Dose-, duration- and age-dependent effects of zoledronic acid on bone structure and mechanical properties in growing rice rats.

BACKGROUND

Zoledronic acid (ZOL), a potent bisphosphonate, is increasingly used off-label in pediatric bone disorders, but its long-term effects on the growing skeleton remain underexplored. This study aimed to investigate the impact of ZOL dose, treatment duration, and age at treatment initiation on femoral structure and mechanical properties in growing rice rats, addressing a critical knowledge gap.

METHODS

Two complementary preclinical studies were performed in female rice rats. Study 1 examined dose-dependent effects by administering ZOL (0, 8, 20, 50, 125 µg/kg) every 4 weeks, starting at age 4 weeks, for up to 30 weeks. Study 2 investigated age at treatment initiation (4, 16, or 22 weeks) and durations (6, 12, or 18 weeks) using a single oncologic dose of ZOL (80 µg/kg every 4 weeks). Femoral cancellous and cortical pQCT assessed bone mineral content (BMC), volumetric bone mineral density (vBMD), area and microstructure. 3-point bending of the femoral diaphysis was used to determine biomechanical properties.

RESULTS

ZOL increased total metaphyseal BMC, vBMD, and area, with oncologic doses (20-125 µg/kg) producing 15-25% greater increases in metaphyseal BMC than the osteoporosis dose (8 µg/kg) after 18-30 weeks of treatment. Cortical parameters (area and periosteal circumference) and mid-diaphyseal mechanical properties (ultimate load, moment of inertia) also increased when treatment began in young, growing rats and was maintained for 18-24 weeks, although clear dose-response effects were limited. When ZOL started later, skeletal responses were attenuated and required longer treatment durations to become significant.

CONCLUSIONS

ZOL enhances metaphyseal and cortical bone properties while improving mechanical strength, particularly when treatment is initiated at an early age. The skeletal response depends on both duration and age at initiation. Notably, ZOL dose-response effects are pronounced in cancellous bone. Cortical structural and mechanical properties exhibit a nonlinear response, with significant differences observed only at extended treatment durations.