A novel pharmacological approach of musculoskeletal losses associated with simulated microgravity.

Exposure to microgravity (weightlessness) is known to cause rapid bone and muscle losses. We have used the hind limb-suspended (HLS) rat model to simulate microgravity-induced musculoskeletal losses in order to assess resulting hormonal changes and to develop a novel pharmacological countermeasure. Previously, we demonstrated significant decreases in circulatory hormonal levels [serum thyroxin, 1,25(OH)2 vitamin D (p<0.05), and serum testosterone (p<0.001)] in HLS rats. Both thyroxin and 1,25(OH)2 vitamin D levels returned to normal soon after removal from HLS, while testosterone levels matched normal levels only after a further 3-4 weeks. However, even by day 42, bone mineral density (BMD) remained significantly lower, although serum hormones were back to normal. Because serum testosterone levels become undetectable in HLS rats, we hypothesized that the replacement of testosterone during HLS could prevent musculoskeletal losses. Based on these data, an intervention study was carried out to assess the efficacy of testosterone and synthetic anabolic steroid, nandrolone decanoate (ND), in prevention of weightlessness-induced musculoskeletal losses. HLS rats (control) had a significant reduction of muscle volume (42.9 -/+ 3.0, versus 56 -/+ 1.8 in ground control rats; p<0.01). Both testosterone and ND treatments prevented this muscle loss (51.5 -/+ 2 cm(3) and 51.6 -/+ 1.2, respectively; a 63% improvement, p<0.05). Similarly, BMD of the placebo-treated HLS rats was significantly lower than that of ground control rats (0.416 -/+ 0.011 versus 0.354 -/+0.014, p<0.05), and testosterone and ND prevented this bone loss (0.404 -/+ 0.013 versus. 0.409 -/+ 0.011, respectively). These data suggest that both testosterone and ND therapy can minimize the musculoskeletal losses associated with exposure to simulated weightlessness. Experiments using the combination of bisphosphonate and testosterone demonstrated complete protection of both muscle and bone in these HLS rats. Therefore, considering that: 1) testosterone is anabolic to osteoblasts and muscle cells and also decreases the rate of bone turnover, 2) serum testosterone levels are markedly suppressed in simulated weightlessness, and 3) testosterone replacement therapy prevented musculoskeletal losses in HLS rats, we propose that the musculoskeletal losses observed in this animal model (i.e., simulated microgravity) are related to their testosterone deficiency. Since serum sex hormones levels are markedly reduced in this model of simulated microgravity, androgen replacement with a bisphosphonate seems to be a rational counter.