Differential effects on bone of estrogen receptor α and androgen receptor activation in orchidectomized adult male mice

Androgens may regulate the male skeleton either directly by stimulation of the androgen receptor (AR) or indirectly by aromatization of androgens into estrogens and, thereafter, by stimulation of the estrogen receptors (ERs). To directly compare the effect of ER activation on bone in vivo with the effect of AR activation, 9-month-old orchidectomized wild-type and ER-inactivated mice were treated with the nonaromatizable androgen 5α-dihydrotestosterone, 17β-estradiol, or vehicle. Both ERα and AR but not ERβ activation preserved the amount of trabecular bone. ERα activation resulted both in a preserved thickness and number of trabeculae. In contrast, AR activation exclusively preserved the number of trabeculae, whereas the thickness of the trabeculae was unaffected. Furthermore, the effects of 17β-estradiol could not be mediated by the AR, and the effects of 5α-dihydrotestosterone were increased rather than decreased in ER-inactivated mice. ERα, but not AR or ERβ, activation resulted in preserved thickness, volumetric density, and mechanical strength of the cortical bone. ERα activation increased serum levels of insulin-like growth factor I, which were positively correlated with all the cortical and trabecular bone parameters that were specifically preserved by ERα activation but not by AR activation, suggesting that insulin-like growth factor I might mediate these effects of ERα activation. Thus, the in vivo bone-sparing effect of ERα activation is distinct from the bone-sparing effect of AR activation in adult male mice. Because these two pathways are clearly distinct from each other, one may speculate that a combined treatment of selective ER modulators and selective AR modulators might be beneficial in the treatment of osteoporosis.