Osteoporosis is a disorder characterized by reduced bone mass, impaired bone quality and a propensity to fracture. For decades, this disease was considered a syndrome characterized by back pain, vertebral fractures and osteopenia on plain films. Identifying secondary causes of low bone mass was the principle objective of most clinicians. However, in the last ten years, osteoporosis as a primary disorder, has become a major focus. During this time, significant progress has been made in both defining this disorder and in understanding its complex pathogenesis. In addition, a consensus has emerged concerning the strength of the association between low bone mineral density and fracture risk, and the importance of qualitative aspects of the skeleton, as additional risk determinants. Almost all population studies have confirmed that for a one standard deviation below young normal mean bone mineral density (at virtually any skeletal site) there is a nearly two fold greater risk of a subsequent hip fracture(1). Momentum increased after the World Health Organization published their original recommendations in 1994, so that by 2001, most clinicians and investigators defined osteoporosis solely on a bone mass measurement more than 2.5 standard deviations below young normal reference ranges(2). Although this "bar" has been used to establish prevalence estimates and to define high risk individuals who should be considered for treatment, it is also evident that even this definition demands a better understanding of the pathophysiologic processes that result in low bone mass, and a more thorough review of 'bone quality'. Indeed, despite the strength of the association between BMD and fracture risk, it is now clear that qualitative determinants such as bone turnover, mineralization, and trabecular connectivity also contribute to risk. In this paper I will review the mechanisms responsible for altering bone architecture and strength in such a way as to enhance the likelihood of fragility fractures. Irrespective of the epidemiology and pathogenesis of osteoporosis, the stark fact remains that this disease has significant morbidity and mortality. Just as importantly, understanding how this disorder develops and progresses, has important socio- economic as well as medical consequences.

Estimating exactly how many women have osteoporosis has depended on the working definition of this disease and the appropriate diagnostic criteria(3). Prior to the widespread application of bone densitometry, osteoporosis was rarely diagnosed and then only in women with symptomatic vertebral fractures and osteopenia. Indeed, for too long, hip fractures, the end point of this metabolic syndrome, were either written off as a consequence of aging, or ignored in respect to treatment. Bone mass measurements changed all that, especially when it became clear that a single bone mineral density (BMD) measurement at any site was a very strong predictor of future spine and hip fractures(1,2,4). As such, the definition of osteoporosis began to evolve, and estimates of how many people were affected by this disease changed. When the World Health Organization (WHO) set a cut off point of 2.5 standard deviations below a young normal mean value for BMD in the spine or hip of postmenopausal women, as an indicator of osteoporotic risk, estimates of disease prevalence soared(5). Finally, the appearance of larger epidemiologic studies such as The Study of Osteoporotic Fractures (SOF), provided even better estimates of disease onset and course(4,6).

Currently most estimates suggest that there are approximately 0.3 million hip fractures per annum in the U.S. and 1.7 million hip fractures in Europe(7,8). Virtually all of these events can be attributed to osteoporosis, whether primary or secondary. The female to male ratio of hip fractures is approximately 2:1.0(6,9). Not surprisingly, the occurrence of these fractures increase exponentially with age. In contrast, the incidence of wrist fractures in the UK and the US ranges from about 400- 800 per 100,000 women but is relatively stable over several decades of older life(9). Women are far more likely to suffer a Colle's fracture than a man (i.e. a ratio upwards of 10:1 by age 75)(9). Compression fractures of the vertebrae are much more difficult to estimate because often, these can be asymptomatic. Best estimates are that more than a million American postmenopausal women will suffer a spine fracture in the course of a single year(9-11). The female to male ratio of occurrence is approximately 2:1. Moreover, both symptomatic, and radiographic (morphometric) fractures that are not tied to symptoms, are associated with significant morbidity and disability(10). Finally, estimates about disease prevalence in women and men without fractures, but with low BMD (-2.5 or lower) vary greatly, but place the overall number at close to 25 million Americans(9,12).

Bone loss as a result of aging/and or estrogen deficiency is the predominant pathophysiologic disorder of primary osteoporosis. However, the frequent use of glucocorticoids in both men and women, contribute dramatically to the total number of individuals with very low BMD and/or osteoporotic fractures. It is estimated that more than 5 million American men are afflicted with osteoporosis, based on either the presence of osteoporotic fractures(i.e. vertebral compressions, wrist fractures, hip fractures, or humerus/tibial fractures) or low bone mineral density(11). However, the number of good cohort studies in men with this disease is limited, and a more complete epidemiologic picture of male osteoporosis will become clearer after the completion of the MROS study which is being conducted at several sites around the country.

More frightening than estimates of the extent of low bone mass in the population in the year 2007, is the projected near doubling in the prevalence of fractures over the next half century(7). Whereas, osteoporosis often was considered a disorder of old Northern European women, it is now clear that this disease can occur in postmenopausal African Americans, that it is much more common in men than previously appreciated, and that the use of glucocorticoids and/or immunosuppressive therapies for transplant patients, markedly enhances the risk of subsequent fracture.

Several risk factors predispose individuals to osteoporotic fractures. For a hip fracture, these include age greater than 65 years, a previous spine or hip fracture, maternal history of a hip fracture, poor neuromuscular function, weight loss after the age of 50, and low body mass index(1,13)(See Table 1). Falls are a major cause of fractures, and in all clinical situations, some degree of trauma can be linked to the injury(14). But many osteoporotic patients suffer fractures with very minimal trauma, and this feature is pathognomic of the skeletal fragility which accompanies low bone mass. It is for this reason that the most common risk factor for fractures of the spine, hip or wrist remains low bone mineral density(15). The continuous but inverse relationship between BMD and fracture is consistent at all points below the mean suggesting there is no threshold effect (15,16). And, it is applicable at virtually every skeletal site from the spine to finger to the calcaneus. Moreover, the advent of newer technology to measure bone mass has allowed widespread screening for risk as well as defining risk reduction with therapy. Notwithstanding the strength of the inverse relationship of BMD to fracture risk, it is important to note that the presence of a previous fracture is also an extremely important, BMD independent risk for subsequent fracture. This is important clinically since the recognition of fracture at any BMD defines a skeleton which likely has poor bone quality, and hence is likely to fracture again.

Bone mass measurement defines mineral content per area of bone. In the laboratory, bone density by DXA is a very strong predictor of bone strength and accounts for about 80% of the variability in the breaking strength of a single femur(16a). Thus, a very low bone mass can be linked to increased skeletal fragility with a great degree of confidence. But, there are other determinants of bone strength, often referred to as qualitative measures, including the rate of bone turnover, the extent of trabecular connectivity, cortical and periosteal bone size and skeletal morphometry (See Figure 1 and Table 1). Indeed, much progress has been made in quantifying several aspects of bone 'quality' utilizing tools such as single energy QCT of the spine/hip, extreme CT (uCT) of the radius or tibia, histomorphometry and magnetic resonance imaging of the radius (16a). However, more work needs to be done to validate these measures in humans, and to ascertain their role in clinical medicine. Still, in vivo, bone mineral density represents the most accurate, cost effective and easiest parameter for risk assessment(15). In part, two-dimensional DXA measurements integrate actual bone mineral content in both trabecular and cortical compartments with bone size. Due to the strong association between bone density and future fractures, this phenotype remains an excellent surrogate for defining both the genetic and acquired components of the disease process.

Adult bone mass represents the end result of two processes; acquisition of peak bone mass during adolescence and maintenance of bone density during the middle and later years. Changes in bone mass result from physiologic and pathophysiologic processes in the bone remodeling cycle(17). This can occur during the stage of accelerated linear growth in adolescence, or much later in life, usually after menopause in women. The bone remodeling cycle is a tightly coupled process whereby bone is resorbed at approximately the same rate as new bone is formed. Basic multicellular units (BMUs) compose the remodeling unit of bone and include: osteoclasts which stimulate bone resorption, osteoblasts, which are responsible for new bone formation, and osteocytes, older osteoblasts surrounded by bone and present in a reduced state of activity(18) (See Figure 2). Activation of the remodeling cycle serves two functions in the adult skeleton: 1) to produce a supply rapidly, as well as chronically, of calcium to the extracellular space; 2) to provide elasticity and strength to the skeleton. When the remodeling process is uncoupled so that resorption exceeds formation, bone is lost. On the other hand, during peak bone acquisition, formation exceeds resorption resulting in a net gain of bone. Remodeling is more pronounced in the trabecular skeleton (e.g. spine, calcaneus and proximal femur) and is the most metabolically active component of bone, in part because of its proximity to the marrow space. However, trabecular bone is also extremely vulnerable to perturbations by local or systemic factors that can cause significant imbalances in bone turnover.

The bone remodeling cycle begins with activation of resting osteoblasts on the surface of bone and marrow stromal cells. This is followed by a cascade of signals originating from the activated osteoblasts, to osteoclasts and their precursors. These intercellular signals recruit and differentiate multinucleated cells from hematopoietic stem cells(17). After osteoclast- induced bone resorption, matrix components such as TGF-beta and IGF-I, as well as collagen, osteocalcin and other protein and mineral components, are released into the micro environment. Growth factors released by resorption contribute to the recruitment of new osteoblasts to the bone surface, which begin the process of collagen synthesis and biomineralization. In healthy adults as many as two million remodeling sites may be active at any given time, and it is estimated that nearly one fourth of all trabecular bone is remodeled each year. In general resorption takes only 10-13 days, while formation is much more deliberate and can take upwards of three months (Figure 2). Under ideal circumstances, by the end of the cycle, the amount of bone resorbed equals the amount reformed.

Osteoporosis has been classically defined in a pathogenic manner as an uncoupling in which resorption exceeds formation resulting in a net loss of bone. However, it is also apparent that some individuals have impaired peak bone acquisition. This scenario may be more common than previously appreciated and almost certainly represents inherited or acquired alterations in the rate of either bone formation or bone resorption during a critical period when several hormones in synchrony orchestrate a marked increase in bone mass.

There are several key components of the remodeling cycle which are susceptible to systemic and local alterations and when perturbed, can lead to deleterious changes in bone mass. In particular, activation of remodeling via the osteoblast, and recruitment of osteoclasts, represent the two most vulnerable sites in the cycle. A third site that could be altered by disease states is the osteocyte, an entombed fully differentiated osteoblast that connects to the surface osteoblasts, and likely senses mechanical stimulation. Remodeling of the skeleton with coupling of resorption to formation, is a normal process that usually is initiated by the osteocyte in response to mechanical loading or stress. Interestingly, remodeling may end with the osteocyte as well, since it produces a protein, sclerostin, which inhibits osteoblast activity by antagonizing the Wnt and BMP pathways. Uncoupled remodeling occurs during menopause, with estrogen deprivation, or in response to endogenous parathyroid hormone fluxes, cytokine stimulation, growth hormone surges, glucocorticoid excess or changes in serum calcium. For the most part, estrogen deprivation remains one of the most common and critical elements in shifting resorption rates to a higher set point. Although bone formation initially can "catch up", the length of time for each component of the remodeling cycle clearly favor resorption over formation as the process of laying down new bone requires the interaction of several processes (see Figure 2). But, it is still unclear why falling estrogen levels, which is a universal event during the menopausal years, causes such rapid bone loss in a relatively small percentage of women. Clearly, factors such as peripheral conversion of testosterone to estradiol, adrenal androgen production, and genetic determinants, as well as other local signals may also be important. Although not identified in humans, mice have strong heritable determinants that affect the rate of acute bone loss.

The nature of the osteocyte-osteoblast-osteoclast interaction has been one of the most active areas of investigation (see Figure 2). External signals (such as PTH, growth hormone, interleukin-1, estrogen deprivation) to resting osteoblasts and stromal cells cause these cells to release a potpourri of cytokines (i.e. interleukins such as IL-1, -6, -11 as well as m-CSF, tumor necrosis factor (TNF) and TGF-beta) which enhance the recruitment and differentiative function of multinucleated giant cells destined to become bone resorbing cells(17-19). However, one of the most critical pathways in the osteoblast-osteoclast interaction scheme is the RANKL- Osteoprotogerin (OPG) relationship. OPG is a soluble peptide originally described as a factor which markedly inhibited bone resorption and osteoclast differentiation in vitro(20). This protein is a member of the TNF receptor super-family and its role in bone remodeling is to act as a decoy receptor for the peptide known as osteoprotegrin ligand i.e. OPGL (or RANKL)(21). In fact, RANKL is a surface peptide which when expressed on the osteoblast, binds to the true OPGL receptor (also called RANK-receptor activator of NFkB Ligand) on osteoclasts, and initiates cell-cell contact necessary for osteoclast activation and subsequent bone resorption(21). The OPG, OPGL and RANK system which affects osteoclast differentiation, in addition to the effects of m-CSF on osteoclast proliferation, provide the critical link between osteoclasts and osteoblasts. It has also led to the synthesis of RANKL antibodies that are being studied in human trials as a potential therapeutic agent to slow or inhibit bone resorption. The most widely tested of these is AMG 162- which can be administered once every six months and has a profound effect on suppressing bone resorption.

The osteoblast functions not only to signal osteoclasts during remodeling, but also to lay down collagen and orchestrate mineralization of previously resorbed lacunae in the skeletal matrix. These complex functions are tied to differentiation of mesenchymal stem cells which become osteoblasts and rest on the surface of the remodeling space(17). Recruitment of stem cells to osteoblasts, rather than adipocytes is a critical step in bone formation and requires a series of factors that enhance differentiation. One of the most important components of this process is Cbfa1, a transcription factor which is essential in the early differentiative pathway of stem cells to bone and away from adipocytes(22). Regulation of Cbfa1 has become a major focus of work in the last three years, as investigators have begun to consider novel ways to enhance bone formation.

With activation of resting osteoblasts, these cells synthesize several types of collagen as well as elaborating a series of growth factors such as IGF-I, IGF-II, TGF-b. These, in turn, are necessary for further recruitment of bone forming cells(23). In addition, osteoblasts deposit growth factors in the skeletal matrix where they are stored in latent forms, and released during subsequent remodeling cycles. After deposition of new bone, some osteoblasts are encased by matrix. These osteocytes, are still viable, although less metabolically active and, can, through newly developed caniculi, provide signals to other bone cells. Indeed, there is some evidence that osteocytic signals are important in the so-called "mechanostat", the gravitary sensing device which modulates bone formation, as well as initiating normal remodeling sequences.

The pathogenesis of primary osteoporosis centers on uncoupling of the remodeling sequence by a combination of factors. Bone formation may be normal, suppressed, or slightly reduced in relation to an acceleration of resorption. Glucocorticoid induced osteoporosis also results from an uncoupled remodeling unit. However in this scenario, bone formation is markedly suppressed while bone resorption is generally unchanged, at least during the initial months of treatment. Indeed, next to space travel and zero gravity, no other condition or drug has such a major effect on uncoupling as do glucocorticoids. For the most part, the pathogenesis of glucocorticoid induced osteoporosis centers on four major factors acting on the bone remodeling unit:

All these factors contribute to rapid bone loss during high doses of steroids, and therefore alter skeletal quality. In turn this combination leads to a high rate of spontaneous fractures even at BMD levels that are usually not associated with bone failure.

In summary, the bone remodeling cycle is extremely complex and redundant. The three major cells, osteocytes, osteoblasts and osteoclasts, arise from different stem cells (mesenchymal and hematopoietic respectively) and are under the control of various factors which in harmony orchestrate an orderly remodeling sequence. Their birth and death (i.e. the cycle of recruitment, proliferation and programmed cell death) and the regulatory factors which control those events, are also complex, yet vitally important for understanding the pathogenesis of osteoporosis. Alterations at any stage along the process of recruitment, activation, differentiation or cell death can lead to imbalances in remodeling which eventually would result in bone loss or reduced bone mass. Some of those perturbations are noted below.

The importance of estrogen in maintaining calcium homeostasis in the postmenopausal woman was first established by Fuller Albright more than 60 years ago(24). Since that time more evidence has accumulated from randomized intervention trials demonstrating that hormone replacement (estrogen with or without progesterone) reduces bone turnover and increases bone mass(25). However, these data provide only indirect evidence that estrogen levels are important as pathogenic components of the osteoporosis syndrome. More recent studies provide stronger evidence of the association between low estradiol concentrations and low bone mass. Several investigators have demonstrated that the lowest estradiol levels in postmenopausal women (i.e. <5 pg/ml) are associated with the lowest bone mineral density and the greatest likelihood of fracture(26). In addition, at least one study has shown that males with osteoporosis have lower serum levels of estradiol then do age-matched men who do not have low bone mass(27). Moreover, there are now two case reports describing mutations in either aromatase activity or the estrogen receptor, which has produced a phenotype of severe osteoporosis in men(28,29). In the former case, estrogen replacement therapy for this young man, resulted in a marked increase in spine and hip bone mineral density. In both situations the lack of functional estrogen, despite normal to high levels of testosterone, resulted in severely low bone mineral density(30).

Although declining estradiol levels contribute to the osteoporosis syndrome, the precise molecular events or sequences which result from changes in ambient hormonal concentrations are not clear. In some animal models, estrogen deprivation is associated with a marked increase in IL-6 synthesis from stromal and osteoblastic cells. This is consistent with experimental findings which demonstrate that estrogen regulates the transcriptional activity of the IL-6 promoter(31). However, results in other studies are conflicting. In other experimental paradigms, changes in TNF, IL-11 and IL-1 can all be associated with increased bone resorption(32). Recently RANKL has been identified as a major regulator of osteoclast differentiation. Thus, it seems likely that several cytokines, working in concert, are active during estrogen deprivation, and each can accelerate the process of bone resorption. RANKL, however may be the most critical and necessary for full activation of remodeling. Enhanced bone resorption eventually leads to bone loss from estrogen deprivation since bone formation rates cannot keep up with rates of bone resorption (33).

In contrast to the plethora of studies on bone loss and estrogen, there are few good studies relating androgen deprivation to bone loss in women. Androgen receptors are present on osteoblasts. However, both in vitro and in vivo studies in men have yielded conflicting results. Like estrogen, androgens can regulate the IL-6 promoter and in experimental animals, orchiectomy has been associated with increased IL-6 production and bone loss(32). In men, chronically low androgen levels have been associated with low bone mass, and testosterone replacement can enhance bone mineral density(34). However, estradiol levels in men may be a more important risk factor for fracture than androgen levels. At the present time it is not clear precisely what role androgens play in the maintenance of bone mass in both men and women.

Other more common causes of male osteoporosis include alcoholism, glucocorticoid excess, and hypercalcuria (see Table 3). In the first two cases, hypogonadism remains a pathogenic feature of the osteoporosis syndrome. Less frequently, men with non-tropical sprue or an endocrinopathy such as thyrotoxicosis can present with multiple fractures and low bone mass (see Table 3).

In women, bone loss is accelerated immediately after menopause. However, recent studies demonstrate that markers of bone resorption are also very high later in life. In particular, women in their 80s and 90s have been noted to lose bone at a rate of greater than 1% per year from the spine and hip(35). Contrary to earlier studies, it is now evident that the older woman who is not as physically active, and is not on estrogen, is at extremely high risk of bone loss and subsequent fractures. The pathogenesis of this process is multifactorial although dietary calcium deficiency, leading to secondary hyperparathyroidism, certain plays a central role. The average calcium intake of women in their 8th and 9th decades of life is between 700 and 800 mg/day(36). If vitamin D intake is also suboptimal (serum levels of 25 OH vitamin D <30 ng/ml, or 80 mmol/l), secondary hyperparathyroidism is assured. PTH stimulates osteoblasts and provokes the remodeling sequence including the elaboration of several cytokines that accelerate bone resorption. Unfortunately, in most elders, bone formation is not enhanced although the reasons for this are not entirely clear. Overall this leads to further uncoupling in the bone remodeling cycle, and significant bone loss. Among elders with poor calcium intake who live in northern latitudes, seasonal changes in vitamin D can aggravate bone loss even further and may account for as much as 2% bone loss during the winter months(37,37a). Whether increased bone loss is an independent risk factor for future fractures in the elderly remains somewhat controversial necessitating further studies to define such a risk.

There is now abundant evidence that declining serum levels of vitamin D stimulate PTH release and increases bone turnover. As noted above, such changes are often not associated with concomitant increases in bone formation, thereby accelerating bone loss. Many older individuals already have established osteoporosis. Coincidental vitamin D deficiency due to poor intake, absent sunlight exposure, or impaired conversion of vitamin D to its active metabolite, can result in osteomalacia as well as aggravating pre-existent osteoporosis(38). In a very recent study from Boston, LeBoff et al reported that more than 50% of elders who presented with a hip fracture were frankly vitamin D deficient(39). Combining vitamin D deficiency with inadequate calcium intake enhances the likelihood of rapid bone loss in a very susceptible population. Still, it is unclear how secondary hyperparathyroidism causes bone loss. Chronic elevations in PTH secretion due to primary or tertiary hyperparathyroidism, have been associated with low bone mass at several skeletal sites including the radius. Elevated PTH levels in older women have been associated with bone loss in some studies but not in others. In elderly individuals, it has been reported that PTH levels are closely correlated with increased synthesis of an insulin-like growth factor binding protein (IGFBP-4) which suppresses IGF action on bone cells(23,40). Since IGF-I is an important growth factor for osteoblasts, it is conceivable that PTH down regulates IGF activity during states of relative calcium/and or vitamin D deficiency. This would shift the remodeling balance towards preserving intravascular calcium concentrations, while inhibiting new calcium incorporation into the skeletal matrix. This response makes teleological sense although further studies are needed to assess whether serum IGFBP-4 is a reliable marker of calcium deficiency in older individuals(41). In sum, there is little doubt that calcium and vitamin D insufficiency are prominent causes of accelerated bone loss in the elderly.

As noted previously, high circulating levels of glucocorticoids have a significant impact on bone acquisition and maintenance. In 1932 Harvey Cushing recognized the syndrome of endogenous steroid excess which included marked osteopenia and fractures(42). Long term exposure to pharmacologic doses of glucocorticoids results in significant bone loss and enhanced marrow adipogenesis as marrow stromal cells differentiate down the fat lineage . In addition to having direct effects on the osteoclast and osteoblast, glucocorticoids also induce secondary hypogonadism and hyperparathyroidism, impaired vitamin D metabolism, muscle atrophy and hypercalcuria (See Table 2). All these factors contribute to a rapid and sustained loss of bone during the first few months of steroid therapy(43). The addition of other immunosuppressants such as cyclosporine has been shown to aggravate bone loss by further increasing bone resorption. As the number of organ transplants have increased exponentially over the last decade, the prevalence of post-transplantation osteoporosis has risen substantially. Steroid induced osteoporosis is now considered the second most common cause of low bone mass in the general population(44).

Peak bone mass is acquired between the ages of 12-16 years. It is the high point of bone acquisition and represents the sum of several processes including a marked increase in bone formation(45). Boys tend to reach peak 2 years later than girls and their bone mineral density is higher than women at all skeletal sites. In part this relates to a greater cross-sectional bone area in males than females(45a), Peak bone mass results from linear growth and consolidation of cortical and trabecular components. Acquisition is most rapid during the latter stages of puberty and coincides with maximum growth hormone secretion, high serum IGF-I levels, and rising levels of estradiol and testosterone. In addition, calcium absorption is maximum and skeletal accretion is optimal. All these processes combine over a relatively short period of time to produce a bone mass which subsequently plateaus and then falls during later life. It is estimated that more than 60% of adult bone mass can be related to peak acquisition. Hence understanding the mechanisms responsible for low bone mass must include perturbations in peak bone acquisition.

There are several hormonal, environmental and heritable determinants of peak bone mass. These include estrogen/testosterone, growth hormone/IGF-I, calcium/vitamin D and unknown genetic factors. If each is perturbed, dramatic alterations in peak bone mass may occur, setting the stage for low bone density throughout life. Gonadal steroids are important not only to bone maintenance but also to acquisition. During puberty, estrogen and testosterone levels rise and contribute to consolidation of bone mass. Estrogen is also necessary for epiphysial closure. Studies of a male with an estrogen receptor mutation and men with an aromatase deficiency have established that estradiol is critical for bone acquisition(28-30). These young men share several phenotypic characteristics including tall stature unfused epiphysis, and very low bone mass. Hence, there must be a threshold effect for estradiol in men, and this effect must be time dependent. Similar conclusions can be drawn from studies in women. Acquired deficiencies in estrogen, such as anorexia nervosa, or chemotherapy induced ovarian dysfunction, result in low peak bone mass and lead to subsequent risk for osteoporosis(46,47). Similar findings have been noted in patients with untreated Turner's syndrome and in men with Klinefelter's syndrome.

The timing of gonadal steroid surges are critical for bone acquisition since there is a relatively short window of time in which bone formation is favored and matrix synthesis is markedly enhanced. That window is likely to be less than three years and earlier in girls than boys. Probably the best study which addressed this issue comes from a retrospective analysis of men in their thirties who underwent late onset of puberty (i.e. at the age of 17 or 18) but were otherwise normal by full endocrine testing(48). These men had significantly lower bone mineral density than age matched men who went through puberty at the normal time. These data suggest that timing as well as quantity of gonadal steroids are critical for bone acquisition.

Pubertal surges of estrogen and androgens are also important for priming the growth hormone/ IGF-I axis. Rising levels of both contribute to growth hormone surges which lead to increases in circulating and tissue expression of IGF-I, an essential growth factor for chondrocyte hypertrophy and expansion. IGF-I may also be critical in defining the cross-sectional size of bone, a potentially important determinant of bone strength(49). Once again, studies in growth hormone deficient, or growth hormone resistant individuals have established that low levels of circulating IGF-I, especially during puberty, are associated with reduced bone mass(50). In addition, rhGH replacement has been shown to restore linear growth and improve peak bone mass acquisition. Several studies in experimental animals, including inbred strains of mice, have established that IGF-I is important for bone acquisition and the timing of IGF-I peaks coincide with maximal rates of bone formation(51,52). Impairment in production of IGF-I due to acquired disorders such as anorexia nervosa, malnutrition or diabetes mellitus, can also impede peak bone acquisition.

Hormonal abnormalities can not only enhance bone resorption in older individuals, but may blunt the capacity of bone cells to maximize bone formation during adolescence. Clearly, hypogonadal boys and girls have impaired peak bone mass, resulting in low adult bone mineral density. Even one form of contraception, Depo-provera, may reduce estrogen concentrations enough in the teen girl, to reduce her capacity to acquire peak bone mass. Similarly, it seems likely although not proven that smoking during the teen years could impair osteoblast activity and flatten projected trajectories for peak bone acquisition.

In order to mineralize newly synthesized bone, calcium must become bioavailable to the skeletal matrix. In experimental studies in rodents and humans, it is clear that the several pools of available calcium are markedly enhanced during puberty. These include calcium efflux from the gastrointestinal tract, and the calcium pool available for incorporation in the matrix. It is no coincidence that growth hormone surges not only increases IGF-I, (thereby enhancing skeletal growth and matrix biosynthesis) but also result in increases in 1,25 dihydroxyvitamin D (possibly via IGF-I induction of 1, alpha hydroxylase activity), the active metabolite of vitamin D which markedly enhances calcium absorption from the gut(53). Although there are no longitudinal studies in pubertal individuals with prolonged calcium deficiency, several randomized placebo controlled trials in pubertal and pre-pubertal girls and boys have established that supplemental calcium can enhance bone mineral density. In a twin study, in which one twin receives 1200 mg of calcium supplementation, and one receives placebo, radial BMD increases by as much as 5% after three years compared to placebo(54). This study suggests that there is significant gene-environmental interaction, and that even in those individuals with heritable determinants of low peak bone mass, calcium supplementation may provide an important and relatively simple means of protecting individuals from future osteoporotic fractures.

Probably the most important determinant of peak bone mass, but one that has lacked clear definition is the genetic contribution. As noted above, low peak bone mass may be the most important pathogenic factor in the osteoporosis syndrome of later life. And, it appears that at least 50% of peak bone mass is determined by genetic factors(55-57). What are these determinants and how are they modified by environmental factors?

Efforts to define heritable determinants of peak bone mass have been plagued by a number of issues which are also common to other complex diseases. These include the following:

Notwithstanding these barriers it is now clear that bone mineral density is an acceptable phenotype for defining heritable determinants. In addition, bone density is fully quantifiable, and therefore is amenable to complex trait analysis. Moreover, bone density in the population is distributed in a gaussian manner, thereby allowing analyses at the extremes (<-2.0 SD or > 2.0 SD) of the density distribution. Still, large homogeneous populations are needed to ascertain various genetic determinants of bone density in humans. Candidate loci identified by studying polymorphisms in genes such as the vitamin D receptor, collagen IA1, the estrogen receptor, interleukin-1, IGF-I and PTH have generally produced conflicting results, depending on the population, the phenotype, and the number of individuals studied(59). Twin studies examining discordant or concordant phenotypes are also helpful, as are sib-pair studies although the results have been disappointing(60). Recently, polymorphisms in the RANK/RANKL/OPG system have also been identified as being linked to changes in peak bone mass.

Originally Recker and colleagues had identified an extended family with very high bone density and fine mapped the locus to a region in chromosome 11. After several years of intense high through put analysis, that group identified a 'high bone density' gene, lipoprotein receptor protein 5(LRP-5) that was mutated in this family. The low affinity lipoprotein receptor is important in binding wnt, a ligand critical for cell differentiation in several organisms. At the same time, Worman and colleagues identified several children with osteoporosis pseudoganglioma syndrome and subsequently mapped the gene which resulted in 'loss of function' in these individuals. This turned out to also be LRP-5. The very recent discovery of this gene, and the potential pathways that direct osteoblast function and mineralization, have opened up a brand new area of investigation (60a). Indeed, it is now clear that Wnts, a family of 19 proteins, can bind to the LRP5 receptor which in turn is associated with the frizzled receptor, to activate a series of intracellular events, leading to generation of a molecule, beta catenin, which can enter the nucleus and affect gene transcription. Moreover, natural antagonists to the Wnt/Lrp5 signaling system have recently been identified. This pathway shows great promise for future therapeutic interventions.

Although only one bone density gene(LRP5) has been cloned, its function and its allelic effects have suggested that this pathway is important in defining peak bone mass. But, it is also clear that since BMD is a polygenic trait, other genes are soon to be discovered. In addition to the search for osteoporosis genes intervention studies in adolescents have provided insight into the environmental impact on genetic determinants(54). The famous twin study in Indiana revealed that as long as calcium supplementation continued during puberty, young boys could enhance their peak bone mass. In a Swiss study, younger pre-pubertal girls supplemented with a protein product had a significant increase in spine bone density, as did a cohort of pubertal girls receiving a milk powder in England(61,62). Remarkably, in the latter cohort, serum IGF-I levels also rose dramatically, providing further indirect evidence of a link between pubertal status, bone mass and the growth hormone/IGF-I axis.

The pathogenesis of osteoporosis is complex and multifactorial. Alterations in bone density almost certainly represent the final common pathway by which pathologic factors affect risk of future osteoporotic fracture. The interplay of various physiologic processes which result in peak bone mass, and maintenance of adult bone mass are key to understanding the pathogenesis of this disease. Changes in hormonal status, and in particular estradiol, clearly are important factors in both formation and resorption of bone in men and women. Perturbations in growth hormone activity, musculoskeletal function, dietary intake of calcium and vitamin D, and genetic determinants are also important pathogenic factors(53). Defining the role of genetic factors and their interaction with many of the environmental and hormonal determinants that have been established as potential etiologic agents responsible for low bone mass will certainly be the most difficult challenge facing basic and clinical researchers well into the next century. On, the other hand, the strength of data from bench and clinical studies over the last decade, now allows practitioners to confidently diagnose and treat osteoporosis.

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