Modeling anabolic and antiresorptive therapies for fracture healing in a mouse model of osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a genetic bone fragility disorder that features frequent fractures. Bone healing outcomes are contingent on a proper balance between bone formation and resorption, and drugs such as bone morphogenetic proteins (BMPs) and bisphosphonates (BPs) have shown to have utility in modulating fracture repair. While BPs are used for OI to increase BMD and reduce pain and fracture rates, there is little evidence for using BMPs as local agents for fracture healing (alone or with BPs). In this study, we examined wild-type and OI mice (Col1a2+/G610C) in a murine tibial open fracture model with (i) surgery only/no treatment, (ii) local BMP-2 (10 µg), or (iii) local BMP-2 and postoperative zoledronic acid (ZA; 0.1 mg/kg total dose). Microcomputed tomography reconstructions of healing fractures indicated BMP-2 was less effective in an OI setting, however, BMP-2 +ZA led to considerable increases in bone volume (+193% WT, p < 0.001; +154% OI, p < 0.001) and polar moment of inertia (+125% WT, p < 0.01; +248% OI, p < 0.05). Tissue histology revealed a thinning of the neocortex of the callus in BMP-2 treated OI bone, but considerable retention of woven bone in the healing callus with BMP + ZA specimens. These data suggest a cautious approach may be warranted with the sole application of BMP-2 in an OI surgical setting as a bone graft substitute. However, this may be overcome by off-label BP administration.