Investigating the synergistic efficacy of BMP-7 and zoledronate on bone allografts using an open rat osteotomy model

Bone grafts are well-established in the treatment of fracture non-unions but union is still not always achieved. Harvesting autograft is associated with donor site morbidity and the available amount of bone is limited. Allograft is more easily obtained and available in greater quantities but lacks the osteoinductive characteristics of autograft. We have previously shown a synergistic effect of bone morphogenetic protein (BMP-7), systemic bisphosphonates and autograft. In the present study we hypothesized that the combination of allograft+BMP-7+systemic ZA is more effective than autograft alone, which is currently the most frequently used aid in augmenting fracture and non-union healing. Femoral osteotomies were performed on 82 male Sprague Dawley rats and fixed with intramedullary K-wires. The rats were randomized into 7 groups: (i) saline, (ii) autograft, (iii) allograft, (iv) allograft+BMP-7, (v) autograft+zoledronate (ZA), (vi) allograft+ZA and (vii) allograft+BMP-7+ZA. Autografts were harvested from the contralateral tibia. Allografts were obtained from donor rats and frozen. BMP-7 was administered locally in the form of a putty placed circumferentially around the osteotomy. At 2 weeks, the rats were injected with a single dose of either saline or ZA. The rats were sacrificed at 6 weeks and the femurs were evaluated using radiography, histology, μCT and three-point bending tests. Complete radiological healing was seen in all rats in the BMP-7 groups. The callus volume was larger and the calluses were denser with allograft+BMP-7+ZA than in all other groups (μCT, p<0.001). Mechanical testing yielded a substantially higher peak force with the allograft+BMP-7+ZA combination than all other groups (p<0.01, p<0.001). This was further reinforced in the 59% increase in the peak force observed in the osteotomized femurs of the allograft+BMP-7+ZA group compared to the control femurs (p<0.01), whereas significant decreases of 22-27% were observed in the saline or bone-graft alone groups (p<0.01, p<0.05). Thus our results suggest that allograft combined with the anabolic effect of BMP-7 and the anti-catabolic effect of zoledronate is more efficient than autograft alone.