Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling

Abstract

The osteoporosis associated with human hyperthyroidism has traditionally been attributed to elevated thyroid hormone levels. There is evidence, however, that thyroid-stimulating hormone (TSH), which is low in most hyperthyroid states, directly affects the skeleton. Importantly, Tshr-knockout mice are osteopenic. In order to determine whether low TSH levels contribute to bone loss in hyperthyroidism, we compared the skeletal phenotypes of wild-type and Tshr-knockout mice that were rendered hyperthyroid. We found that hyperthyroid mice lacking TSHR had greater bone loss and resorption than hyperthyroid wild-type mice, thereby demonstrating that the absence of TSH signaling contributes to bone loss. Further, we identified a TSH-like factor that may confer osteoprotection. These studies suggest that therapeutic suppression of TSH to very low levels may contribute to bone loss in people.

Figure 1. Hyperthyroid TSHR-deficient mice have greater bone loss than wild-type hyperthyroid mice with intact TSH signaling.

aBMD (A), micro-CT images (B), and individual parameters from vertebral bodies (C) of wild-type (Tshr^+/+) and Tshr^–/– mice implanted with 0-mg (placebo) or 5-mg T₄ pellets (TH) for 21 days. Mean percent changes (±SEM) in vBMD, BV/TV, Tb.N, Tb.Th, Tb.Sp, and Conn.D are shown. **P < 0.01; n = 6–8 mice/group.

Figure 2. TSHR deficiency accelerates bone remodeling in hyperthyroidism.

Representative images of TRAP-labeled (A) or calcein-labeled bones (B), as well as serum C-telopeptide (CTX) (C) and serum osteocalcin (D) levels in wild-type and Tshr^–/– mice implanted with 0-mg (placebo) or 5-mg sustained-release T₄ pellets for 21 days. Scale bars in A and B: 100 μm; B inset, 10 μm. **P < 0.01, ^†P < 0.01; n = 4–9 mice/group.