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Efficacy and Safety of Recombinant Human Bone Morphogenetic Protein-2/Calcium Phosphate Matrix for Closed Tibial Diaphyseal Fracture: A Double-Blind, Randomized, Controlled Phase-II/III Trial

Lyon, Thomas MD; Scheele, Wim MD; Bhandari, Mohit MD, PhD, FRCSC; Koval, Kenneth J. MD; Sanchez, Eduardo Gomez MD; Christensen, Jared PhD; Valentin, Alexandre MD; Huard, Francois MSc, MBA

Journal of Bone & Joint Surgery - American Volume: 4 December 2013 - Volume 95 - Issue 23 - p 2088–2096
doi: 10.2106/JBJS.L.01545
Scientific Articles
Supplementary Content
Disclosures

Background: Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new, injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation.

Methods: Patients were randomized (1:2:2:1) to receive standard of care, which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM, to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone.

Results: Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis, the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks), 1.0-mg/mL rhBMP-2/CPM (13.0 weeks), 2.0-mg/mL rhBMP-2/CPM (15.9 weeks), or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks), 1.0-mg/mL rhBMP-2/CPM (13.4 weeks), 2.0-mg/mL rhBMP-2/CPM (14.3 weeks), and buffer/CPM (16.4 weeks) treatment groups.

Conclusions: In patients with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone.

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

1Department of Trauma Services, Lutheran Medical Center, 150 55th Street, Brooklyn, NY 11220. E-mail address for T. Lyon: TLyon@lmcmc.com

2Pfizer Research, 35 Cambridge Park Drive, Cambridge, MA 02140

3Department of Surgery and Department of Clinical Epidemiology and Biostatistics, McMaster University, 293 Wellington Street North, Suite 110, Hamilton, ON L8L 8E7, Canada

4Department of Orthopaedics, Orlando Regional Medical Center, 1414 Kuhl Avenue, Orlando, FL 32806

5Antiguo Hospital Civil de Guadalajara, Servicio de Ortopedia, Guadalajara, Jal CP44280, Mexico

672 Rutledge Road, Belmont, MA 02478

7Pfizer Global Research & Development, Cœur Défense, La Défense 4, 92931 Paris La Défense CEDEX, France

Copyright 2013 by The Journal of Bone and Joint Surgery, Incorporated
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