Scientific Article   |    
Recombinant Human Bone Morphogenetic Protein-2 for Treatment of Open Tibial Fractures A Prospective, Controlled, Randomized Study of Four Hundred and Fifty Patients
Shunmugam Govender, MD; Cristina Csimma, RPh, MHP; Harry K. Genant, MD; Alexandre Valentin-Opran, MD; Yehuda Amit; Ron Arbel; Hannu Aro; Dan Atar; Michael Bishay; Martin G. Börner; Philippe Chiron; Peter Choong; John Cinats; Brett Courtenay; Robert Feibel; Bernard Geulette; Charles Gravel; Norbert Haas; M. Raschke; Eric Hammacher; D. van der Velde; Philippe Hardy; Michael Holt; Christof Josten; Rupert Ludwig Ketterl; Bennie Lindeque; Günter Lob; Henry Mathevon; Gerald McCoy; D. Marsh; Russell Miller; Everard Munting; Stein Oevre; L. Nordsletten; Amratlal Patel; Anthony Pohl; William Rennie; Peter Reynders; Pol Maria Rommens; Jean Rondia; Willem C. Rossouw; P. J. Daneel; Stephen Ruff; Axel Rüter; Seppo Santavirta; Thomas A. Schildhauer; C. Gekle; Reinhard Schnettler; David Segal; Hanns Seiler; Robert B. Snowdowne; Jouwert Stapert; Gilbert Taglang; Rene Verdonk; Lucas Vogels; Arnulf Weckbach; Andreas Wentzensen; Tadeusz Wisniewski
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Shunmugam Govender, MD
Department of Orthopaedics, 4th Floor, University of Natal, 719 Umbilo Road, Durban, South Africa

Cristina Csimma, RPh, MHP
Alexandre Valentin-Opran, MD
Wyeth Research/Genetics Institute, 87 Cambridge Park Drive, Cambridge, MA 02140. E-mail address for C. Csimma: ccsimma@wyeth.com

Harry K. Genant, MD
Osteoporosis and Arthritis Research Group, University of California at San Francisco, 505 Parnassus Avenue, Suite M392, San Francisco, CA 94143-0628

In support of the research or preparation of this manuscript, H.K. Genant received grants or outside funding from Wyeth Research/Genetics Institute. In addition, H.K. Genant received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (Wyeth Research/Genetics Institute). C. Csimma and A. Valentin-Opran are salaried employees of Wyeth Research/Genetics Institute. BESTT study group investigators received investigator grants for conducting the study.

J Bone Joint Surg Am, 2002 Dec 01;84(12):2123-2134
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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.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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