Combined effects of recombinant human BMP-7 (rhBMP-7) and parathyroid hormone (1–34) in metaphyseal bone healing

Abstract

Fracture healing involves multiple stages of repair and coordinated actions of multiple cell types. Consequently, it may be possible to enhance healing through treatment strategies that target more than one repair process or cell type. The goal of this study was to determine the combined effects of recombinant human bone morphogenetic protein 7 (rhBMP-7) and parathyroid hormone (PTH(1–34)) on metaphyseal bone healing. A wedge-shaped defect was created in the lateral aspect of the distal tibia in female New Zealand white rabbits ( n = 64) and was filled with tricalcium phosphate (TCP). Animals were assigned to four groups: 1) BMP-7 and PTH; 2) BMP-7; 3) PTH; and 4) control (TCP alone). In groups 1 and 2, 200 μg rhBMP-7 was incorporated into the TCP. Animals received daily subcutaneous injections of 10 μg/kg PTH(1–34) (groups 1 and 3) or saline (groups 2 and 4). Healing at 4 weeks was assessed using micro-computed tomography, histology, immunohistochemistry, and mechanical testing. Combined treatment with rhBMP-7 and PTH resulted in increased callus total volume (TV), mineralized volume (BV), average cross-sectional area, and bone mineral content (BMC) as compared to the control group ( p < 0.02). BV and BMC were also higher in the combined treatment group as compared to the BMP-7 group ( p < 0.02); however, tissue mineral density was highest in the BMP-7 group ( p = 0.002). New bone formation in the BMP-7 group was largely restricted to the defect site, while PTH promoted bone formation throughout the defect and surrounding regions. Combined treatment led to greater quantities of woven trabecular bone, increased trabecular thickness, decreased trabecular separation ( p < 0.04), and a trend towards increased numbers of osteoclasts ( p = 0.09). Combined treatment also resulted in increased torsional rigidity and compressive strength as compared to the control and BMP-7 groups ( p < 0.001). These results suggest that the improvements in mechanical function obtained with the combined treatment resulted from differing biological activities of rhBMP-7 and PTH. While the activities of rhBMP-7 appeared to be strictly anabolic, those of PTH appeared to work in the context of coupled remodeling. The combination of both agents led to greater bone volume as well as better microstructural organization and integration of this bone with the surrounding tissues.