Effects of a BMP antagonist on fracture healing in a mouse model

Abstract

Introduction: Fracture healing is a complex process that is responsible for forming a fracture callus to stabilize the site of injury while producing new bone. Delayed fracture healing or the development of non-union as a result of failed fracture healing is a major clinical concern effecting ~10% of all treated fractures. Recent studies have shown that RAP-661, an antagonist of Bone Morphogenetic Proteins (BMP) 2 and BMP-4 binding to its receptor BMPR-1A has shown anabolic efficacy in treating bone loss associated with osteoporosis. The purpose of this study was to assess the effectiveness of the RAP-661 protein as a therapeutic agent to improve fracture healing. Materials and Methods: 34 C57/B6 mice received unilateral mid-shaft transverse right femur fractures. Three study groups used: Vehicle Treated Control (10 mM Tris-Buffered Saline) and RAP-661 in 10 mM TBS either where the drug treatment was administered continuously over the 35 days of the study or administered with a delayed treatment beginning 14 day after fracture. Both drug and vehicle were administered via intraperitoneal injection twice per week. RAP-661 was administered at 10 mg/kg for each injection. The mice were terminally harvested at 35 days. The harvested femora were then tested via microCT analysis for material and structural properties and by mechanical testing for strength and torsional stiffness and rigidity. Results: MicroCT testing showed that both drug groups had increased bone volume and bone volume percentage. Mechanical testing however, showed that the control group was significantly stronger based on its maximal torque to failure than both either drug treatment group. Although not significant, the 35 day delay group showed comparable stiffness and rigidity to the control and trended toward higher values compared to the 35 day continuous group. Conclusion: Although both drugs groups had increased total mineral density and percentage bone volume, they both had significantly lower maximal torque to failure when compared to the control. This discordance indicates that while the RAP-661 improves overall bone accumulation, it is effecting the structural integrity of bone bridging in some manner that compromise the regain of the bone’s normal mechanical strength. Further research will be needed to resolve the mechanism(s) behind this phenomenon. These results indicate that RAP- 661 does not show therapeutic efficacy in promoting fracture healing.