The Journal of Bone and Joint Surgery (American) 85:1425-1435 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.
A Single Percutaneous Injection of Recombinant Human Bone Morphogenetic Protein-2 Accelerates Fracture Repair
Thomas A. Einhorn, MD,
Robert J Majeska, PhD,
Ahamed Mohaideen, MD,
Eric M. Kagel, MD,
Mary L. Bouxsein, PhD,
Thomas J. Turek and
John M. Wozney, PhD
Investigation performed at Boston University Medical Center, Boston, Massachusetts, Mount Sinai Medical Center, New York, New York, and Wyeth Research, Cambridge, Massachusetts
Thomas A. Einhorn, MD
Boston University Medical Center, 720 Harrison Avenue, Suite 808, Boston, MA 02118-2393. E-mail address: thomas.einhorn{at}bmc.org
Robert J. Majeska, PhD
Department of Orthopaedics, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1188, New York, NY 10029-6574
Ahamed Mohaideen, MD
The Center for Bone and Joint Surgery of Palm Beaches, 10131 West Forest Hill Boulevard, Suite 206, West Palm Beach, FL 33414
Eric M. Kagel, MD
San Jose Orthopaedic Associates, 725 East Santa Clara Street, Suite 204, San Jose, CA 95112
Mary L. Bouxsein, PhD
Thomas J. Turek
John M. Wozney, PhD
Wyeth Research, 87 Cambridge Park Drive, Cambridge, MA 02140
In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Wyeth (formerly Genetics Institute). 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). Also, a commercial entity (Wyeth) paid or directed, or agreed to pay or direct, benefits to a research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
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).
Background: Recombinant human bone morphogenetic protein-2 (rhBMP-2), surgically implanted with a matrix material, has been shown to induce bone formation and enhance fracture repair. The purpose of this investigation was to test the hypothesis that a single, local, percutaneous injection of rhBMP-2 would accelerate fracture-healing in a standard rat femoral fracture model.
Methods: Fractures were created, following intramedullary pinning, in the femora of 144 male Sprague-Dawley rats. The animals were divided into three groups of forty-eight each. Six hours after the fracture, one group received an injection of 80 µg of rhBMP-2 in 25 µL of buffer vehicle, one received an injection of 25 µL of buffer vehicle alone, and one did not receive an injection. Twelve animals from each of these three groups were killed at one, two, three, and four weeks after treatment, and the femora were harvested for torsional biomechanical testing. An additional cohort of seventy-two animals, in which a fracture was also created, was divided into the same three treatment groups; six animals from each of these groups was killed at one, two, three, and four weeks; and the femora were processed for qualitative histological analysis.
Results: Torsional biomechanical testing indicated that the stiffness of the rhBMP-2-treated fractures was twice that of both control groups at the two, three, and four-week time-points. The strength of the rhBMP-2-treated fractures was 34% greater than that of the buffer-treated controls (p = 0.03) at three weeks and, at four weeks, was 60% and 77% greater than that of the buffer-treated controls and that of the untreated controls, respectively (p < 0.005). At four weeks, the stiffness and strength of the rhBMP-2-treated fractures were equal to those of the intact contralateral femora, whereas the buffer-treated and untreated fractures were significantly weaker than the intact femora. At two and three weeks, large areas of bone formation, typically spanning the fracture, were observed histologically in the rhBMP-2-treated sites. In contrast, the control fractures exhibited primarily soft cartilaginous callus at these time-points. By four weeks, remodeling of the hard callus and recorticalization were observed in the rhBMP-2-treated fracture sites, whereas cartilage and/or soft tissue was still present in the control fracture sites.
Conclusions: These data demonstrate that a single, local, percutaneous injection of rhBMP-2 accelerates fracture repair in this rat femoral fracture model. This effect appears to result from a combination of the induction of bone formation at the fracture site and acceleration of the rate at which the fracture callus matures.
Clinical Relevance: The ability of an injection of rhBMP-2 to accelerate fracture repair provides a rationale for its use in fractures that do not require operative treatment or that are to undergo operative treatment without direct exposure of the fracture site. In addition, the finding that an injectable compound may produce a bone-graft-like effect suggests the need for additional studies to explore its application to other types of skeletal surgery.
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