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Men do not undergo the equivalent of menopause and, thus, lack the early, accelerated phase of bone loss experienced by women. Castrated men male sex offenders in Czechoslovakia have a pattern of rapid bone loss similar to that of women after menopause Periosteal apposition in the appendicular skeleton continues through life in both men and women, but men add 3-fold more bone by this process than do women This increases the width of the long bones, including the proximal femur, and the same amount of bone distributed over a wider area is stronger.
Thus, the greater biomechanical strength afforded by the wider bones partially compensates for age-related decreases in BMD.
Indeed, Beck et al. However, these analyses did not include measurements of cancellous bone in the proximal femur and, thus, did not take into account the decrease in mechanical strength due to cancellous bone loss that occurred concomitantly with the changes in bone size.
Thus, bone strength was undoubtedly reduced more than they estimated. This phase begins at the menopause, can be prevented by E replacement 6 , 7 , and clearly results from loss of ovarian function. Also, serum T decreases after menopause because of decreases of ovarian T production , but this decrease is only moderate, because T continues to be produced by adrenal cortex and by the ovarian interstitium.
The increase in bone turnover and remodeling imbalance lead to accelerated bone loss, particularly on the endosteal surface of bone. Although the menopause induces rapid bone loss, part of the decrease in BMD that is measured by bone densitometry relates to an increase in the remodeling space induced by the large increase in BMU numbers The rapid bone loss in this phase produces an increased outflow of calcium from bone into the extracellular pool, but hypercalcemia is prevented by compensatory increases in urinary calcium excretion and decreases in intestinal calcium absorption , and by a partial suppression of PTH secretion Although bone responsiveness to infused PTH is enhanced during this phase , this may reflect only the overall increase in BMU numbers.
As reviewed earlier, it is possible that the early rapid phase of bone loss results from a reduced sensing of biomechanical strain by bone cells induced by acute E deficiency. If this concept is correct, it would rationalize the otherwise difficult to explain observation that the rapid phase of postmenopausal bone loss subsides after 4—8 yr.
Thus, when bone mass is reduced to such a level that the mechanostat again senses bone strains as similar to those present before menopause, when E was sufficient, rapid bone loss will cease. Indeed, Heshmati et al. Had the effect of increased E deficiency been on external calcium homeostasis, aromatase treatment would have increased serum PTH further. Also, had the mechanism terminating the rapid phase of bone loss been a high degree of cancellous bone depletion, induction of a more severe degree of E deficiency should not have reactivated the rapid phase of bone loss.
Nonetheless, an effect of reduced bone mass per se on tapering the rate of bone loss cannot be excluded. The late, slow phase of bone loss is associated with progressive increases in levels of serum PTH and in biochemical markers of bone turnover Fig. Moreover, when serum PTH levels were suppressed by a h calcium infusion in groups of young premenopausal and elderly postmenopausal women, the increases in biochemical markers in the postmenopausal women that were present on the control day were no longer present on the calcium infusion day, strongly suggesting that the increased serum PTH was the cause of the increase in bone turnover Because the increases in serum PTH are not associated with increases in serum ionic calcium levels or major abnormalities in renal function, they are indicative of secondary hyperparathyroidism caused by age-related abnormalities in extraskeletal calcium homeostasis.
Indeed, many studies have shown that age impairs calcium absorption and especially impairs the ability to adapt to a lower calcium intake by increasing intestinal calcium absorption Aging also impairs renal calcium conservation , Both abnormalities lead to external calcium wasting.
If the hypothesis that calcium wasting is the cause of the secondary hyperparathyroidism and increased bone resorption associated with aging is correct, these abnormalities should be corrected by calcium supplementation.
In fact, many studies have now shown that calcium supplementation in elderly women retards bone loss and, possibly, also reduces fracture occurrence in late, postmenopausal women Moreover, McKane et al. Changes in serum PTH upper panels and in bone turnover markers lower panels as a function of age in men and women over the age of Data are from a population sample from Rochester, Minnesota Results are expressed as the percentage change from young-adult values.
Serum osteocalcin is a marker for bone formation, and urine N-telopeptide of type I collagen NTx is a marker for bone resorption. For changes in markers of bone turnover, note that increases in women begin at menopause and continue progressively with aging. In men, the increases begin later in life. Note also that the increase in bone resorption exceeds that of bone formation at all ages, indicating a persistent remodeling imbalance.
Serum PTH levels increase in both sexes. Although the proportional increase in men over midlife values is greater than in women, absolute values late in life are similar in both sexes. This discrepancy occurs because the change over life in men is parabolic. There are higher values in young adulthood, which decrease in midlife and then increase in old age.
In contrast, the increase in serum PTH levels in women begins earlier and increase continuously. Values were reduced to a greater degree after E replacement therapy ERT than after Ca supplementation. J Clin Endocrinol Metab The serum PTH begins to increase in women about 10—15 yr after the menopause Fig.
Thus, there may be a transitional interval before the processes leading to secondary hyperparathyroidism become dominant over the direct effect of E deficiency on bone cell function. Thereafter, serum PTH increases throughout life, a progression that may be due, at least in part, to abnormal parathyroid gland function.
Compared with young adult women, they found that elderly women had greater basal, maximal, and nonsuppressible levels of PTH secretion without alterations in the set-point Table 2.
These abnormalities are similar to those found in patients in early renal failure associated with secondary hyperparathyroidism and parathyroid hyperplasia and are consistent with a histological autopsy study showing a trend to parathyroid hyperplasia in elderly women and men Adapted from Ledger et al. Tradition holds that the slow phase of bone loss in elderly women is caused largely by age-related abnormalities in extraskeletal calcium metabolism and that E deficiency plays either no role or only a minor one.
However, in 13 , we proposed that E deficiency is, in fact, the principal cause of both the abnormal extraskeletal calcium metabolism and the secondary hyperparathyroidism and, thus, is the ultimate cause of the slow phase of bone loss.
The compelling data that supported this hypothesis are found in two studies by our group , demonstrating that elderly postmenopausal women receiving long-term E treatment had levels of serum PTH and bone turnover markers that were identical with those of young premenopausal women, whereas the untreated controls had the expected high levels for both variables Fig.
We have attempted to resolve the apparent paradox of how E deficiency produces opposite types of parathyroid function in the two phases of bone loss reviewed above by hypothesizing that there are two types of E action on bone—a direct action on bone cells and an indirect action that is mediated by changes in PTH secretion resulting from E effects on extraskeletal calcium metabolism. E increases intestinal calcium absorption both in experimental animals , and in humans , , acting through intestinal ER E also increases renal calcium conservation , by enhancing tubular calcium resorption Thus, the loss of the direct actions of E on the gut and kidney will result in continued calcium wasting.
Unless these losses are compensated for by very large increases in dietary calcium intake, they will lead to secondary hyperparathyroidism and will contribute to the slow phase of bone loss. Although both phases of postmenopausal bone loss are caused by E deficiency, the mechanisms by which the E deficiency produces the bone loss differ.
We suggest that this accounts for the different patterns observed in the two phases of postmenopausal bone loss. The major characteristics of the early, rapid phase are that it is self-limiting and induces disproportionate cancellous bone loss.
As reviewed earlier, both of these characteristics can be explained by E deficiency resetting the mechanostat. Because of its greater proportion of surfaces interfacing with the bone marrow, cancellous bone, rather than cortical bone, is preferentially lost in this mode.
The major characteristics of the late, slow phase are that it continues indefinitely and that there are similar or even greater losses of cortical than of cancellous bone.
Because the bone loss is driven by the PTH excess, rather than by the sensing of biomechanical strain by bone cells, it will continue as long as the secondary hyperparathyroidism persists. The action of PTH also determines the remodeling characteristics, and the bone loss is not restricted to the endosteal-marrow interface but affects all bone surfaces. These remodeling characteristics are consistent with those observed in patients with mild primary hyperparathyroidism who maintain cancellous volume and structure but lose cortical bone , They are also consistent with the findings that transgenic mice expressing constitutively active PTH receptors in osteoblasts have increased density of cancellous bone but decreased density of cortical bone The relative sparing of cancellous bone may be due to the anabolic action of PTH that is manifested in certain circumstances Although increased bone resorption is the predominant cause of bone loss in postmenopausal women, decreased bone formation also contributes.
Because the components of bone turnover are tightly coupled, an increase in bone resorption will not cause substantial bone loss unless the compensatory increase in bone formation is impaired.
In both phases of postmenopausal bone loss in women, however, bone resorption at the tissue level is higher than formation, indicating impaired compensation Refs. Moreover, Lips et al. These abnormalities generally have been attributed to age-related factors, particularly to decreases in paracrine production of growth factors or to decreases in circulating levels of GH , and IGF-I — However, if E stimulates bone formation, postmenopausal E deficiency could also be a contributing cause.
Indeed, impaired bone formation becomes apparent soon after menopause Direct evidence that E can stimulate bone formation after cessation of skeletal growth was provided by Khastgir et al. Tobias and Compston have reported similar results. It is unclear whether these results represent only pharmacological effects or are an augmentation of physiological effects of E that are ordinarily not large enough to detect. Thus, accumulating data implicate E deficiency as a contributing cause of decreased bone formation with aging.
Nonetheless, there is not a clear consensus on whether E stimulates osteoblast function, and, if it does, what is the relative contribution of increased proliferation and decreased apoptosis.
Although osteoporosis is often considered to be mainly a disease of women, men lose half as much bone with aging and have one third as many fragility fractures that women do Except in the infrequent older man who develops overt hypogonadism, levels of total serum E and T decrease in men only slightly with aging.
Thus, the prevailing opinion has been that sex steroid deficiency is not a major cause of age-related bone loss in men. However, in the last few years, thinking on this issue has undergone a paradigm shift.
It is now clear that the failure of earlier studies to find major decreases in serum levels of total sex steroid in aging men was due to their failure to account for the confounding effect of a 2-fold age-related rise in levels of serum SHBG Ref. Although there is controversy about the reliability of bioavailable Bio; non-SHBG-bound sex steroid measurements, they correlate well with the more well accepted measurement of free levels. Several groups have reported substantial decreases in serum levels of free or Bio sex steroid levels with aging 17 , , The physiological importance of these decreases is reinforced by the reciprocal increases in serum FSH and LH.
Note that changes in serum Bio T are plotted logarithmically to accommodate large differences in levels between sexes. Adapted from Khosla et al. Although Bio E and Bio T decrease with aging in both sexes 17 , the mechanism of the decrease differs: Although the testis does not fail suddenly, as the ovary does, stimulation studies with clomiphene citrate have established that aging men have a decreased testicular secretory reserve capacity In addition, decreases in circulating levels of Bio E in aging men will negatively feed back on the hypothalamus to reduce GH pulsatile secretion further The increased serum SHBG binds tightly to serum T, rendering a progressively larger fraction unavailable to tissues.
Although the decrease in Bio T increases gonadotropin secretion, the aging testis is unable to respond by increasing serum levels of Bio T and E to within the young adult range.
Thus, as shown schematically in Fig. Model for causation of increases in serum SHBG in aging men. This is a complex interaction driven by a reduced secretory capacity of GH by the pituitary and T by the testes. This leads to a vicious cycle: This can be explained by the different actions of the two sex steroids: Both men had undetectable levels of serum E, elevated levels of serum T, unfused epiphyses, and osteopenia. In both, E treatment fused the epiphyses and increased BMD.
Thus, either impaired responsiveness of bone to E or impaired E synthesis leads to osteopenia in young adult men despite T sufficiency. In a relevant experimental study in aged male rats, Vanderschueren et al. In rats, the nonaromatizable androgen DHT decreased biochemical markers of bone turnover and urinary calcium excretion in immature rats, although it is unclear whether these effects were due to its skeletal or extraskeletal actions One possible interpretation of these data is that aromatization of T to E followed by binding of E to the ER is the preferred pathway for androgen action, but when this is blocked or when a high dosage of an androgen is administered, the AR-mediated pathway is used as a default pathway to modulate bone cell function.
Nonetheless, eight recent, community-based, observational studies 17 , — , — have uniformly demonstrated by multivariate analysis that E, rather than T, was the main predictor of BMD at all sites, except for certain cortical bone sites in the appendicular skeleton.
However, because the prevailing BMD of elderly men is the algebraic summation of the amount of bone that is gained during growth and maturation and the amount lost with aging, these correlations could reflect either or both processes. In a population-based cohort, Khosla et al. Also, when 50 elderly men were treated for 6 months with raloxifene or placebo, Doran et al.
Interestingly, population-based studies show that only about half of men aged 70 are below this level, whereas almost all postmenopausal women are. This may explain, in part, why all aging women lose bone but only some aging men do.
Finally, Falahati-Nini et al. Fifty-nine elderly men mean age, 68 yr were made pharmacologically hypogonadal by administration of the GnRH agonist leuprolide and had the conversion of androgens to E blocked by administration of the aromatase inhibitor letrozole. During a 3-wk lead-in, all subjects received replacement dosages of T and E by patch.
The sex steroids were then withdrawn and the subjects were randomly assigned to treatment groups of E alone, T alone, both, or neither. Bone turnover markers were assessed before randomization and after 3 wk of treatment.
An effect of androgens on bone resorption is consistent with the presence of AR in human osteoclasts For bone formation markers, however, serum osteocalcin was maintained by both E and T, whereas serum COOH-terminal type I procollagen peptide was maintained only by E.
Because osteocalcin is a late marker of osteoblast differentiation, these data are consistent with the observation in vitro by Kousteni et al. Collectively, these results Fig. Thus, age-related decreases in serum Bio E may be the major cause of bone loss and osteoporosis in aging men. Finally, Lanyon and Skerry have suggested that the effect of bone strain on maintaining bone mass in men also is mediated by the ER.
Experimental testing of the relative importance of E and T in suppressing bone turnover in elderly men. After suppression of sex steroid production by GnRH agonist treatment and blocking conversion of androgens to E with aromatase inhibition, subjects were randomly assigned to groups treated with T, E, both, or neither.
Panel A shows the effects of treatment on the resorption markers, urinary deoxypyridinoline Dpd and N-telopeptide of type I collagen NTx. The possibility of a small effect on T on opposing this increase cannot be excluded. Levels of serum bone alkaline phosphatase did not change data not shown.
Withdrawal of E and T leads to a decrease in markers indicating that bone formation was being stimulated. For significance of change from baseline: If E, rather than T, is mainly responsible for regulating bone resorption and if both E and T regulate bone formation, how can sexual dimorphism of the skeleton occur?
The answer to this question appears to be that osteoblasts in different regions of the skeleton will respond differentially to one or the other sex steroid.
Tetracycline-based studies in rats have shown that periosteal bone formation is inhibited by E but is stimulated by T 46 , These findings are consistent with the observation that one of the major skeletal differences between sexes is that men have larger appendicular bones and thicker cortical widths. In addition to these direct skeletal effects, androgens also increase intestinal calcium absorption , although it is unclear whether they enhance renal calcium homeostasis as E does.
The patterns of bone gain and bone loss described earlier and the mechanisms that cause them occur in everyone.
Yet only about one in two women and one in six men develop fractures due to osteoporosis. Even accounting for the occurrence of falls and trauma that predispose certain individuals to fracture, there remains a wide variability of peak bone mass and of rates of bone loss with aging. Because of the overriding importance of sex steroids in determining and in maintaining bone mass in both sexes, variability in the levels of serum sex steroids, in the responsiveness of bone to a given serum level, or both could contribute to the variability of bone gain during puberty and bone loss with aging.
The relationship between individual differences in sex steroid levels and rates of bone acquisition during puberty needs further examination. However, Lorentzon et al. See the review by Grumbach for more details.
There also is insufficient information about the relationship between individual differences in sex steroid levels and the rate and duration of the accelerated phase of bone loss in the early postmenopause. We have hypothesized that women who develop vertebral or distal forearm fractures during the first 15—20 yr after menopause are those who have experienced disproportionate cancellous bone loss. This contrasts with type II osteoporosis, which occurs in the entire population of aging women and men, is associated with hip and other fractures later in life, and can be attributed to the effects of the slow phase of bone loss.
Women with type I osteoporosis have higher bone turnover and a larger remodeling imbalance but do not have consistently lower levels of serum sex steroids as compared with nonosteoporotic control women. However, these earlier studies could be criticized because the assays for assessing sex steroid levels then available were relatively insensitive.
Thus, we have recently reexamined this issue using new ultrasensitive assays in 40 typical type I osteoporotic women with vertebral fractures and in 40 age-matched control women. Previous studies have shown that E replacement will normalize bone turnover in these patients. Thus, the data are consistent with the hypothesis that the type I osteoporosis fracture syndrome is mainly the result of increased responsiveness of bone to E deficiency that is evident in the presence of low serum E levels but that is overcome by restoring premenopausal high serum E levels.
This is likely to be caused by a genetically determined change such as polymorphism s of a gene or genes involved in receptor or postreceptor sex steroid signaling see next section. Moreover, it is possible that these same polymorphisms also may lead to impaired E enhancement of skeletal growth and maturation, resulting in reduced peak bone mass.
More information is available on the relationship between late postmenopausal bone loss and serum E levels assessed by ultrasensitive assays. In three nested case-control studies from the Study of Osteoporotic Fractures, elderly women with lower levels of serum E and higher levels of serum SHBG had lower cross-sectional BMD values at the calcaneus, proximal radius, proximal femur, and lumbar spine ; higher rates of bone loss from the calcaneus and proximal femur ; and increased risk for vertebral and hip fractures after adjusting for age.
We have reanalyzed our population-based data from Rochester, Minnesota. Although the correlations between serum E levels and bone loss in late postmenopausal women were significant, they may underestimate the restraining effect on bone loss of extragonadal E synthesis, which is virtually the exclusive source of circulating E levels in women after menopause.
Depending on the gradient between circulating concentrations and intracellular concentrations in intracrine cells, local synthesis could play a major role in sex steroid action. Based on the effect on bone turnover markers induced by administration of the potent aromatase inhibitor letrozole to postmenopausal women, Heshmati et al. Moreover, because the process is substrate limited, it is likely that the large age-related decreases in levels of circulating C19 adrenal precursors reduce extragonadal E synthesis and, thus, further enhance bone loss.
Interestingly, the decline begins in young adulthood and, for the most part, continues throughout life This raises the possibility that part of the bone loss that has been documented to occur in premenopausal women , may relate to these decreases. Finally, it is possible that changes in the pattern of serum E metabolism could affect bone loss. Using the ovariectomized mouse model, Westerlind et al.
Indeed, Lim et al. After T or E binds to its respective receptor, the hormone-receptor complex disassociates from heat shock proteins, dimerizes, forms complexes with various coactivator proteins , and binds to E or T response elements in DNA directly or by protein-protein bridging to other DNA binding sites. Genetic polymorphisms could modify any step of this complex pathway, thus affecting the responsiveness of bone cells to E.
In a multivariate analysis in healthy adolescent boys, Lorentzon et al. In postmenopausal women, a TA repeat polymorphism was associated with lower BMD , and increased risk for osteoporotic fractures In a group of early postmenopausal Finnish women followed for 5 yr, Salmen et al. Although these associations are intriguing, they are far from conclusive.
Finally, individual differences in the effect of E deficiency on extraskeletal calcium metabolism could affect osteoporosis risk.
This possibility was suggested by Heshmati et al. Whether this defect is part of an alteration in the E-signaling system is not known. Variability in the concentration of serum T, the rate of aromatization of T to E, or bone responsiveness to T also could affect the rate of bone loss in aging men. Polymorphisms of the aromatase gene have been related to both female and male osteoporosis.
As a corollary to his mechanostat hypothesis, Frost has suggested in various publications summarized in Refs. Indeed, in a population sample, Proctor et al. Moreover, Center et al. Nonetheless, there are a number of reasons for believing that the action of sex steroids on bone is of equal, or of even greater, importance to the conservation of bone mass. First, the high correlation between total skeletal muscle mass and total body bone mass is an overestimate because both variables are highly correlated with body size.
Second, part of the high correlation between muscle and bone mass may be related to changes in age-related factors that affect both correlates, such as decreases in serum T, GH, and IGF-I. Third, E therapy initiated soon after menopause essentially prevents significant bone loss for at least 8 yr after menopause , but a regular exercise program has not been demonstrated to do so. Finally, elite woman distance runners who become amenorrheic develop severe bone loss despite subjecting their skeleton to large biomechanical loads This is consistent with the concept that the major function of the mechanostat is to add bone during growth but that it is less able to add bone to the adult skeleton It should be also noted that T has a direct effect on increasing muscle mass and strength Studies should be made to quantify the independent effects of biomechanical strains and sex steroid action on the maintenance of bone mass and, especially, to determine in vivo the interaction between these two positive determinants.
Other than changes in serum levels of sex steroids and PTH, the two most important causes of age-related bone loss are abnormalities in the vitamin D-endocrine and in the GH-IGF-I regulatory systems. Reduced serum concentrations of both of the active vitamin D metabolites— hydroxyvitamin D [25 OH D] and 1, OH 2 D—occur with aging in both sexes. Nutritional vitamin D deficiency may contribute to the secondary hyperparathyroidism and bone loss with aging because decreases in serum 25 OH D correlate inversely with serum PTH levels and directly with BMD However, nutritional vitamin D deficiency is unlikely to be the major cause of secondary hyperparathyroidism in most elderly women because, as mentioned earlier, E replacement normalizes the increase in serum PTH levels , Nonetheless, house-bound persons with inadequate exposure to UV radiation and poor nutrition, especially populations who reside in countries with higher latitudes, such as Great Britain and France, and where dairy products are not fortified with vitamin D, may be at risk for vitamin D deficiency bone loss.
However, Lips et al. Serum levels of the physiologically active vitamin D metabolite, 1, OH 2 D, also decrease with aging, at least relative to the concomitant increases in serum PTH Elderly women infused with PTH had a blunting of the stimulated increases in serum 1, OH 2 D levels relative to changes in young adults Aging decreases the amplitude and frequency of GH secretion , which leads to decreased hepatic production of IGF-I.
Thus, decreased systemic and skeletal production of IGF-I may contribute to decreases in bone formation with aging. Other changes in endocrine function with aging appear to make smaller contributions to bone loss. Those persons who achieve a higher peak bone mass in young adulthood are less likely to develop osteoporosis as age-related bone loss ensues, whereas those with low levels are clearly at greater risk , The relative contribution of peak bone mass and bone loss to the BMD in an elderly woman or man is unclear.
Some have estimated, however, that about half of the variance in cancellous BMD and one third of the variance of cortical BMD in women by age 70 is due to bone loss — In a study of women with vertebral fractures and their daughters, Tabensky et al. As reviewed in Section IX , differences in serum levels of or responsiveness to sex steroids could contribute to the large variability in peak bone mass.
Nonetheless, the combined effects of nonhormonal factors such as heredity, activity, calcium intake, and protein and caloric nutrition are substantial In addition to genetic polymorphisms involving sex steroids that affect BMD, other allelic variations have been described.
In addition, studies in inbred mice have made quantitative trait localizations of additional genes that affect bone density, size, and structure [see the review by Nguyen et al. These include use of certain drugs such as corticosteroids; diseases such as malabsorption, anorexia nervosa, and renal hypercalciuria; and behavioral factors such as smoking, alcohol abuse, and inactivity. Some of these sporadic factors, however, may exert their effect on bone by impairing production of sex steroids.
For example, smoking increases the catabolism of E and anorexia nervosa or excessive exercise may result in hypothalamic-induced amenorrhea.
It is important to recognize that bone loss from these secondary factors is superimposable on that induced by decreases in sex steroid production. We propose that E deficiency is the major cause of both the early, accelerated and the late, slow phases of bone loss in postmenopausal women and contributes substantially to the continuous phase of bone loss in aging men. To this can be added the important roles of E and T in the development of peak bone mass during and after the pubertal growth spurt.
Although E deficiency is the primary cause of the two phases of bone loss in women and the single phase in men, the downstream mediators differ, as is shown schematically in Fig.