Abstract
Background: The combination of pharmacological therapy and exercise is frequently recommended for osteoporosis management; however, whether antiresorptive agents may interfere with exercise-induced bone adaptation remains unclear. This study aimed to investigate the independent and combined effects of zoledronate and treadmill exercise on bone microarchitecture and mechanical strength in an ovariectomized rat model. Methods: Twenty-four female Sprague Dawley rats underwent ovariectomy and were assigned to four groups: Control, zoledronate (ZA), treadmill exercise (T), and combined zoledronate and exercise (ZA + T). An additional sham-operated group was included. Zoledronate was administered as a single subcutaneous injection, and a 6-week treadmill exercise routine was implemented. Bone microarchitecture was assessed using micro-computed tomography, and a three-point bending test was employed for evaluation of mechanical properties. Results: The combined ZA + T group demonstrated significant improvements in trabecular bone parameters, including bone volume/tissue volume and trabecular number, compared with the Control group. Mechanical strength parameters, including maximum load and stiffness, were also significantly enhanced in the ZA + T group. Cortical bone parameters exhibited no significant changes. Conclusions: Treadmill exercise did not attenuate the effects of zoledronate, and may offer additive benefits in enhancing trabecular bone microarchitecture and mechanical strength. These findings suggest that exercise therapy can complement bisphosphonate treatment and contribute to optimizing therapeutic strategies for osteoporosis, supporting the potential utility of combined pharmacological and exercise-based interventions for improving bone health.