Hypogonadism is considered to be one of the major risk factors for osteoporosis in men. However, the mechanisms of bone loss caused by androgen deficiency are still unclear. In the present study, we sequentially investigated the skeletal and hormonal effects of androgen deficiency in aged orchiectomized (ORX) rats over a time period of 9 months. One hundred seventy 13-month-old male Fischer-344 rats were either ORX or sham-operated (SHAM). Eight rats served as baseline controls. After in vivo fluorochrome labeling, groups of 8 -15 SHAM and ORX rats each were killed at 2 weeks and at 1, 2, 3, 4, 6, and 9 months postsurgery. As expected, ORX induced a fall in serum total and free testosterone levels, but also reduced serum estradiol concentrations. Cancellous bone area (BAr) in the proximal tibia but not in the first lumbar vertebral body showed an age-dependent decline in SHAM rats. Relative to SHAM controls, ORX rats had significantly reduced cancellous BAr after 2 weeks post-ORX in the tibia and after 2 months post-ORX in the vertebral body. Thereafter, vertebral and tibial cancellous BAr continued to decline in ORX animals throughout the study. Osteoclast number (NOc), osteoblast surface, bone formation rate (BFR), and activation frequency were increased in ORX animals from 1 month postsurgery until the end of the trial. Moreover, in close temporal association with the histomorphometric findings, serum osteocalcin and urinary excretion of collagen crosslinks and calcium were elevated in ORX rats. In a stepwise model of multiple regression analysis using estradiol and free and total testosterone as independent variables, estradiol was the only significant predictor of histomorphometric indices of bone formation and bone resorption in SHAM and ORX rats. These data show that androgen deficiency induces substantial loss of cancellous bone in the axial and appendicular skeleton of aged male rats and that this osteopenia is associated with a sustained increase in bone turnover. Thus, the skeletal effects of androgen withdrawal in aged male rats appear to resemble those induced by estrogen withdrawal in female rats. Furthermore, our study suggests that estradiol may act as a physiological suppressor of bone remodeling in aged male rats. (J Bone Miner Res 2000;15:1085-1098)
Bisphosphonates inhibit bone loss through inhibition of osteoclast-mediated bone resorption. At low doses, vitamin D metabolites can prevent bone loss in models of osteopenia in rats by an antiresorptive effect, while at high doses they also stimulate osteoblast activity and show an anabolic effect. Therefore, combined therapy with bisphosphonates and vitamin D analogs might be expected to be more effective than either treatment alone.
ABSTRACT:Introduction: Hypogonadism is considered to be one of the major risk factors for osteoporosis in men. Here, we sequentially studied the effects of androgen deficiency on cortical bone in aged orchiectomy (ORX) rats. Materials and Methods: One hundred seventy 13-mo-old male Fischer-344 rats were either ORX or shamoperated. After in vivo fluorochrome labeling, groups of 8-15 SHAM and ORX rats each were killed at 2 wk and 1, 2, 3, 4, 6, and 9 mo after surgery. To examine the effects of testosterone replacement therapy, 9-mo-old ORX rats were supplemented with testosterone undecanoate at a weekly dose of 6 mg/kg for 4 mo. Cortical bone changes in the tibial shaft were monitored by pQCT analysis and by bone histomorphometry. Results: SHAM rats did not show age-related bone loss at the tibial diaphysis. pQCT analysis and bone histomorphometry showed cortical bone osteopenia in ORX rats, beginning from 2 mo after surgery until the end of the study. Androgen deficiency induced a sustained decrease in periosteal bone formation during the first 4 mo after ORX. However, although periosteal expansion of the tibial shaft tended to be slower in ORX rats compared with SHAM controls, the reduction in total cross-sectional area in ORX animals reached statistical significance only at 4 mo after surgery. The major mechanism for cortical bone loss in aged ORX rats was a progressive expansion of the marrow cavity, which was associated with an initial increase in endocortical eroded perimeter at 1 and 2 mo after surgery, followed by a sustained increase in endocortical bone formation until the end of the study. All these changes were prevented in aged ORX rats receiving testosterone supplementation in an insulin-like growth factor system-independent fashion. Conclusions: We conclude that androgen deficiency-induced cortical bone loss in aged, nongrowing rats is mainly caused by augmented endocortical bone remodeling.
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