Estrogen and Fracture Risk in Men

Abstract

The sex steroid hormones are important for acquisition and maintenance of bone mass in both sexes. Alterations in their levels can become relevant in the pathogenesis of osteoporosis either because deficiency leads to suboptimal acquisition of peak bone mass or because deficits in adulthood can lead directly to bone loss. Whereas estrogens have been shown to be critically important in these respects for the female skeleton, their role in male skeletal health has only recently become appreciated. This is caused, in part, by assumptions that sex steroid action insofar as skeletal health is concerned is sex specific: estrogens for women and androgens for men. These assumptions are rational because circulating androgens predominate in men, and estrogens predominate in women. Moreover, alterations in androgen levels (i.e., hypogonadism) in the growing male skeleton or in the context of the aging male skeleton or diseases associated with hypogonadism have been often related with secondary osteoporosis and increased fracture risk in men.1-3 In 1994, a landmark case report of a young man with a disruptive homozygous mutation in the estrogen receptor α (ERα) gene led to a rather sudden realization that estrogens are important for male skeletal health.4 The case report described a very tall man with low bone mass, increased bone turnover, unfused epiphyses, delayed bone age, and continued linear growth. His baseline estradiol and estrone levels were markedly above normal, reflecting a physiological attempt to compensate for an ERα receptor than could not bind estrogen. Although bound and free testosterone as well as dihydrotestosterone concentrations were normal, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were elevated. A recent re-evaluation of this man after 7 yr showed a 9.8% decrease in lumbar spine BMD, despite calcium and vitamin D supplementation.5 Subsequent to this first report, similar skeletal phenotypes have been described in at least eight men whose estrogen deficiency is not marked by an abnormal estrogen receptor but by an inactivating mutation in the CYP19 gene encoding aromatase, the enzyme responsible for the conversion of androgens to estrogens.6-13 In these men, circulating estrogen levels are remarkably low or undetectable, whereas androgens are normal or even elevated. In contrast to the ERα-deficient man who cannot respond to estrogen therapy, these aromatase-deficient men respond well to estrogen with rapid fusion of the epiphyses and a significant increase in BMD.7, 9, 12, 14, 15 With this background, one can quite reasonably revisit the classical observation assigning differences among male and female skeletal growth to androgens or estrogens, respectively. It is likely that the growing male skeleton is also dependent on estrogens and that many aspects of skeletal maturation previously believed to be dependent on androgens may, in fact, be driven by estrogen. Similarly, both observational and interventional studies have shown that that estrogens (perhaps more than androgens) are also important not only during skeletal growth, but also in the maintenance of bone mass in aging men.16-20 However, despite the increasing evidence of a more dominant role of estrogens than testosterone on bone turnover and BMD in men, the relative role of estrogens and androgens on fracture risk in men has remained understudied. In a large, population-based, cross-sectional study of elderly men from the Rancho-Bernardo Study, low estradiol levels were associated with vertebral fractures.21 Men in the lowest quintile of total estradiol had a significantly higher risk for prevalent fracture than those in the highest quintile, whereas men with low testosterone levels had no significant increased risk for fracture. These associations were confirmed in a prospective study in 793 men from the Framingham Study followed for up to 18 yr,22 but not in similar studies of elderly men from the Rotterdam, Tromso, and Dubbo cohorts.23-25 Indeed, serum testosterone, but not estradiol levels, predicted incident fracture risk independent of BMD in elderly men from the Dubbo Osteoporosis Epidemiology Study.25 These conflicting results might be because of the fact that these prospective studies have been underpowered, including few incident fractures, and most of them have analyzed sex steroid levels using immunoassay-based techniques with questionable specificity at lower concentrations. It is in this context that the paper by Mellström et al.26 in this issue of JBMR is of particular interest. These investigators analyzed the predictive role of serum sex steroids, as measured by the specific gas chromatography–mass spectrometry technique, for fracture risk in a large sample of elderly men from the prospective population-based MrOS Swedish cohort, consisting of subcohorts from three different cities. Incident fractures occurring after the initial baseline visit were clinically validated by review of radiology reports. Consistent with previous reports, testosterone and estradiol levels, and particularly their free (bioavailable) fractions, decreased significantly with age, whereas sex hormone binding globulin (SHBG) levels increased with age. The main finding of this study was that in multivariate analyses, free estradiol and SHBG, but not free testosterone, were independent predictors of all fractures. Indeed, in age-adjusted analyses, testosterone, estradiol, and their bioavailable fractions, when examined separately, were all inversely, whereas SHBG was directly, related to fracture risk, although only free estradiol was a significant predictor of fractures in all three cities studied. This is an understandable observation, because circulating estrogen and testosterone levels are highly correlated, and only a small fraction of estradiol is derived directly from the testes, whereas >85% comes from peripheral aromatization of circulating androgen precursors. To complement their observation, Mellstrom et al. analyzed the effect of having low estradiol and/or low testosterone in their population and showed that subjects with low estradiol levels had an increased risk of fractures independent of testosterone status. This implies that, when testosterone levels are low, the presence of normal estradiol concentrations (likely caused by increased peripheral aromatase activity) are sufficient to prevent fractures and that serum estradiol is the major sex steroid with an impact on fracture risk in this cohort of elderly men. In fact, subjects with high testosterone but low estradiol levels had an increased risk of fractures as well. Importantly, in this study, patient inclusion was broad, with inability to walk without aids as the sole exclusion criterion. Thus, these results are readily applicable to the general population of older men. Nonetheless, as the authors state in discussion, this could also imply that the effects of sex steroid levels in their population-based cohort may be confounded by existing comorbidities. Therefore, consistent with previous evidence,27 low estrogen levels might, in part, be more generally a marker of poorer health and frailty. This hypothesis may explain the fact that association between estrogen and fractures was attenuated, but remained significant, after adjustment for BMD. The inverse relationship between serum estradiol levels and fracture risk was nonlinear, with a strong relationship at estradiol levels below 16 pg/ml (59 pM), corresponding to 6.2 pg/ml (23 pM) for calculated free estradiol. This observation further reinforces and extends the concept of a threshold estradiol level for skeletal health in men.16, 17 Thus, it seems that not only are estradiol levels above a given threshold necessary to regulate bone turnover and maintain BMD in older men,16-19 but they are also important for preventing fractures. The threshold levels for total and bioavailable estradiol proposed in the study of Mellstrom et al. are slightly lower than those previously described for BMD or bone turnover markers. This could be related at least in part to differences between the gas chromatography–mass spectrometry technique used in this study and the immunoassay-based techniques used in previous studies. However, a similar threshold for total estradiol (18 pg/ml) below which incident hip fracture risk increases was previously described in a population-based cohort of 852 men from the Framingham Study.22 Thus, even though these and the previous findings do not definitely exclude a role for testosterone in bone health, it seems clear that estrogen is the dominant sex steroid defining fracture risk in men and that there is a threshold for this effect. Because recent findings using QCT would suggest a better defined threshold for cortical than trabecular bone,28 one could speculate that these fractures in aging men are more dependent on cortical bone losses. This is also consistent with the sex differences observed in the age-related changes of bone microstructure. Whereas postmenopausal women show a progressive loss of trabeculae with an increase in trabecular separation with age, men undergo trabecular thinning but no substantial loss of trabecular number or any major increase in trabecular separation.29, 30 Thus, because the decreases in trabecular thickness have a much lower impact on bone strength compared with decreases in trabecular number,31 it is likely that a consistent component of fracture risk in men is caused by reduction in cortical rather than to trabecular bone strength. This could also explain why the threshold estradiol level for fracture is lower than the threshold level associated with bone loss (i.e., a greatest decrease in estrogen level is needed to affect both trabecular and cortical compartments and thus to increase fracture risk in men). Importantly, the preservation of trabecular number is lost in hypogonadal men32 but not in the man with the ERα loss of function mutation,5 suggesting that this parameter may be regulated by androgens. This could also explain why, in the Framingham cohort, hip fractures risk was greatest in men with both low estradiol and low testosterone levels.22 Clearly, further studies are needed to fully address this issue. Collectively, these findings do potentially have important clinical implications. Thus, should estradiol be used as a screening test to identify men at risk for osteoporosis, and should it now routinely be used as part of the diagnostic evaluation of male osteoporosis? The answer at this point is probably yes, but it depends on the availability of reliable, standardized estradiol assays. Recent data have suggested that mass spectroscopy would be the preferred method for assessing estradiol levels in men because of its increased specificity at lower concentrations.33 However, this technique is not currently widely available and has considerably higher cost than immunoassays. Importantly, cross-calibration of mass spectroscopy instrumentation should be easier than standardization of immunoassays, so that increased use of mass spectroscopy for measuring estradiol levels should help in standardizing measurements across institutions. As assays for low levels of serum estradiol become more accurate and available, it may also be useful to measure estradiol concentrations in men. In addition, a still unaddressed issue is the sensitivity and specificity of a low estradiol level (below some defined threshold) for identifying men with osteoporosis based on DXA. Another important clinical implication of this study relates to whether SHBG and testosterone levels be measured in addition to estradiol? Mellstrom et al. clearly indicate that serum testosterone did not add significantly to the value of the serum estradiol measurement in terms of fracture risk; however, other similar reports are not consistent with this observation.22 Conversely, SHBG was an independent predictor of fracture risk in the population-based MrOS Sweden cohort, and subjects with high SHBG had increased fracture rates irrespective of estrogen status. This raises the hypothesis of a different and yet unknown role of SHBG in skeletal health, in addition to its function of binding circulating sex hormones, thereby reducing their bioavailable fractions.34 Additional issues need further resolution. Because only a small fraction of circulating estradiol is derived directly from the testes, it is likely that peripheral aromatization of testicular and adrenal androgen precursors to estrogen exerts a key role in maintaining estradiol levels above the required threshold with aging.35 This may have important implications for the use of nonaromatizable selective androgen receptor modulators for the treatment of male osteoporosis,36 particularly in hypogonadal men. Are they doomed to failure in terms of reducing fracture risk in men, based on these considerations? An additional unsolved issue is which tissue site of aromatase activity is the most important in terms of bone metabolism in men. The consistent association between circulating estradiol levels, BMD, and fracture risk, reported in the study of Mellstrom et al. and in several other studies, suggests that, although local aromatization in bone may contribute significantly to skeletal homeostasis,37, 38 a minimum circulating level of estradiol (derived from nonskeletal peripheral aromatization) is necessary to prevent bone loss in elderly men. However, it is possible that circulating estrogen levels simply reflect local estrogen status within the bone and that locally produced estradiol exerts an even greater impact on bone physiology than circulating plasma estradiol levels. Finally, it is also likely that individual differences might be present among males because of variability in aromatase activity and/or estrogen sensitivity and that this variability may be relevant for skeletal homeostasis, particularly in elderly subjects, in whom age-related declines in testicular and adrenal androgen precursors are common.38, 39 Recent studies suggested that polymorphic variation of the aromatase (CYP19) gene may account at least in part for these differences in aromatase activity.40, 41 Besides genetic considerations, additional mechanisms have been proposed in which aromatase activity and estrogen production could be modulated under certain circumstances in different tissues,35 although this issue has been poorly studied to date. Thus, even though there is no doubt that estrogen exerts a major role in male skeletal homeostasis, further studies are needed to better understand the exact mechanisms of action of estrogen in bone, to clarify the androgen contribution on bone homeostasis, and to define how genetic, environmental, pathologic, and pharmacological influences might modulate estrogen production and sensitivity in males, thereby affecting skeletal health.