4. Discussion
Androgens are an interesting candidate treatment for simultaneous bone loss and muscle atrophy as shown by previous preclinical studies on disuse osteosarcopenia [14,16,20,33,35,36]. However, it is unclear whether the preventive actions of androgens on disuse osteoporosis are mediated via a direct effect on bone or merely result from indirect androgen effects on muscle. Our main findings are that both T and DHT mitigate BTx-induced trabecular bone resorption, in line with the known effects of AR on trabecular bone maintenance [3,6–10]. This confirms findings in ARKO mice which have been reported to display greater hindlimb unloading-induced bone loss [48]. Orchidectomy increased not only bone resorption but also bone formation, as assessed by dynamic histomorphometry (Fig. 3B) and serum osteocalcin and TRAcP 5b concentrations (Table 1). This is expected since bone formation and resorption are coupled, and androgens are known to inhibit trabecular bone resorption by restraining bone turnover via an effect on osteoblasts [49,50]. Thus, although androgens did not preserve trabecular bone via an effect on bone formation in our study, the effect of T may be different during growth since it was recently reported that disuse reduced trabecular bone formation which was restored by T at supraphysiological doses in young rats [20]. In both short-term and long-term experiments however, we found that T was more effective than DHT in restoring trabecular bone volume. T also prevented BTx-induced endosteal expansion whereas DHT did not, suggesting that aromatization and estrogens are important for these effects of T. This is in line with the known effects of ERα on the trabecular and endosteal compartment in male mice [2, 3,9,51]. Thus, although pure androgens may exert some antiresorptive effects on the trabecular compartment, high-dose T therapy may be more effective given the importance of aromatization for male skeletal health.
