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.
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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