Zoledronate Treatment Has Different Effects in Mouse Strains with Contrasting Baseline Bone Mechanical Phenotypes

Introduction: Bisphosphonates are highly effective in reducing fracture risk, yet some individuals treated with these agents still experience fracture. The goal of this study was to test the hypothesis that genotype influences the effect of zoledronate on bone mechanical properties.

Methods: Skeletally mature male mice from genetic backgrounds known to have distinct baseline post-yield properties (C57/B6, high post-yield displacement; A/J, low post-yield displacement) were treated for 8 weeks with saline (VEH) or zoledronate (ZOL, 0.06 mg/kg subcutaneously once every 4 weeks) in a 2 × 2 study design. Ex vivo μCT and mechanical testing (4-pt bending) were conducted on the femur to assess morphological and mechanical differences.

Results: Significant drug and/or genotype effects were found for several mechanical properties and significant drug × genotype interactions were found for measures of strength (ultimate force) and brittleness (total displacement, strain to failure). Treatment with ZOL affected bone biomechanical measures of brittleness (total displacement (-25 %) and strain to failure (-23 %)) in B6 mice significantly differently than in A/J mice. This was driven by unique drug × genotype effects on bone geometry in B6 animals yet likely also reflected changes to the tissue properties.

Conclusion: These data may support the concept that properties of the bone geometry and/or tissue at the time of treatment initiation play a role in determining the bone's mechanical response to zoledronate treatment.