The Journal of Bone and Joint Surgery (American). 2006;88:1258-1265.
doi:10.2106/JBJS.E.00499
© 2006 The Journal of Bone and Joint Surgery, Inc.
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Recombinant Human Bone Morphogenetic Protein-2 in Open Tibial Fractures

A Subgroup Analysis of Data Combined from Two Prospective Randomized Studies

Marc F. Swiontkowski, MD1, Hannu T. Aro, MD, PhD2, Simon Donell, MD3, John L. Esterhai, MD4, James Goulet, MD5, Alan Jones, MD6, Philip J. Kregor, MD7, Lars Nordsletten, MD, PhD8, Guy Paiement, MD9 and Amratlal Patel, MD3

1 Department of Orthopaedic Surgery, University of Minnesota, 2450 Riverside Avenue South, Suite R200, Minneapolis, MN 55454. E-mail address: swion001{at}umn.edu
2 University of Turku and University Central Hospital of Turku, FIN-20520 Turku, Finland
3 Institute of Orthopaedics, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, United Kingdom
4 Department of Orthopaedic Surgery, University of Pennsylvania Hospital, 3400 Spruce Street, Philadelphia, PA 19104-4271
5 Department of Orthopaedics, University of Michigan Hospital, 1500 East Medical Center Drive, TC2914, Ann Arbor, MI 48109-0328
6 University of Texas Southwestern, 5323 Harry Hines Boulevard, Room G8.238B, Dallas, TX 75390-8883
7 Vanderbilt University, 131 Medical Center South, 2100 Pierce Avenue, Nashville, TN 37212
8 Orthopaedic Centre, Ullevål University Hospital, N-0407 Oslo, Norway
9 Mission Orthopaedics, 27800 Medical Center Road, Suite 126, Mission Viejo, CA 92861

A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).

NOTE: The authors gratefully acknowledge the participation of the following BESTT study group investigators: Dr. Yehuda Amit, Sheba Medical Center, Tel Hashomer; Dr. Ron Arbel, Tel Aviv Medical Center, Tel Aviv; Prof. Hannu Aro, Turku University Hospital, Turku; Prof. Dan Atar, Soroka Medical Center, Beer Sheva; Mr. Michael Bishay, Royal United Hospital, Bath; Prof. Dr. med. Martin G. Börner, Berufsgenossenschaftliche Unfallklinik, Frankfurt; Prof. Philippe Chiron, Hôpital Rangueil-Traumatologie, Toulouse; Prof. Peter Choong, St. Vincent's Hospital, Melbourne, Victoria; Dr. John Cinats, University of Alberta Hospital, Edmonton, Alberta; Dr. Brett Courtenay, St. Vincent's Medical Clinic, Sydney, New South Wales; Dr. Robert Feibel, Ottawa General Hospital, Ottawa, Ontario; Dr. Bernard Geulette, Clinique St. Pierre, Ottignies; Prof. Shunmugam Govender, University of Natal, Durban; Dr. Charles Gravel, Hôpital Charles LeMoyne, Greenfield Park, Quebec; Prof. Dr. med. Norbert Haas and Prof. Dr. med. M. Raschke, Rudolf-Virchow-Klinikum, Berlin; Dr. Eric Hammacher and Dr. D. van der Velde, Academisch Ziekenhuis Utrecht, Utrecht; Prof. Philippe Hardy, Hôpital Ambroise Paré, Paris; Dr. Michael Holt, Royal Brisbane Hospital, Brisbane, Queensland; Prof. Dr. med. Christof Josten, Universität Leipzig Zentrum für Chirurgie, Leipzig; Prof. Dr. med. Rupert Ludwig Ketterl, Kreiskliniken Traunstein-Trostberg, Traunstein; Prof. Bennie Lindeque, Pretoria Academic Hospital, Pretoria; Prof. Dr. med. Günter Lob, Chirurgische Klinik der LMU, Munich; Dr. Henry Mathevon, Centre Hopitalier Général de Dunkerque, Dunkerque; Mr. Gerald McCoy and Prof. D. Marsh, Royal Victoria Hospital, Belfast; Mr. Russell Miller, Alfred Hospital, Melbourne, Victoria; Dr. Everard Munting, Clinique Universitaire St. Luc, Brussels; Dr. Stein Oevre and Prof. L. Nordsletten, Ulleval Hospital, Oslo; Mr. Amratlal Patel, Norfolk and Norwich County Hospital, Norwich; Mr. Anthony Pohl, Royal Adelaide Hospital, Adelaide, South Australia; Dr. William Rennie, Health Sciences Centre, Winnipeg, Manitoba; Dr. Peter Reynders, Universitair Ziekenhuis Gasthuisberg, Louvain; Prof. Dr. med. Pol Maria Rommens, Universitätsklinikum, Mainz; Dr. Jean Rondia, Hôpital de la Citadelle, Liege; Dr. Willem C. Rossouw and Dr. P.J. Daneel, Tygerberg Hospital, Cape Town; Dr. Stephen Ruff, Royal North Shore Hospital, St. Leonards, New South Wales; Prof. Dr. med. Axel Rüter, Zentralklinikum Augsburg, Dritte Chirurgische Klinik, Augsburg; Prof. Seppo Santavirta, Helsinki University Central Hospital, Helsinki; Dr. med. Thomas A. Schildhauer and Dr. med. C. Gekle, Berufsgenossenschaftliche Kliniken Bergmannsheil, Bochum; Prof. Dr. med. Reinhard Schnettler, Universitätsklinik, Unfallchirurgische Klinik, Giessen; Prof. David Segal, Hadassah Medical Organization, Jerusalem; Prof. Dr. med. Hanns Seiler, Zentralkrankenhaus Reinkenheide, Bremerhaven; Prof. Robert B. Snowdowne, National Hospital, Bloemfontein; Prof. Jouwert Stapert, Academisch Ziekenhuis Maastricht, Maastricht; Dr. Gilbert Taglang, Centre de Traumatologieet d'Orthopédie, Strasbourg; Prof. Dr. Rene Verdonk, Universitair Ziekenhuis Gent, Gent; Dr. Lucas Vogels, Academisch Ziekenhuis Rotterdam, Rotterdam; Prof. Dr. med. Arnulf Weckbach, Chirurgische Universitäts-klinik und Poliklinik, Würzburg; Prof. Dr. med. Andreas Wentzensen, Berufsgenossenschaftliche Unfallklinik, Ludwigshafen; and Dr. Tadeusz Wisniewski, Brenthurst Clinic, Parktown (Johannesburg). In addition, the authors also gratefully acknowledge the participation of the following United States study group investigators: Dr. Robert Bucholz, Dallas, Texas; Dr. Robert M. Dalsey, Haddonfield, New Jersey; Dr. John L. Esterhai, Philadelphia, Pennsylvania; Dr. Paul R. Gregory, Carmichael, California; Dr. James Goulet, Ann Arbor, Michigan; Dr. Andrew R. Jones, Chapel Hill, North Carolina; Dr. Philip J. Kregor, Nashville, Tennessee; Dr. Stuart Marshall, La Jolla, California; Dr. Guy Paiement, Mission Viejo, California; Dr. Roy Sanders, Tampa, Florida; Dr. Marc Swiontkowski, Minneapolis, Minnesota; and Dr. Alan Jones, Dallas, Texas.

In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from Wyeth Research/Genetics Institute and Medtronic Sofamor Danek. In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (Wyeth Research/Genetics Institute). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Background: The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to improve the healing of open tibial shaft fractures has been the focus of two prospective clinical studies. The objective of the current study was to perform a subgroup analysis of the combined data from these studies.

Methods: Two prospective, randomized clinical studies were conducted. A total of 510 patients with open tibial fractures were randomized to receive the control treatment (intramedullary nail fixation and routine soft-tissue management) or the control treatment and an absorbable collagen sponge impregnated with one of two concentrations of rhBMP-2. The rhBMP-2 implant was placed over the fracture at the time of definitive wound closure. For the purpose of this analysis, only the control treatment and the Food and Drug Administration-approved concentration of rhBMP-2 (1.50 mg/mL) were compared. Patients who anticipated receiving planned bone-grafting as part of a staged treatment were excluded from enrollment.

Results: Fifty-nine trauma centers in twelve countries participated, and patients were followed for twelve months postoperatively. Two subgroups were analyzed: (1) the 131 patients with a Gustilo-Anderson type-IIIA or IIIB open tibial fracture and (2) the 113 patients treated with reamed intramedullary nailing. The first subgroup demonstrated significant improvements in the rhBMP-2 group, with fewer bone-grafting procedures (p = 0.0005), fewer patients requiring invasive secondary interventions (p = 0.0065), and a lower rate of infection (p = 0.0234), compared with the control group. The second subgroup analysis of fractures treated with reamed intramedullary nailing demonstrated no significant difference between the control and the rhBMP-2 groups.

Conclusions: The addition of rhBMP-2 to the treatment of type-III open tibial fractures can significantly reduce the frequency of bone-grafting procedures and other secondary interventions. This analysis establishes the clinical efficacy of rhBMP-2 combined with an absorbable collagen sponge implant for the treatment of these severe fractures.

Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.


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