Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial.

BACKGROUND: Currently, the treatment of diaphyseal tibial fractures associated with substantial bone loss often involves autogenous bone-grafting as part of a staged reconstruction. Although this technique results in high healing rates, the donor-site morbidity and potentially limited supply of suitable autogenous bone in some patients are commonly recognized drawbacks. The purpose of the present study was to investigate the benefit and safety of the osteoinductive protein recombinant human bone morphogenetic protein-2 (rhBMP-2) when implanted on an absorbable collagen sponge in combination with freeze-dried cancellous allograft. METHODS: Adult patients with a tibial diaphyseal fracture and a residual cortical defect were randomly assigned to receive either autogenous bone graft or allograft (cancellous bone chips) for staged reconstruction of the tibial defect. Patients in the allograft group also received an onlay application of rhBMP-2 on an absorbable collagen sponge. The clinical evaluation of fracture-healing included an assessment of pain with full weight-bearing and fracture-site tenderness. The Short Musculoskeletal Function Assessment (SMFA) was administered before and after treatment. Radiographs were used to document union, the presence of extracortical bridging callus, and incorporation of the bone-graft material. RESULTS: Fifteen patients were enrolled in each group. The mean length of the defect was 4 cm (range, 1 to 7 cm). Ten patients in the autograft group and thirteen patients in the rhBMP-2/allograft group had healing without further intervention. The mean estimated blood loss was significantly less in the rhBMP-2/allograft group. Improvement in the SMFA scores was comparable between the groups. No patient in the rhBMP-2/allograft group had development of antibodies to BMP-2; one patient had development of transient antibodies to bovine type-I collagen. CONCLUSIONS: The present study suggests that rhBMP-2/allograft is safe and as effective as traditional autogenous bone-grafting for the treatment of tibial fractures associated with extensive traumatic diaphyseal bone loss. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence.

Subchondral fractures in osteonecrosis of the femoral head: comparison of radiography, CT, and MR imaging.

OBJECTIVE: Our objective was to compare the sensitivity of unenhanced radiography, CT, and MR imaging in revealing subchondral fractures. SUBJECTS AND METHODS: Forty-five subjects with stage I and stage II osteonecrosis of the femoral head were included in the study as part of a multicenter clinical trial to evaluate the effectiveness of recombinant human bone morphogenetic protein as an adjuvant treatment to core decompression. Patients were evaluated with radiography, CT, and MR imaging 6 and 12 months after surgery. RESULTS: At 6 months, 18 fractures were shown on CT scans, but only 12 were detected on radiographs and six, on MR images. At 12 months, 20 subchondral fractures were detected on CT scans, but only 17 were seen on radiographs and 11, on MR images. Compared with CT, MR imaging has a sensitivity and specificity of 38% and 100%, and unenhanced radiography has a sensitivity and specificity of 71% and 97%, respectively. On T2-weighted MR images, the subchondral fractures were visualized as crescentic high-signal-intensity lines, and in all patients, on the corresponding CT scans, the fracture clearly breached the femoral cortex. CONCLUSION: CT reveals more subchondral fractures in osteonecrosis of the femoral head than unenhanced radiography or MR imaging. The high-signal-intensity line seen on T2-weighted MR images appears to represent fluid accumulating in the subchondral fracture, which may indicate a breach in the overlying articular cartilage.

Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients.

BACKGROUND: The treatment of open fractures of the tibial shaft is often complicated by delayed union and nonunion. The objective of this study was to evaluate the safety and efficacy of the use of recombinant human bone morphogenetic protein-2 (rhBMP-2; dibotermin alfa) to accelerate healing of open tibial shaft fractures and to reduce the need for secondary intervention. METHODS: In a prospective, randomized, controlled, single-blind study, 450 patients with an open tibial fracture were randomized to receive either the standard of care (intramedullary nail fixation and routine soft-tissue management [the control group]), the standard of care and an implant containing 0.75 mg/mL of rhBMP-2 (total dose of 6 mg), or the standard of care and an implant containing 1.50 mg/mL of rhBMP-2 (total dose of 12 mg). The rhBMP-2 implant (rhBMP-2 applied to an absorbable collagen sponge) was placed over the fracture at the time of definitive wound closure. Randomization was stratified by the severity of the open wound. The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively. RESULTS: Four hundred and twenty-one (94%) of the patients were available for the twelve-month follow-up. The 1.50-mg/mL rhBMP-2 group had a 44% reduction in the risk of failure (i.e., secondary intervention because of delayed union; relative risk = 0.56; 95% confidence interval = 0.40 to 0.78; pairwise p = 0.0005), significantly fewer invasive interventions (e.g., bone-grafting and nail exchange; p = 0.0264), and significantly faster fracture-healing (p = 0.0022) than did the control patients. Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the fracture at the postoperative visits from ten weeks through twelve months (p = 0.0008). Compared with the control patients, those treated with 1.50 mg/mL of rhBMP-2 also had significantly fewer hardware failures (p = 0.0174), fewer infections (in association with Gustilo-Anderson type-III injuries; p = 0.0219), and faster wound-healing (83% compared with 65% had wound-healing at six weeks; p =0.0010). CONCLUSIONS: The rhBMP-2 implant was safe and, when 1.50 mg/mL was used, significantly superior to the standard of care in reducing the frequency of secondary interventions and the overall invasiveness of the procedures, accelerating fracture and wound-healing, and reducing the infection rate in patients with an open fracture of the tibia.

Clinical evaluation of recombinant human bone morphogenetic protein-2.

Recombinant human bone morphogenetic protein-2 is an osteoinductive protein that plays a pivotal role in bone growth and regeneration. Several hundred studies were conducted in the past 7 years in numerous animal models to establish unequivocally the efficacy, safety, mechanism of action, pharmacokinetics, and surgical handling properties of recombinant human bone morphogenetic protein-2, building a solid foundation for clinical development programs. Pilot clinical trials have shown the feasibility and safety of recombinant human bone morphogenetic protein-2 treatment, and defined the effective dose for its use in open long bone fractures and for augmentation or preservation of the alveolar bone in the dental ridge. Prospective observational clinical studies helped define clinical efficacy end points, identify significant variables, and estimate appropriate population sample size for pivotal clinical trials. Pivotal clinical trials of recombinant human bone morphogenetic protein-2 are underway in patients with open tibial shaft fractures and in patients with a deficiency of the alveolar ridge.