Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions

Abstract

Background: The role of bone morphogenetic proteins (BMPs) in osseous repair has been demonstrated in numerous animal models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7) has now been produced and was evaluated in a clinical trial conducted under a Food and Drug Administration approved Investigational Device Exemption to establish both the safety and efficacy of this BMP in the treatment of tibial nonunions. The study also compared the clinical and radiographic results with this osteogenic molecule and those achieved with fresh autogenous bone.

Materials and methods: One hundred and twenty-two patients (with 124 tibial nonunions) were enrolled in a controlled, prospective, randomized, partially blinded, multi-center clinical trial between February, 1992, and August, 1996, and were followed at frequent intervals over 24 months. Each patient was treated by insertion of an intramedullary rod, accompanied by rhOP-1 in a type I collagen carrier or by fresh bone autograft. Assessment criteria included the severity of pain at the fracture site, the ability to walk with full weight-bearing, the need for surgical re-treatment of the nonunion during the course of this study, plain radiographic evaluation of healing, and physician satisfaction with the clinical course. In addition, adverse events were recorded, and sera were screened for antibodies to OP-1 and type-I collagen at each outpatient visit.

Results: At 9 months following the operative procedures (the primary end-point of this study), 81% of the OP-1-treated nonunions (n = 63) and 85% of those receiving autogenous bone (n = 61) were judged by clinical criteria to have been treated successfully (p = 0.524). By radiographic criteria, at this same time point, 75% of those in the OP-1-treated group and 84% of the autograft-treated patients had healed fractures (p = 0.218). These clinical results continued at similar levels of success throughout 2 years of observation, and there was no statistically significant difference in outcome between the two groups of patients at this point (p = 0.939). All patients experienced adverse events. Forty-four percent of patients in each treatment group had serious events, none of which were related to their bone grafts. More than 20% of patients treated with autografts had chronic donor site pain following the procedure.

Conclusions: rhOP-1 (BMP-7), implanted with a type I collagen carrier, was a safe and effective treatment for tibial nonunions. This molecule provided clinical and radiographic results comparable with those achieved with bone autograft, without donor site morbidity.

Fig. 1

Radiographs of a 34-year-old male patient treated with osteogenic protein-1 (OP-1) and 33 months following a closed, comminuted tibial fracture sustained in a motor vehicle accident. Prior treatment included intramedullary rod fixation, fresh bone autograft, a fibulectomy, and external electrical stimulation. The clinical and radiographic results were considered successful at both 9 and 24 months following treatment with an intramedullary rod and OP-1. A: Immediate postoperative radiograph. B: Radiograph 9 months following treatment with OP-1. C: Radiograph 24 months following treatment with OP-1.

Fig. 2

Radiographs of a female patient, 34 years old at entry into this study, who sustained an open, comminuted, grade III-B tibial fracture as a result of a motor vehicle accident. Prior treatment include multiple debridements, implantation of antibiotic impregnated beads, a vascularized free soft-tissue flap, external fixation and, on two occasions, fresh bone autografts. The patient was treated by re-debridement, intramedullary fixation, and implantation of osteogenic protein-1 (OP-1) 14 months following the original injury. Despite abundant new-bone formation and mild pain during full weight-bearing at 9 and 31 months, this patient was considered a treatment failure because of incomplete bone bridging. A: Preoperative radiograph. B: Radiograph 3 months following treatment with OP-1. C: Radiograph 9 months following treatment with OP-1. D: Radiograph 31 months following treatment with OP-1.