Spared bone mass in rats treated with thyroid hormone receptor TR beta-selective compound GC-1

Thyrotoxicosis is frequently associated with increased bone turnover and decreased bone mass. To investigate the role of thyroid hormone receptor-beta (TRbeta) in mediating the osteopenic effects of triiodothyronine (T-3), female adult rats were treated daily ( 64 days) with GC-1 (1.5 mug/100 g body wt), a TRbeta-selective thyromimetic compound. Bone mass was studied by dual-energy X-ray absorptiometry of several skeletal sites and histomorphometry of distal femur, and the results were compared with T-3-treated (3 mug/100 g body wt) or control animals. As expected, treatment with T-3 significantly reduced bone mineral density (BMD) in the lumbar vertebrae (L-2-L-5), femur, and tibia by 10-15%. In contrast, GC-1 treatment did not affect the BMD in any of the skeletal sites studied. The efficacy of GC-1 treatment was verified by a reduction in serum TSH (-52% vs. control, P < 0.05) and cholesterol (-21% vs. control, P < 0.05). The histomorphometric analysis of the distal femur indicated that T-3 but not GC-1 treatment reduced the trabecular volume, thickness, and number. We conclude that chronic, selective activation of the TRbeta isoform does not result in bone loss typical of T-3-induced thyrotoxicosis, suggesting that the TRbeta isoform is not critical in this process. In addition, our findings suggest that the development of TR-selective T-3 analogs that spare bone mass represents a significant improvement toward long-term TSH-suppressive therapy.