Background: Local bisphosphonate delivery may be a solution to prevent periprosthetic bone loss and improve orthopedic implants fixation. In load-bearing implants, periprosthetic bone is exposed to high mechanical demands, which in normal conditions induce an adaptation of bone. In this specific mechanical situation, the modulation of the bone response by bisphosphonate remains uncertain. Methods: We assessed the combined effects of zoledronate and mechanical loading on bone adaptation using an in-vivo axial compression model of the mouse tibia and injections of zoledronate. Bone structure was quantified with in-vivo µCT before and after the period of stimulation and the biomechanical properties of the tibias were evaluated with 3 point-bending tests after sacrifice. Findings: Axial loading induced a localized increase of cortical thickness and bone area. Zoledronate increased cortical thickness, bone perimeter, and bone area. At the most loaded site of the tibia, the combined effect of zoledronate and mechanical stimulation was significantly smaller than the effect of zoledronate plus the effect of mechanical loading. Interpretations: The results of this study suggested that a negative interaction between zoledronate and mechanical loading might exist at high level of strain.