Reversal of weightlessness-induced musculoskeletal losses with androgens: quantification by MRI.

Microgravity causes rapid decrement in musculoskeletal mass is associated with a marked decrease in circulatory testosterone levels, as we reported in hindlimb-suspended (HLS) rats. In this model which simulates microgravity, we hypothesized that testosterone supplementation should prevent these losses, and we tested this in two studies. Muscle volumes and bone masses were quantitated by using magnetic resonance imaging (MRI) on day 12. In the first study, 12-wk-old Sprague-Dawley rats that were HLS for 12 days lost 28.5% of muscle volume (53.3 +/- 4.8 vs. 74.5 +/- 3.6 cm3 in the ground control rats; P < 0.001) and had a 5% decrease in bone mineral density (BMD) (P < 0.05). In the second study, 30 male 12-wk-old Wistar rats were HLS and were administered either a vehicle (control), testosterone, or nandrolone decanoate (ND). An additional 20 rats were used as ground controls, one-half of which received testosterone. HLS rats had a significant reduction in muscle volume (42.9 +/- 3.0 vs. 56 +/- 1.8 cm3 in ground control rats; P < 0.01). Both testosterone and ND treatments prevented this muscle loss (51.5 +/- 2 and 51.6 +/- 1.2 cm3, respectively; a 63% improvement; P < 0. 05). There were no statistical differences between the two active treatment groups nor with the ground controls. Similarly, there was an 85% improvement in BMD in the testosterone group (1.15 +/- 0.04 vs. 1.04 +/- 0.04 density units in vehicle controls; P < 0.05) and a 76% improvement in the ND group (1.13 +/- 0.07 density units), whereas ground control rats had a BMD of 1.17 +/- 0.03 density units. Because serum testosterone levels are markedly reduced in this model of simulated microgravity, androgen replacement seems to be a rational countermeasure to prevent microgravity-induced musculoskeletal losses.

Prevention of corticosteroid-induced bone loss with nitric oxide donor nitroglycerin in male rats.

Nitric oxide (NO) has been reported to inhibit osteoclastic bone resorption. We examined the bone sparing effect of NO on prevention of corticosteroid-induced bone loss in older male rats. Recently, we demonstrated that NO donor nitroglycerin (NG) can alleviate ovariectomy-induced bone loss, and the protective effects of estrogens on bone are mediated through NO [Bone 18(4):301-304; 1996]. Therefore, we chose to study a different model (i.e., steroid-induced osteoporosis in males) to evaluate whether NG can inhibit the bone loss associated with corticosteroid therapy. Twenty-five 32-week-old male Wistar rats were randomly assigned to five groups (n = 5/group). They received either vehicle, methylprednisolone (7 mg/kg per week), NO synthase inhibitor L-NAME (25 mg/kg per day), NO donor nitroglycerin (NG, 0.2 mg twice daily), a combination of prednisolone+NG, or prednisolone plus L-NAME, respectively. Prior to treatment and at the end of the 6 week treatment period, bone mineral density (BMD) of the lumbar spine was measured by dual energy X-ray absorptiometry scanning. Administration of prednisolone significantly decreased BMD (-9.50%, p < 0.05). The group receiving NG with prednisolone (-2.34%) and the group treated with NG alone (-0.36%) were not statistically different from the control group (-0.11%). Similar to the changes in BMD, femur weights were also significantly lower in prednisolone-treated rats (1.09 +/- 0.01 g vs. 1.17 +/- 0.03 in controls; p < 0.05). However, the rats receiving prednisolone together with NG were able to maintain their femur weights (1.13 +/- 0.02). There was a reduction of 9.5% of BMD (p < 0.05) and 7.8% of femoral weight (p < 0.05) in rats treated with L-NAME. A 50%-70% reduction of the percentage trabecular bone volume in the proximal tibia and distal femur and a 50% reduction of the midshaft cortical area was seen after corticosteroid therapy, and these too were prevented by administration of NG. Here, we demonstrate, for the first time, that supplementation with a NO donor compound can counteract prednisolone-induced bone loss.