The Effects of Androgens on Bone Metabolism: Clinical Aspects

Over the past two decades, evidence has accumulated that similar to women, estrogen is the main regulator of bone metabolism in men. A large body of work has, however, demonstrated the important direct role of androgens in skeletal growth as well as in bone remodeling, in addition to the indirect effects of androgens following their aromatization to estrogens. Androgens are responsible for a number of differences in skeletal development that occur during puberty and differentiate girls from boys. This bone modeling continues during early adulthood to confer further increases in bone strength. Most notably, androgens seem to be the key determinant of adult bone size, with comparatively less impact on bone mineral density and peak bone mass. Furthermore, androgenic effects include an increase in lean mass that provides increased mechanical loading on the skeleton to further increase bone strength. Most of the androgenic impact on bone metabolism can be observed in rare conditions such as aromatase deficiency where a “purely androgenic skeleton” continues to grow in adulthood but does not reach peak maturity without the contribution of estrogen. Conversely, in subjects with the rare condition of androgen insensitivity, lack of androgen action does not delay epiphyseal closure but does yield a shorter stature than occurs in normal males. Testosterone has modest antiresorptive effects and also plays a role in mediating bone formation. In adults, states of androgen deprivation are associated with a significant reduction in bone mineral density and consequently an increased risk of fracture. With aging, bioavailable levels of both testosterone and estradiol decline significantly, partly as a result of an increase in sex hormone-binding globulin production. The decline in androgen levels parallels a decline in both cortical and trabecular bone mineral density, with an associated increase in the risk of hip and vertebral fragility fractures as compared to the general population (Seeman et al., Am J Med 75(6):977–983, 1983). In contrast to men with significant hypogonadism in whom testosterone hormone replacement has shown unequivocal skeletal benefits, studies that have evaluated testosterone treatment either in eugonadal men or in men with an age-related decline in testosterone levels have shown contradictory results. Finally, selective androgen receptor modulators are currently being evaluated in preclinical and early phase clinical trials, with reported skeletal and physical benefits.