Sclerostin blockade and zoledronic acid improve bone mass and strength in male mice with exogenous hyperthyroidism

Abstract

Hyperthyroidism in mice is associated with low bone mass, high bone turnover, and high concentrations of sclerostin, a potent Wnt inhibitor. Here, we explored the effects of either increasing bone formation with sclerostin antibodies (Scl-Ab) or reducing bone turnover with bisphosphonates on bone mass and strength in hyperthyroid mice. Twelve-week-old C57BL/6 male mice were rendered hyperthyroid using L-thyroxine (T4; 1.2 mg/mL added to the drinking water) and treated with 20 mg/kg Scl-Ab twice weekly or 100 mg/kg zoledronic acid (ZOL) once weekly or phosphatebuffered saline for 4 weeks. Hyperthyroid mice displayed a lower trabecular bone volume at the spine (242%, P,0.05) and the distal femur (255%, P,0.05) compared with euthyroid controls. Scl- Ab and ZOL treatment of hyperthyroid mice increased trabecular bone volume at the spine by threefold and twofold, respectively. Serum bone formation and resorption markers were increased in hyperthyroid mice and suppressed by treatment with ZOL but not Scl-Ab. Trabecular bone stiffness at the lumbar vertebra was 63% lower in hyperthyroid mice (P<0.05) and was increased fourfold by Sci-Ab (P<0.001) and threefold by ZOL treatment (P<0.01). Bone strength based on ultimate load, which was 10% lower in hyperthyroidism, was increased by Scl-Ab by 71% and ZOL by 22% (both P<0.001). Increased proportion of low mineralized bone seen in hyperthyroid mice was restored by treatmentwith Scl-Ab and ZOL. Thus, bone-forming and antiresorptive drugs prevent bone loss in hyperthyroid mice via different mechanisms.