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

Thyrotoxicosis is frequently associated with increased bone turnover and decreased bone mass. To investigate the role of thyroid hormone receptor-β (TRβ) in mediating the osteopenic effects of triiodothyronine (T ₃), female adult rats were treated daily (64 days) with GC-1 (1.5 μg/100 g body wt), a TRβ-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 μg/100 g body wt) or control animals. As expected, treatment with T₃ significantly reduced bone mineral density (BMD) in the lumbar vertebrae (L₂-L₅), 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 T₃ but not GC-1 treatment reduced the trabecular volume, thickness, and number. We conclude that chronic, selective activation of the TRβ isoform does not result in bone loss typical of T ₃-induced thyrotoxicosis, suggesting that the TRβ isoform is not critical in this process. In addition, our findings suggest that the development of TR-selective T₃ analogs that spare bone mass represents a significant improvement toward long-term TSH-suppressive therapy.