bone turnover. They
synthesise osteoid but also initiate bone resorption by secreting proteases which
remove surface osteoid. Osteoclasts are the cells ultimately responsible for bone
resorption (Doherty et al., 2006). The function of osteocytes is not well understood.
2.2. Bone remodelling
Bone is a dynamic tissue, which is constantly being broken down and re-built via a
process known as remodelling. Remodelling results in the removal of bone mass from
areas of low mechanical stress whilst new bone is laid down in areas where
mechanical loads are transmitted repeatedly. This is a critical process for maintaining
normal bone structure (Marcus et al., 2001). Bone remodelling occurs on the surface
of trabecular bone, within small packets of cells called basic multicellular units
(BMUs) (Frost, 1991). The process of remodelling starts with the recruitment and
activation of osteoclast precursors in response to local release of chemotactic factors
in response to areas of damage. Osteoblasts regulate the differentiation of these cells
to mature osteoclasts which are responsible for bone resorption. The molecular
mechanism of this interaction has been elucidated: osteoblasts produce Receptor
Activator of NF-κB Ligand (RANKL) which binds to the RANK receptor on the
surface of osteoclasts and osteoclast precursors. This receptor-ligand interaction
promotes the differentiation of osteoclasts precursors into mature, functional
osteoclasts. Osteoblasts can secrete osteoprotegrin (OPG) which is a decoy receptor
that inhibits RANK/RANKL interactions, thus acting as an anti-resorptive cytokine.
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Osteoclasts form a tight sealing zone to the bone surface and resorb a discrete area of
bone by secreting hydrochloric acid and proteolytic enzymes, which help to dissolve
mineral and digest bone matrix, respectively. This process gradually liberates
cytokines and growth factors embedded in the osteoid. Once resorption is complete,
osteoclasts undergo apoptosis. The resorption phase is limited and followed by a brief
reversal phase during which osteoclast activity ceases. Bone formation then begins
which is substantially longer than the other three phases. Osteoblast precursors are
attracted to the site of the resorption by the local factors produced during the
resorption process. Here they mature and deposit new bone matrix which is then
mineralised to form mature bone. These cells are then embedded in the matrix as
osteocytes or undergo apoptosis. The enzyme alkaline phosphatase, which is produced
by the osteoblasts, is primarily responsible for calcification of the matrix (Doherty et
al., 2006).
2.2.1. Regulation of bone remodelling
In normal adults, there is a balance between the amount of bone resorbed by
osteoclasts and the amount of bone formed by osteoblasts and this process is tightly
balanced or ‘coupled’. Consistent with this, kinetic studies using radiotracers can
estimate the rates of bone formation and have shown that when bone resorption
increases, bone formation also increases (Harris & Heaney, 1969). This coupling is
essential to avoid bone loss during remodelling.
Bone remodelling is a complex process, regulated by locally produced cytokines,
growth factors, systemic hormones and mechanical factors. At the molecular level,
these factors are thought to exert their influence by modulating local expression of
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RANK, RANKL or OPG (Doherty et al., 2006). Some stimulators of bone resorption
appear to increase RANKL expression on osteoblasts and some can also decrease
OPG expression (Raisz, 2005). In fact, the RANK/RANKL/OPG system is thought to
be a critical pathway for osteoclast maturation and function (Boyle et al., 2003). Other
cells types may also be involved in RANK/RANKL interactions. T-lymphocytes can
produce soluble RANKL as well as inhibitory and stimulatory cytokines and so can
influence osteoclast development and function (Graham et al., 2006).
3. Calcium metabolism
Calcium has a vital role in the human body due to its involvement in a number of
biological functions such as extracellular and intracellular signalling, muscle
contraction and nerve impulse transmission. Intracellular free ion calcium levels are
typically maintained at levels 10,000 times less than that of extracellular calcium
(Marcus et al., 2001). This is achieved by calcium sequestering proteins which ensure
that functional cellular proteins remain dormant until they are activated by a rising
calcium concentration in certain cytosolic compartments.
In the serum, calcium normally ranges from 2.2-2.6 mM. It exists in three main forms:
as free ions, protein bound complexes and ionic complexes (Peacock, 2010). It is the
free ions that are physiologically relevant as bound calcium is not available to the
tissues (Kumar & Clark, 2005). Outside the blood vessels, cells detect the free ion
calcium concentration in the extracellular fluid which is tightly controlled. Most of
the body’s calcium (99%) is present within bone in the form of hydroxyapatite
(Peacock, 2010). Here it not only provides skeletal strength but also serves as a
dynamic reservoir, serving to maintain constant extracellular calcium levels.
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3.1. Calcium homeostasis is critical
Since calcium plays a key role in many important physiological processes, it is critical
to maintain its extracellular concentration within a narrow physiological range. This is
achieved by the actions of three main end organs: the intestines, kidneys and bones
coupled with the actions of parathyroid hormone (PTH) and vitamin D metabolites, as
well as by locally produced factors. The regulation of phosphate is intimately
associated with that of calcium but will not be considered here.
Dietary intake and absorption are essential to provide adequate amounts of calcium to
maintain body stores. Calcium balance is a result of the net effect of intestinal
absorption compared to renal, intestinal and sweat gland excretion, on the bone
calcium reservoir.
Absorption of calcium in the small intestine may be influenced by other dietary
components. In the absence of vitamin D, absorption of calcium is reduced. The
primary source for vitamin D in humans is photoactivation in the skin of 7dehydrocholesterol to cholecalciferol. This is an inactive form and is then
hydroxylated by the liver to 25-hydroxyvitamin D3 and by renal 1-α hydroxylase to
the active metabolite 1, 25-dihydroxyvitamin D3.
A series of events occur in response to diminished levels of ionised calcium
concentration in the plasma in order to attempt to restore this. The parathyroid chief
cells in the parathyroid glands detect this change via the calcium sensing (G-protein
coupled) receptor on their cell surface. These cells secrete PTH in response which is
an important regulator of calcium metabolism and exerts multiple effects. PTH
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enhances calcium absorption in the intestine indirectly by upregulating 1-α
hydroxylase, thereby increasing the levels of the potent metabolite 1, 25dihydroxyvitamin D3. This metabolite acts on the intracellular vitamin D receptor
(VDR) which is distributed widely amongst tissues including along the entire length
of the small intestine (Avioli, 2000). The vitamin D metabolite binds VDR, forming a
complex that acts as a transcription factor. This upregulates expression of various
calcium transport proteins including calcium binding proteins (calbindins) in the
enterocytes.
PTH and 1, 25-dihydroxyvitamin D3 both stimulate release of calcium from bone by
increasing osteoclast activity and promoting bone remodelling by upregulating
RANKL expression on osteoblasts. Consequently, RANK signalling and release of
factors by the osteoblasts result in differentiation of osteoclast precursors and
activation of mature osteoclasts. There is an increase in osteoclast activity and
mobilisation of calcium from bone thereby elevating the Ca2+ concentration in plasma
(Rang et al., 2005). Both PTH and 1, 25-dihydroxyvitamin D3 stimulate active
calcium reabsorption from the renal tubules.
Hypocalcaemia is a much greater risk in adults than is hypercalcaemia, however in
infants and young children, both these states are a potential threat (Marcus et al.,
2001). When serum calcium levels rise, hormones respond in order to reverse this
change. The increased calcium concentration acts via feedback inhibition to decrease
PTH release. Calcitonin is released by the parafollicular (C cells) in thyroid gland. Its
main effect is on bone where it binds to a specific receptor inhibiting bone resorption.
It also acts on the kidney to decrease calcium reabsorption in the tubules. However in
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adults, the role of calcitonin is uncertain. A total thyroidectomy where calcitonin is no
longer produced appears to be of little consequence, suggesting that its actions may
not be of great significance on adult skeletal remodelling (Rang et al., 2005).
4. The pathology of post-menopausal osteoporosis
In the diseased state, the mechanical properties of bone deteriorate to the extent that
under normal loading conditions fractures occur more readily. Bone strength depends
mainly on two factors. The first is bone mass, which is reflected by the BMD. The
second is the bone quality which encompasses several features including bone
microarchitecture and composition. The reduction in bone mass which occurs in postmenopausal osteoporosis has been widely regarded as the critical event that results in
increased fracture rates (Mosekilde, 2008). However, some studies suggest that
osteoporosis involves the loss of both bone mass and microarchitecture.
The decrease in bone mass can be linked to a change within the bone physiology.
Viewing this simplistically, uncoupling occurs between the normally tightly linked
processes of bone resorption and bone formation. Excessive bone resorption causes a
loss of bone mass and there is inadequate bone formation in response to this (Becker,
2006). The amount of bone mass (peak bone mass) which is present at the start is also
critical. The time needed for osteoclasts to resorb bone is relatively short, in the order
of weeks, while the time needed for osteoblasts to form bone is relatively long, in the
order of months. Therefore, any process which increases the rate of remodelling in
post-menopausal women will also result in a net loss of bone (Becker, 2006). There is
a wealth of information concerning the potential factors which cause an uncoupling
between bone resorption and formation, some of which will be explored.
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4.1. Oestrogen deficiency
In both men and women, there is steady decline in oestrogen levels with increasing
age. This is superimposed on by the sudden decrease in oestrogen levels in women at
the menopause. The concept that oestrogen is central to the development of
osteoporosis was based on the observation that post-menopausal women are at the
greatest risk of developing osteoporosis. At onset of menopause, women appear to
have an accelerated bone turnover which is transient, lasting approximately 4-8 years,
which is then followed by a slower, indefinite bone loss (Clowes et al., 2005; Riggs et
al., 2002). This model suggests that the initial accelerated bone loss phase is due to
oestrogen deficiency and is characterised by excessive trabecular bone loss which in
turn predisposes to vertebral and Colles’ fractures in the immediate post-menopausal
years (Avioli, 2000). Although the second phase of bone loss has been associated with
factors related to aging, oestrogen is still thought to play a role in this. At the onset of
menopause, an increased rate of bone turnover appears to be primarily due to an
increase in bone resorption, more than a decrease in bone formation since both
resorption and formation rates have been found to increase (Raisz, 2005). Oestrogen
deficiency increases the rate of bone remodelling and the amount of bone lost in each
remodelling cycle (Raisz, 2005).
At a molecular level, oestrogen acts at multiple sites which can be broadly divided
into those that are known to act directly on bone versus those that are extra-skeletal.
The direct skeletal effects are mediated by the presence of oestrogen receptors (ERα
and ERβ) on cells involved in the BMU. Oestrogen is thought to have an inhibitory
effect on osteoclasts but in its absence the number of osteoclasts increases, thereby
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increasing bone resorption. Oestrogen stimulates OPG production in osteoblasts
which has an anti-resorptive effect which decreases in its absence.
Oestrogen is thought to mediate many effects indirectly via oestrogen receptors which
are present on other cells within the human bone marrow including cells of the
immune system and stromal cells, which also upregulate OPG production upon
exposure. Oestrogen deficiency alters the production of RANKL on these cells which
is an important determinant of bone resorption (Sipos et al., 2009).
Recently there has been much interest in the indirect effects of oestrogen deficiency
on bone, mediated by immune cells, particularly T-lymphocytes. It is thought that the
lack of oestrogen causes activation of T-lymphocytes which then release a variety of
cytokines including RANKL and TNF-α. These have a strong stimulatory effect on
osteoclast recruitment, maturation and prolonged survival, whilst decreasing their
apoptosis. This is thought to significantly increase the pool of active osteoclasts,
resulting in net bone resorption. Other cytokines such as IL-17 are speculated to cause
osteoblast apoptosis, thereby decreasing bone formation (Becker, 2006). Increased
production of proinflammatory mediators including IL-1, IL-6, TNF-α, IFN-γ are now
widely accepted to play a role in pathogenesis (Sipos et al., 2009). It has been
demonstrated that in ovariectomised mice, oestrogen deficiency also leads to an
accumulation of reactive oxygen species (ROS) which activates T-cells which in turn
increases TNF-α production, thereby further contributing to the pro-inflammatory
state. It is possible that oestrogen exerts its protective effect by suppressing ROS
formation (Raisz, 2005). Clearly, the effects on oestrogen deficiency are complex and
not yet completely understood.
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4.2. Changes in calcium metabolism
Aging is thought to be an important risk factor for bone loss and fracture (Clowes et
al., 2005). Riggs et. al., first proposed the existence of a senile osteoporotic
syndrome, characterised by the loss of both trabecular and cortical bone, predisposing
to hip and vertebral fractures. It has been proposed that this type of osteoporosis
affects both sexes and accounts for the slower bone loss suffered by post-menopausal
women after the initial phase of fast bone loss (Riggs et al., 1982).
The changes in calcium metabolism which accompany an increase in age have been
widely documented. These changes can predispose older people to secondary
hyperparathyroidism, where an elevated level of PTH is present in response to
hypocalcaemia. Blood PTH levels have been found to increase with age, with
supranormal levels occurring in some elderly patients that have symptomatic
osteoporosis (Avioli, 2000). This form of secondary hyperparathyroidism may
contribute towards a decrease in bone mass and osteoporosis. Normally, PTH is a
powerful hormone which promotes bone resorption in response to hypocalcaemia.
However, an elevated level of PTH results in an imbalance leading to net bone
resorption. This is thought to result in a decrease in bone mass resulting in an
increased risk of fracture.
An elevated PTH level is thought to be a compensatory response to the excess loss of
calcium by the aging body and the resulting chronic hypocalcaemia. There are several
ways in which this hypocalcaemia arises. The efficiency of calcium absorption via the
intestine declines with age. In particular there is decreased active transport of calcium
by the duodenum which may be coupled with a calcium poor diet. The reabsorption of
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calcium in the kidneys, normally mediated by PTH has been shown to decline. In
addition, the expression of renal and intestinal calbindins, which normally serve an
important role in calcium uptake, has also been shown to decrease (van Abel et al.,
2006).
Changes are known to occur in vitamin D physiology with aging which also impact
calcium uptake. It has been documented that the level of 25-hydroxyvitamin D3 , a
marker of clinical vitamin D status, declines with aging (Avioli, 2000). There are
several possible mechanisms by which a reduction in vitamin D occurs. There may be
reduced skin exposure to the ultraviolet β rays of the sun which are needed to promote
vitamin D synthesis via photoactivation of 7-dehydrocholesterol, particularly in those
who are housebound or institutionalised. This is worsened in the winter months when
the UV β rays do not reach the Earth’s surface in the temperate zones and must be
compensated for by ingestion of vitamin D via the diet, which may be lacking. With
aging,
the skin becomes thinner
and contains reduced amounts of 7-
dehydrocholesterol. Therefore vitamin D production via the skin can decrease by
several fold. Some studies suggest that the synthesis of 25-hydroxyvitamin D3 and 1,
25-hydroxyvitamin D3 decreases due to impaired hepatic and renal hydroxylation, the
latter possibly being due to a limited reserve of 1α-hydroxylase (Avioli, 2000). In
addition, the capacity of 1, 25 dihydroxyvitamin D3 to stimulate calcium absorption
via the gut reduces with age due to the presence of reduced levels of this metabolite
(van Abel et al., 2006). Vitamin D deficiency has also been implicated in
neuromuscular impairment and an increased risk of falls (Raisz, 2005).
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Oestrogen deficiency is thought to play an important role in the second phase of bone
loss in post-menopausal women due to its extra-skeletal effects on calcium
metabolism (Riggs et al., 2002). When present, this hormone is thought to stimulate
active calcium (re)absorption in both kidneys and duodenum (van Abel et al., 2006).
Oestrogen deficiency is thought to heighten the sensitivity of bone to PTH, thus
enhancing the effects of an elevated PTH level, so accelerating bone resorption.
Receptors for vitamin D and PTH are present on cells of the immune system, such as
macrophages and T-lymphocytes suggesting that these hormones may play a role in
modulation of immune cells as well as in bone metabolism. As with oestrogen
deficiency, T-lymphocytes have been implicated as possible mediators in the process
of PTH induced loss of bone mass. Some preliminary evidence suggests that Tlymphocytes are important for the communication between PTH and stromal cells in
the bone marrow which support osteoclast development. In the presence of PTH, a
greater pool of osteoclasts can develop via cross-talk from stromal cells and Tlymphocytes. There is some evidence of a potential link between T-lymphocytes and
the action by which PTH drives bone resorption in a mouse model (Pacifici, 2010),
although other cells of the immune system may be involved.
4.3. Factors driving the loss of bone mass
A quest in understanding the pathology of osteoporosis has been to identify the key
factor which drives the loss of bone mass. It is evident that the pathology involved in
this process is complex and there almost certainly appears to be more than one driving
factor.
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Oestrogen deficiency and secondary hyperparathyroidism, coupled with vitamin D
deficiency, act by expanding the osteoclast pool and are both important drivers of
bone loss. Furthermore, there appears to be some interplay between these factors;
oestrogen deficiency impacts calcium absorption and increases sensitivity to PTH.
Therefore it is not possible to identify which of these factors is the most dominant as
their effects may be synergistic.
More recently it has emerged that T-lymphocytes, and possibly other immune cells,
contribute to the pathogenesis of osteoporosis. There is evidence that both hormonal
regulators and immune cells seem to be able to regulate osteoblast and osteoclast
differentiation and function (Clowes et al., 2005). Oestrogen deficiency and
hyperparathyroidism, and other regulators/hormones, may act by a common
mechanism involving T-lymphocyte activation. T-lymphocytes may secrete cytokines
to modify the differentiation and activity of osteoclasts and osteoblast towards a net
balance of bone resorption.
A number of other factors have been implicated in the pathology of osteoporosis apart
from oestrogen deficiency and hyperparathyroidism. Lowered levels of insulin growth
factor 1 (IGF-1), have been associated with aging and the development of
osteoporosis. Leptin, secreted by adipose tissue, has been found to have complex
actions on osteoblasts (Raisz, 2005).
5. Effects of calcium supplementation
If osteoporosis was a disease resulting only from a deficiency in calcium, then
calcium and vitamin D supplementation (which would increase calcium uptake)
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would be expected to treat or altogether prevent this disease. The effect of providing
calcium alone or with vitamin D supplementation to post-menopausal women and the
outcomes of this in terms of bone loss and fracture rates have been extensively
studied.
Data from published studies is not straightforward and often conflicting. A metaanalysis conducted in 2007, encompassing 29 studies, found that calcium with or
without vitamin D had a protective effect against fractures in subjects over 50 years of
age (Tang et al., 2007). In another report, analyses of 32 controlled trials found
calcium supplementation was protective against higher rates of bone loss in postmenopausal women (Nordin, 2009). However, results from other meta-analyses and
studies have reported that supplementation failed to make a significant difference to
BMD or fracture risk.
In studies where a positive effect was observed, the greatest benefit occurred in those
with low daily intake of calcium and/or vitamin D, particularly in those who were
institutionalised. Conversely, a positive effect was not observed in those who were
calcium replete and had high daily intakes. This confirms that elevating calcium and
vitamin D levels, if they are below a certain threshold, does have a positive effect on
lowering BMD and enhancing fracture risk. This is consistent with the model of
hyperparathyroidism induced loss of bone mass.
Calcium supplementation may act by reducing the level of PTH which is a driver for
bone resorption. Although in some cases supplementation has been shown to attenuate
the rate of bone loss, it is clear that it does not prevent a loss in bone mass altogether.
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This strongly suggests that although hyperparathyroidism is a driver for bone loss, it
is not the only factor positively influencing this process. This adds weight to the
concept that osteoporosis is much more complex than merely being a case of chronic
hypocalcaemia. Calcium supplementation may not prevent bone loss stimulated by
the other drivers of bone remodelling/resorption, of which there may be several, and
not all of which may be known at present. For this reason it is not likely to be useful
as the sole treatment. Oestrogen deficiency is another driver and consistent with this is
the fact that oestrogen replacement therapy and oestrogen receptor modulators (which
mimic oestrogen), both have been shown to decrease the bone fracture risk. In line
with this, a meta-analysis study has shown that BMD increases from hormone
replacement therapy were significantly greater in women who also took calcium
supplementation than those who did not (Avioli, 2000). This suggests that the effect
of reducing the impact of two factors which are thought to stimulate a loss in bone
mass is greater than the impact of reducing one. This is consistent the idea that their
actions are synergistic.
Therefore, supplementation with calcium alone or with vitamin D may be of benefit
as an adjunct to other therapies, particularly for those who have low daily intakes, but
generally it is not being used as monotherapy. This is because it is unlikely to
significantly attenuate the effects of other factors which stimulate bone resorption so
will not be able to prevent a significant or complete loss of bone mass.
6. Conclusion
The premise that ‘post-menopausal osteoporosis is a calcium related disorder’ implies
that hypocalcaemia is the main driver for the increased fragility of bone and the
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development of osteoporotic disease. The pathology of this disease is far more
complex than this statement suggests. While a decline in calcium levels may drive
bone remodelling via PTH secretion, the development of hypocalacaemia and
hyperparathyroidism during the aging process are complicated. Furthermore, this is
clearly not the only driving factor stimulating bone resorption.
Osteoblasts and osteoclasts are the main cells in the bone remodelling cycle whose
interactions are coordinated by the RANK/RANKL/OPG system. Normally, the
processes of bone resorption and bone formation are tightly coupled such that there is
no net change in the amount of bone. Oestrogen deficiency at onset of menopause and
aging are two important known risk factors for the development of osteoporosis.
Oestrogen deficiency stimulates the release of proinflammatory cytokines which
ultimately increase osteoclast maturation, inhibition of osteoclast apoptosis and so
push the balance towards bone resorption. Consistent with this, women can undergo
an acceleration of bone loss at the onset of menopause. Oestrogen deficiency is
clearly a driver for the loss of bone mass.
In post-menopausal women, the lack of oestrogen may be compounded by secondary
hyperparathyroidism associated with aging which may also drive bone loss. As a
result of multiple mechanisms, the levels of calcium and vitamin D in the body may
decrease with the process of aging. Normally calcium levels in the body extracellular
fluid are tightly regulated in narrow limits for optimum functioning of physiological
processes. A chronic hypocalcaemia, also contributed to by a lack of oestrogen,
results in elevated PTH levels over sustained periods. This hormone can exert
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powerful effects which ultimately results in an expanded osteoclast pool and net bone
resorption. PTH is another hormone that drives the loss of bone mass.
Rather than one factor being the main driver for loss of bone mass, it is possible that
PTH and oestrogen deficiency, and other factors, act cumulatively along a common
pathway to shift the balance towards bone resorption. A more recent theory is that
cells of the immune system are intimately involved with bone regulation. They can
alter the cytokine milieu that the osteoclast and osteoblasts precursors within the bone
marrow are exposed to, thus influencing not only their differentiation but also their
function. There is now evidence to suggest that specific T-cell subsets release
osteoclastogenic cytokines which play a major function in the pathways involving
PTH and oestrogen loss (Pacifici, 2010). However at present, much of the work
demonstrating involvement of immune cells is limited to rodent models and so further
research is needed in this area to demonstrate a more direct relevance to humans. If
further supporting evidence for this becomes available, it may be more appropriate to
think of osteoporosis not as a calcium related disease, but as an immune related
disease or even as an inflammatory disease.
Given that aging and oestrogen deficiency are two key risk factors and that clearly not
all elderly women develop osteoporosis, there are other factors which can influence
these processes at the molecular level. A low body mass, smoking, an excessive
alcohol intake and family history (genetics) are some of the other known risk factors
for osteoporosis. If calcium deficiency was the main cause of osteoporosis then
calcium
supplementation
should
treat
or
prevent
this
disease.
Calcium
supplementation may attenuate the fracture risk and loss of BMD in some studies but
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the evidence has been conflicting and does not demonstrate a complete prevention of
the loss of BMD. BMD reduction continues, albeit at a reduced rate, despite the
presence of abundant calcium and vitamin D levels. This strongly supports the notion
that the pathology of the disease is more complex and that there are other driving
factors.
In summary, we are still far from having a coherent understanding of how the main
cells involved in remodelling are regulated and the factors that influence their
differentiation and function. The challenge is to develop a complete picture of the
multiple complex processes that drive the pathology of osteoporosis such that
improved therapeutic or prophylactic agents can be developed .
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7. References
Avioli, L.V. (2000). The Osteoporotic syndrome, 4th edn: Academic Press
Becker, C. (2006). Pathophysiology and clinical manifestations of osteoporosis. Clin
Cornerstone 8, 19-27.
Boyle, W., Simonet, W. & Lacey, D. (2003). Osteoclast differentiation and
activation. Nature 423, 337-342.
Clowes, J. A., Riggs, B. L. & Khosla, S. (2005). The role of the immune system in
the pathophysiology of osteoporosis. Immunol Rev 208, 207-227.
Doherty, M., Lanyon, P. & Ralston, S. H. (2006). Davidson's Principles and
Practice of Medicine, 20th edn: Elsevier.
Frost, H. M. (1991). A new direction for osteoporosis research: a review and
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