Androgen deficiency induces high turnover osteopenia in aged male rats: a sequential histomorphometric study

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 cross-links 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.