Background: Bisphosphonates reduce fracture risk and increase bone mineral density (BMD) in postmenopausal women with osteoporosis; however, their effects on bone mechanical properties remain uncertain. As direct mechanical testing of bone is not feasible in humans, preclinical models provide critical insight into the mechanical effects of therapy. While no animal model fully replicates the human condition, non-human primates are among the most translationally relevant due to their skeletal, hormonal, and metabolic similarity to humans. This study aimed to quantify the effects of bisphosphonates on structural mechanical properties in ovariectomized non-human primates and to identify factors explaining variability in these effects.

Methods: A systematic search was conducted in CINAHL, Embase, PubMed, SPORTDiscus, and Web of Science. Studies of ovariectomized non-human primates reporting structural mechanical outcomes (ultimate load, stiffness, or work-to-failure) were eligible. A random-effects meta-analysis was performed. Associations between ultimate load and potential moderators, including skeletal site, BMD, and treatment duration, were examined using meta-regression.

Results: Fourteen studies were identified; thirteen used an immediate-treatment design and one a delayed-treatment approach. Only immediate-treatment studies were included in the meta-analysis (mean treatment duration of 15.7 months post-ovariectomy). Ovariectomy significantly reduced ultimate load relative to sham controls at the spine, but not at femoral sites. Compared with untreated ovariectomized animals, bisphosphonate-treated animals exhibited greater ultimate load at the spine (SMD=0.77; 95% CI 0.43 to 1.10) and femoral neck (SMD=0.48; 95% CI 0.04 to 0.92), but not at the femoral shaft (SMD=0.38; 95% CI -0.04 to 0.81). Stiffness was higher at the spine (SMD=0.61; 95% CI 0.40 to 0.82) but not at femoral sites. No significant effects were observed for work-to-failure at any site. Effects on ultimate load were site-dependent, positively associated with BMD differences, and appeared to attenuate with longer treatment duration.

Conclusion: Early bisphosphonate therapy preserves bone structural strength in ovariectomized non-human primates in a site-specific manner, with effects closely linked to BMD. However, the absence of effects on work-to-failure indicates a dissociation between structural strength and energy absorption capacity. These findings provide mechanistic insight into the mechanical effects of bisphosphonates but should be interpreted in the context of clinical fracture outcomes.