دانلود رایگان مقاله اثرات ضد آندروژن دراستفاده نامناسب ترابکولار مستقل استئوپنی

ABSTRACT

Aging hypogonadal men are at increased risk of osteoporosis and sarcopenia. Testosterone is a potentially appealing strategy to prevent simultaneous bone and muscle loss. The androgen receptor (AR) mediates antiresorptive effects on trabecular bone via osteoblast-lineage cells, as well as muscle-anabolic actions. Sex steroids also modify the skeletal response to mechanical loading. However, it is unclear whether the effects of androgens on bone remain effective independent of mechanical stimulation or rather require indirect androgen effects via muscle. This study aims to characterize the effects and underlying mechanisms of androgens on disuse osteosarcopenia. Adult male mice received a unilateral botulinum toxin (BTx) injection, and underwent sham surgery or orchidectomy (ORX) without or with testosterone (ORX + T) or dihydrotestosterone (ORX + DHT) replacement. Compared to the contralateral internal control hindlimb, acute trabecular number and bone volume loss was increased by ORX and partially prevented DHT. T was more efficient and increased BV/TV in both hindlimbs over sham values, although it did not reduce the detrimental effect of BTx. Both androgens and BTx regulated trabecular osteoclast surface as well as tartrate-resistant acid phosphatase expression. Androgens also prevented BTx-induced body weight loss but did not significantly influence paralysis or muscle atrophy. BTx and ORX both reduced cortical thickness via endosteal expansion, which was prevented by T but not DHT. In long-term follow-up, the residual trabecular bone volume deficit in sham-BTx hindlimbs was prevented by DHT but T restored it more efficiently to pre-treatment levels. Conditional AR deletion in late osteoblasts and osteocytes or in the satellite cell lineage increased age-related trabecular bone loss in both hindlimbs without influencing the effect of BTx on trabecular osteopenia. We conclude that androgens have antiresorptive effects on trabecular disuse osteopenia which do not require AR actions on bone via muscle or via osteocytes.

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.