Rekombinantes humanes Bone Morphogenetic Protein-2 (rhBMP-2, Dibotermin-alfa) bei offenen Tibiaschaftfrakturen: Ergebnisse einer prospektiv randomisierten kontrollierten Studie an 450 Patienten

Abstract

Purpose: Tibial shaft fractures are difficult to treat and often result in re-operations. This clinical study evaluated the osteoinductive potential of rhBMP-2 to improve outcomes in patients with open tibia fractures. Methods: 450 patients were enrolled in this prospective, controlled, randomized trial. All patients received Standard care (SC: intramedullary nail fixation and routine soft tissue management) and were randomized to lof 3 groups: SC or SC plus rhBMP-2 (0.75 or 1.5 mg/mL) implanted on an absorbable collagen sponge (ACS), at the time of definitive wound closure. The primary efficacy endpoint was the proportion of patients requiring secondary interventions to promote fracture healing within 12 months postoperatively. Other outcome measures included fracture and soft tissue healing rates and safety assessments. Results: Ninety-four percent of patients completed the 12-month follow-up. Patients treated with rhBMP-2/ACS experienced significantly fewer secondary interventions (dose-dependent overall rate reduction; P= 0.0017). Patients receiving rhBMP-2/ACS (1.50 mg/mL) had a 44% reduced risk of secondary intervention compared to SC control patients (RR = 0.56; 95% CI = 0.40 to 0.78; pairwise P = 0.0005). The rhBMP-2/ACS 1.50 mg/mL group showed a 59% reduction in the number of invasive interventions (bone grafting and exchange nailing) compared with SC controls (P = 0.0264; chi-square test for goodness of fit). Significantly fewer secondary interventions were required for Gustilo IIIB injuries among patients who received rhBMP-2 1.50 mg/mL (52% reduction; P = 0.0074) and rhBMP-2 0.75 mg/mL (49% reduction; P = 0.0157) compared with SC controls. rhBMP-2 was effective across all groups irrespective of recent smoking history. A significantly greater proportion of patients in the rhBMP-2/ACS 1.50 mg/mL group was healed compared with SC controls at all visits, from 10 to 52 weeks postoperatively. Fracture healing time (Kaplan-Meier analysis) was significantly reduced among rhBMP-2/ACS 1.50 mg/mL patients compared to SC controls (probability of healing for 50% of patients was observed at 145 days vs.184 days; P = 0.0022 [Wilcoxon]). Infection rates were comparable between groups. Furthermore, a significantly decreased incidence of infections in the limb under study was observed among Gustilo IIIA and IIIB fractures in the rhBMP-2/ACS 1.50 mg/mL group compared with Standard care (P = 0.0219). The rhBMP-2/ACS 1.50 mg/mL group also experienced significant reductions in hardware failure (P= 0.0174), and pain after the first month of follow-up (P = 0.0343), and a significantly higher rate of wound healing at 6 weeks (83% versus 65%; P = 0.001) compared with SC controls. Conclusion: This study demonstrated that rhBMP-2/ACS (1.50 mg/mL) improves the probability and rate of bone and soft tissue healing. rhBMP-2/ ACS (1.5 mg/mL) was safe and significantly more effective than current standard of care. The observed reduction in infection rate, acceleration in soft-tissue healing, and reduction in pain may relate to an increased vascular supply in newly induced bone.