Influence of glucocorticoid and bone morphogenetic protein on fracture healing using a rat closed femoral fracture model

The purpose of this study was to examine the effects of pharmocologic doses of prednisolone on fracture healing using a closed femoral fracture model in the rat and to determine whether the bone morphogenetic protein, osteogenic protein-1 (OP-1), would augment fracture healing during glucocorticoid therapy. One hundred and ninety-two male Sprague-Dawley rats received subcutaneous implants of either timed-release prednisolone (equivalent to 2.2 mg/kg/day) or placebo pellets. Two weeks following implantation, surgery was performed for intramedullary pin placement and subsequent femur fracture using the established closed fracture method in the rat. In a subset of rats, a limited approach to the femur was performed for application of OP-1 and collagen carrier or collagen carrier alone. Femurs were harvested at 10, 28, and 42 days for radiographic analysis, at 28 and 42 days for biomechanic analysis, and at 3, 10, 21, 28, and 42 days for histomorphometric analysis. For the groups used to evaluate the effects of prednisolone, radiographs showed no significant difference in fracture callus at 10 days. However, measurements at 28, and 42 days revealed significantly less fracture callus in rats treated with prednisolone. Femurs harvested at 28 days for biomechanic analysis withstood significantly less maximum torsion to failure and were significantly reduced in stiffness in rats treated with prednisolone. Histomorphometric analysis revealed significantly less total callus at 21, and 42 days, and less hard callus at 42 days in prednisolone treated rats. However, cartilaginous soft callus was greater in rats treated with prednisolone at 42 days. Differences between prednisolone treatment and control groups for application of OP-1 or collagen alone were not detected for radiographic, biomechanic, or histomorphometric analyses at any time. However, comparison of application of OP-1 or collagen alone in prednisolone treatment groups revealed significantly greater fracture healing with OP-1 compared to collagen alone. These results show that prednisolone treatment significantly inhibits fracture healing, and specifically inhibits the process of endochondral ossification. OP-1 is highly effective in counteracting the inhibitory effects of prednisolone treatment on fracture healing, and may be an important adjunct to fracture repair in patients receiving glucocorticoid therapy.