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Recombinant Human Bone Morphogenetic Protein-2: A Randomized Trial in Open Tibial Fractures Treated with Reamed Nail Fixation
Hannu T. Aro, MD, PhD1; Shunmugam Govender, MBBS, MD, FRCS2; Amratlal D. Patel, FRCS3; Philippe Hernigou, MD4; Arturo Perera de Gregorio, MD5; Gheorghe Ion Popescu, MD6; Jane Davis Golden, MHP7; Jared Christensen, PhD7; Alexandre Valentin, MD7
1 Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland. E-mail address: hannu.aro@utu.fi
2 Department of Orthopaedics, University of Kwazulu-Natal, Durban 4013, South Africa
3 Department of Orthopaedics, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, United Kingdom
4 Service d'Orthopédie et de Traumatologie, Hôpital Henri Mondor, 51, avenue du Maréchal de Lattre de Tassigny, Créteil 94010, France
5 S°. de Traumatologia y Cirugia Ortopedica, Hospital Principe de Asturias, ctra. de Meco s/n, Alcalá de Henares (Madrid) 28805, Spain
6 Orthopaedics and Trauma Clinic, Emergency Hospital, Calea Floreasca 8 Sector 1, 014461 Bucharest, Romania
7 Pfizer, Inc., 35 Cambridge Park Drive, Cambridge, MA 02140
View Disclosures and Other Information
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Wyeth Research, a subsidiary of Pfizer, Inc. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Wyeth Research, a subsidiary of Pfizer, Inc.).

Investigation performed at Turku University Hospital, Turku, Finland; University of Kwazulu-Natal, Durban, South Africa; Norfolk and Norwich University Hospital, Norwich, United Kingdom; Hôpital Henri Mondor, Créteil, France; Hospital Principe de Asturias, Madrid, Spain; Emergency Hospital, Bucharest, Romania; and Pfizer, Inc., Cambridge, Massachusetts
A commentary by Timothy Bhattacharyya, MD, is linked to the online version of this article at jbjs.org.

Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 May 04;93(9):801-808. doi: 10.2106/JBJS.I.01763
A commentary by Timothy Bhattacharyya, MD, is available here
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Abstract

Background: 

Recombinant human bone morphogenetic protein-2 (rhBMP-2) improves healing of open tibial fractures treated with unreamed intramedullary nail fixation. We evaluated the use of rhBMP-2 in the treatment of acute open tibial fractures treated with reamed intramedullary nail fixation.

Methods: 

Patients were randomly assigned (1:1) to receive the standard of care consisting of intramedullary nail fixation and routine soft-tissue management (the SOC group) or the standard of care plus an absorbable collagen sponge implant containing 1.5 mg/mL of rhBMP-2 (total, 12.0 mg) (the rhBMP-2/ACS group). Randomization was stratified by fracture severity. The absorbable collagen sponge was placed over the fracture at wound closure. The primary efficacy end point was the proportion of subjects with a healed fracture as demonstrated by radiographic and clinical assessment thirteen and twenty weeks after definitive wound closure.

Results: 

Two hundred and seventy-seven patients were randomized and were the subjects of the intent-to-treat analysis. Thirteen percent of the fractures were Gustilo-Anderson Type IIIB. The proportions of patients with fracture-healing were 60% and 48% at week 13 (p = 0.0541) and 68% and 67% at week 20 in the rhBMP-2/ACS and SOC groups, respectively. Twelve percent of the subjects underwent secondary procedures in each group; more invasive procedures (e.g., exchange nailing) accounted for 30% of the procedures in the rhBMP-2/ACS group and 57% in the SOC group (p = 0.1271). Infection was seen in twenty-seven (19%) of the patients in the rhBMP-2/ACS group and fifteen (11%) in the SOC group (p = 0.0645; difference in infection risk = 0.09 [95% confidence interval, 0.0 to 0.17]). The adverse event incidence was otherwise similar between the treatment groups.

Conclusions: 

The healing of open tibial fractures treated with reamed intramedullary nail fixation was not significantly accelerated by the addition of an absorbable collagen sponge containing rhBMP-2.

Level of Evidence: 

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

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    References

    Accreditation Statement
    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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    Paul Levin, MD
    Posted on May 20, 2011
    Ethical Considerations of Randomized Clinical Trials
    Orthopaedic Surgeon, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York

    To the Editor:

    In the article “Recombinant Human Bone Morphogenetic Protein-2: A Randomized Trial in Open Tibial Fractures Treated with Reamed Nail Fixation”, (2011;93:801-8), the authors state that a control group was not assigned to receive an absorbable collagen sponge without rhBMP-2 because “it was considered to be unethical”. I disagree with this assertion and I believe that the failure of having three experimental groups (standard of care, implantable sponge without rhBMP-2 and sponge with rhBMP-2) compromised the validity of the study.

    Prospective randomized trials in the surgical literature are rarely seen. A supposition is made in surgical research that the surgeon is going to do the best treatment and therefore the careful oversight, as seen in the introduction of new medications, is often forgone. Unfortunately, the presumption that we can treat a condition with a new innovative operation has frequently been proven to be wrong and many individuals have been harmed by a dangerous intervention which was not effective. The ethics of sham surgery is debated in the literature. Advocates contend that sham surgical trials are the optimal and ethical method to determine the efficacy of a new surgical procedure (1,2). Others believe that it leads to an unnecessary risk of harm on the control group (3). Despite this concern, ground breaking surgical trials with sham controls have been successfully performed, with strict IRB oversight, in the study of Parkinson’s disease and osteoarthritis of the knee (4,5). The authors in this present study contend that it would be “unethical” to place a foreign body in an open wound and risk infection, but they didn’t find an ethical dilemma in placing the same foreign body in the wound with rhBMP-2. Although a prior investigation on healing of a rabbit ulnar osteotomy did not demonstrate a beneficial effect from an implanted collagen sponge, animal models of fracture healing have been notoriously poor predictors of fracture stimulation response in humans (6).

    The present design compromised the validity of the study in two important areas. First, an improved speed and percentage of successful union could not be differentiated between the benefit of the sponge, the rhBMP-2, or both. Second, by eliminating a placebo group with implantation of an untreated sponge the investigators sacrificed the benefit of completing a double blinded study. The failure to demonstrate a benefit of the rhBMP-2 doesn’t allow one to retrospectively justify the study design. While I understand the authors concern over placing a foreign body into an open wound, I do not believe it is valid to justify it for the rhBMP-2 group and not a control group.

    Individuals volunteer to participate in medical trials for a variety of reasons. Some hope to receive the new treatment for their own benefit while others truly hope that their participation will improve medical care for others. It is imperative that the researchers design their study to achieve the best clinical information to benefit future medical care and assure that the volunteer’s participation was fruitful. Compromising the validity of the study to prevent an ethical lapse may actually compromise our ethical responsibilities to the individuals volunteering to participate in the study.

    References

    1. Miller FG. Sham surgery: an ethical analysis. Am J Bioethics. 2003;3:41-8.

    2. Freeman TB, Vawter DE, Leaverton PE, Godbold JH, Hauser RA, Goetz CG, Olanow CW. Use of placebo surgery in controlled trials of a cellular-based therapy for Parkinson’s disease. N Engl J Med. 1999;341:988-92.

    3. Macklin R. The ethical problems with sham surgery in clinical trials. N Engl J Med. 1999;341:992-6.

    4. Freed CR, Greene PE, Breeze RE, Tsai W, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344:710-9.

    5. Mosley JB, O’Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, Hollingsworth JC, Ashton CM, Wray NP. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002;347:81-8.

    6. Bouxsein ML, Turek TJ, Blake PA, Meek RN, Broekhuyse HM. Recombinant human bone morphogenetic protein-2 accelerates healing in a rabbit ulnar osteotomy model. J Bone Joint Surg Am. 2001;83:1219-30.

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