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Sclerostin Blockade and Zoledronic Acid Improve Bone Mass and Strength in Male Mice With Exogenous Hyperthyroidism
Elena Tsourdi1,2, Franziska Lademann1,2, Michael S Ominsky3
1Department of Medicine III, Technische Universität Dresden Medical Center, 01307 Dresden, Germany.
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 µg/mL added to the drinking water) and treated with 20 mg/kg Scl-Ab twice weekly or 100 µg/kg zoledronic acid (ZOL) once weekly or phosphate-buffered saline for 4 weeks. Hyperthyroid mice displayed a lower trabecular bone volume at the spine (-42%, P < 0.05) and the distal femur (-55%, 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 treatment with Scl-Ab and ZOL. Thus, bone-forming and antiresorptive drugs prevent bone loss in hyperthyroid mice via different mechanisms.
Insights
Hyperthyroidism causes bone loss in mice. Sclerostin antibodies and bisphosphonates effectively reversed this bone loss, improving bone mass and strength through distinct mechanisms.
Area of Science:
- Endocrinology
- Bone Biology
- Pharmacology
Background:
- Hyperthyroidism in mice leads to reduced bone mass, increased bone turnover, and elevated sclerostin levels.
- Sclerostin is a key inhibitor of the Wnt signaling pathway, crucial for bone formation.
Purpose of the Study:
- To investigate the efficacy of sclerostin antibodies (Scl-Ab) and bisphosphonates (ZOL) in restoring bone mass and strength in a mouse model of hyperthyroidism.
- To compare the distinct mechanisms of action of bone-forming (Scl-Ab) and antiresorptive (ZOL) agents in counteracting hyperthyroid-induced bone loss.
Main Methods:
- Male C57BL/6 mice were induced into a hyperthyroid state using l-thyroxine (T4).
- Mice received treatments of Scl-Ab, zoledronic acid (ZOL), or a control (phosphate-buffered saline) for four weeks.
- Bone volume, stiffness, strength, and serum markers of bone turnover were assessed.
Main Results:
- Hyperthyroid mice exhibited significantly lower trabecular bone volume in the spine and femur compared to controls.
- Both Scl-Ab and ZOL treatments substantially increased trabecular bone volume and stiffness in hyperthyroid mice.
- While ZOL suppressed bone turnover markers, Scl-Ab did not, indicating different therapeutic actions. Bone strength was improved by both agents.
Conclusions:
- Sclerostin antibodies and bisphosphonates are effective in preventing and potentially reversing bone loss associated with hyperthyroidism in mice.
- These treatments restore bone mass and strength through different pathways: Scl-Ab by promoting formation and ZOL by inhibiting resorption.
- The findings highlight the potential of targeted therapies for managing bone complications in hyperthyroid conditions.
