Augmentation of autologous bone graft by a combination of bone morphogenic protein and bisphosphonate increased both callus volume and strength

Abstract

Background and purpose Bone morphogenic proteins (BMPs) can be used in non-unions to replace autograft. BMPs induce osteoblasts and (less well known) also osteoclasts, which can in turn be controlled by a bisphosphonate. In the present study, our aim was to improve the biological effect of autologous bone graft by adding an anabolic BMP, with or without bisphosphonates, in an open-fracture model prone to non-union.

Methods Rat femurs were osteotomized and fixed with an intramedullary K-wire. Autograft was placed at the osteotomy, mixed with either saline or BMP-7. After 2 weeks, the rats had a single injection of saline or of a bisphosphonate (zoledronate). The rats were killed after 6 weeks and the femurs were evaluated by radiography, micro-CT, histology, and 3-point bending test.

Results All fractures healed. The callus volume was doubled in the BMP-treated femurs (p < 0.01) and increased almost 4-fold in the femurs treated with both BMP and systemic zoledronate (p < 0.01) compared to autograft. In mechanical testing, the autograft group reached approximately half the strength of the contralateral, non-osteotomized femur (p < 0.001). By adding BMP to the autograft, the strength was doubled (p < 0.001) and with both BMP and systemic zoledronate, the strength was increased 4-fold (p < 0.001) compared to autograft alone.

Interpretation The combination of BMP and bisphosphonate as an adjunct to autograft is superior to autograft alone or combined with BMP. The combination may prove valuable in the treatment of non-unions.

All the authors participated in the conception and design of the study, and in writing and approval of the manuscript. In addition, PB and MT carried out the animal experiment, PB the mechanical testing, and HI the micro-CT analysis and the statistics.

The project was supported by the Swedish Research Council (project 2031), the Greta and Johan Kock Foundation, the Alfred Österlund Foundation, the Maggie Stephens Foundation, the Thure Carlsson Foundation, Vinnova, and the Medical Faculty of Lund University. BMP-7 (Osigraft) was a gift from Stryker Biotech, Malmö, Sweden and the zoledronate (Zometa) was a gift from Novartis, North Ryde, NSW, Australia.