Testosterone Prevents Orchidectomy-Induced Bone Loss in Estrogen Receptor-α Knockout Mice

Abstract

To examine the role of the estrogen receptor-α (ERα) during male skeletal development, bone density and structure of aged ERαKO mice and wild-type (WT) littermates were analyzed and skeletal changes in response to sex steroid deficiency and replacement were also studied. In comparison to WT, ERαKO mice had smaller and thinner bones, arguing for a direct role of ERα to obtain full skeletal size in male mice. However, male ERαKO mice had significantly more trabecular bone as assessed both by pQCT and histomorphometry, indicating that ERα is not essential to maintain cancellous bone mass. Six weeks following orchidectomy (ORX), both WT and ERαKO mice showed high-turnover osteoporosis as revealed by increases in serum osteocalcin and decreases in trabecular (−38% and −58% in WT and ERαKO, respectively) and cortical bone density (−5% and −4% in WT and ERαKO, respectively). Administration of testosterone propionate (T, 5 mg/kg/day) completely prevented bone loss both in ERαKO and in WT mice. As expected, estradiol (E2, 60 μg/kg/day) replacement did not prevent cancellous bone loss in ORX ERαKO mice. However, E2 stimulated bone formation at the endocortical surface in ORX ERαKO, suggesting that osteoblasts may respond to nonERα-mediated estrogen action. In conclusion, although functional ERα may play a significant role during male skeletal development, this receptor does not seem essential for androgen-mediated skeletal maintenance in older male mice.