Thyroid-Stimulating Hormone Restores Bone Volume, Microarchitecture, and Strength in Aged Ovariectomized Rats*

Abstract

We show the systemic administration of low levels of TSH increases bone volume and improves bone microarchitecture and strength in aged OVX rats. TSH's actions are mediated by its inhibitory effects on RANKL-induced osteoclast formation and bone resorption coupled with stimulatory effects on osteoblast differentiation and bone formation, suggesting TSH directly affects bone remodeling in vivo.Introduction: Thyroid-stimulating hormone (TSH) receptor haploinsufficient mice with normal circulating thyroid hormone levels have reduced bone mass, suggesting that TSH directly affects bone remodeling. We examined whether systemic TSH administration restored bone volume in aged ovariectomized (OVX) rats and influenced osteoclast formation and osteoblast differentiation in vitro. Materials and Methods: Sprague-Dawley rats were OVX at 6 months, and TSH therapy was started immediately after surgery (prevention mode; n ‫ס‬ 80) or 7 mo later (restoration mode; n ‫ס‬ 152). Hind limbs and lumbar spine BMD was measured at 2-or 4-wk intervals in vivo and ex vivo on termination at 8-16 wk. Long bones were subjected to CT, histomorphometric, and biomechanical analyses. The direct effect of TSH was examined in osteoclast and osteoblast progenitor cultures and established rat osteosarcoma-derived osteoblastic cells. Data were analyzed by ANOVA Dunnett test. Results: In the prevention mode, low doses (0.1 and 0.3 g) of native rat TSH prevented the progressive bone loss, and importantly, did not increase serum triiodothyroxine (T3) and thyroxine (T4) levels in aged OVX rats. In restoration mode, animals receiving 0.1 and 0.3 g TSH had increased BMD (10-11%), trabecular bone volume (100-130%), trabecular number (25-40%), trabecular thickness (45-60%), cortical thickness (5-16%), mineral apposition and bone formation rate (200-300%), and enhanced mechanical strength of the femur (51-60%) compared with control OVX rats. In vitro studies suggest that TSH's action is mediated by its inhibitory effects on RANKL-induced osteoclast formation, as shown in hematopoietic stem cells cultivated from TSH-treated OVX rats. TSH also stimulates osteoblast differentiation, as shown by effects on alkaline phosphatase activity, osteocalcin expression, and mineralization rate. Conclusions: These results show for the first time that systemically administered TSH prevents bone loss and restores bone mass in aged OVX rats through both antiresorptive and anabolic effects on bone remodeling.

Pituitary-bone connection in skeletal regulation

“…However, in vivo, in rats, TSH, injected up to once every 2 weeks, inhibits ovariectomyinduced bone loss 28 weeks following ovariectomy [73]. Calcein-labeling provides evidence for a direct anabolic action of intermittent TSH [69]. In humans, Martini et al [70] showed an increase in procollagen type I N propeptide (PINP), a marker of bone formation, validating the conclusion that bolus doses of TSH are indeed anabolic.…”

“…At least 20 clinical studies have since documented tight and highly reproducible correlations between low TSH levels, bone loss, bone geometry, and fracture risk in patient cohorts across the globe . Evidence also shows that TSH protects the skeleton by exerting anti-resorptive and anabolic actions in rodent models and in people [37,[62][63][64][65][66][67][68][69][70][71].…”

“…While it inhibits osteoblastogenesis in bone marrow-derived cell cultures, TSH stimulates differentiation and mineralization in murine cell cultures through a Wnt5a-dependent mechanism [67]. Likewise, in vivo, intermittently administered TSH is anabolic in both rats and mice [69,73]. Thus, the effect of TSH may be differentiation stage-dependent.…”

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

“…In the context of conflicting data on a functional role for TSH in skeletal development, our data, which were corrected for serum TSH levels, outline the importance of local T 3 for bone metabolism. (13)(14)(15)(16)(17)(35)(36)(37)(38) Two recent papers by Bassett and colleagues, (18,19) who studied mice with complete or haploinsufficiency of TRa and -b, concluded that TRa regulates both skeletal development and adult bone maintenance.…”

Thyroid Disorders and Bone Mineral Homeostasis

“…Systemic administration of TSH to ovariectomised rats has been shown to prevent bone loss and restore bone mass (Sampath et al, 2007;Sun et al, 2008) have demonstrated that intermittent administration of exogenous TSH in ovariectomised rats and mice have anti-resorptive effects. Recent findings indicate that TSH might play a crucial role in bone turnover in humans.…”