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