No anti-angiogenic effect of clinical dosing regimens of a single zoledronic acid injection in an experimental bone healing site

Abstract: Introduction: An anti-angiogenic effect of bisphosphonates has been reported in different experimental models. Zoledronic acid is currently administered in osteoporotic patients as a single 5 mg injection once a year and its vascular effect in bone has not been yet evaluated. Materials and methods: The vascular dose effect of a single injection of zoledronic acid was evaluated on healing vascularization developed under a bone chamber implanted on the calvaria of 30 rats. After 3 weeks of healing, the rats were randomized into 3 groups receiving an injection of either physiologic saline solution (PSS) or zoledronic acid tested at  120 μg/kg, the equivalent of a 5 mg dose of zoledronic acid in humans (Z120), and  400 μg/kg, a supra-pharmacologic dose (Z400). A longitudinal follow-up of the healing vascular network was carried out at days (D) 1, 3, 6, 9, 12, 15 and 28 after injection by intravital imaging. Variations in vascular density, total length of the vascular network and mean diameter of vascular network branches were determined by image analysis (Aphelion® software). Results: A decrease was observed in both vascular density and total length of the network in control and treated groups (time effect). No difference in variation in vascular density was observed between the PSS group and the Z120 group at any time point (p =NS). A trend to a higher decrease in vascular density was noted between D12 and D15 in the Z400 group. A significant decrease in total length was noted at D15 in the Z400 group (p =0.03) compared to the PSS group, whereas no change was noted in rats treated with  120 μg/kg compared to PSS rats on any of the follow-up days (p =0.2). No variation in mean diameter of vascular network branches was noted in any of the three groups at any of the follow-up days (p =0.53). Conclusion: A single injection of clinically relevant dosing regimens of zoledronic acid may not have a notable impact on vascularization in bone sites. The anti-angiogenic effect of bisphosphonates seems to express itself, in our model, at higher doses than those used in patients treated for osteoporosis. [Copyright &y& Elsevier]