Time for treating bone fracture using rhBMP-2: a randomised placebo controlled mouse fracture trial

Although the mechanisms of osteoinduction by bone morphogenic proteins (BMPs) are increasingly understood, the most appropriate time to administer BMPs exogenously is yet to be clarified. The purpose of this study was to investigate when BMP may be administered to a fracture arena to maximise the enhancement of healing. Forty mice with externally fixed left femoral fractures were randomised into four groups: Group I, the control group was given a placebo of 30 microl saline at day 0; Groups II, III and IV were given 30 microl saline plus 2.5 microg rhBMP-2, at post-operative days 0, 4 or 8, respectively. Sequential radiographs were taken at days 0, 8, 16. On day 22 the mice were sacrificed and both femora were harvested for biomechanical assessment in 3-point bending and histological evaluation. Radiographic analysis indicated that healing of fractures in Groups II and III was significantly greater (p < 0.05) than those in Groups I and IV, at both 16 and 22 days post-fracture. The highest median bone mineral content at the fracture site was evidenced in Group III and II. Furthermore, Group III also had the highest relative ultimate load values, followed by Groups II, IV and I. Greater percentage peak loads were observed between Group I and both Groups II and III (p < 0.05). Histological examination confirmed that at 22 days post-fracture, only fractures in Groups II and III had united with woven bone, and Groups I and IV still had considerable amounts of fibrous tissue and cartilage at the fracture gap. Data presented herein indicates that there is a time after fracture when rhBMP administration is most effective, and this may be at the time of surgery as well as in the early fracture healing phases.