Estrogen and Fracture Risk in Men

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. In 1994, a landmark case report of a young man with a disruptive homozygous mutation in the estrogen receptor (ER ) gene led to a rather sudden realization that estrogens are important for male skeletal health. 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 ER receptor than could not bind estrogen. Although bound and free testosterone as well as dihydrotestosterone concentrations were normal, luteinizing hormone (LH) and folliclestimulating 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. 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. In these men, circulating estrogen levels are remarkably low or undetectable, whereas androgens are normal or even elevated. In contrast to the ER -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. 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. 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. 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, but not in similar studies of elderly men from the Rotterdam, Tromso, and Dubbo cohorts. Indeed, serum testosterone, but not estradiol levels, predicted incident fracture risk independent of BMD in elderly men from the Dubbo Osteoporosis Epidemiology Study. 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. 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 The authors state that they have no conflicts of interest.