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rhBMP-2/Calcium Phosphate Matrix Accelerates Osteotomy-Site Healing in a Nonhuman Primate Model at Multiple Treatment Times and Concentrations
Howard Seeherman, PhD, VMD1; Rebecca Li, PhD1; Mary Bouxsein, PhD2; Hyun Kim, PhD1; X. Jian Li, MD1; Erica A. Smith-Adaline, PhD1; Maria Aiolova, PhD3; John M. Wozney, PhD1
1 Women's Health and Musculoskeletal Biology, Wyeth Discovery Research, 200 Cambridge Park Drive, Cambridge, MA 02140. E-mail address for H. Seeherman: hseeherman@wyeth.com
2 Orthopedics Biomechanics Laboratory, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215
3 ETEX, Cambridge, University Park at MIT, 350 Massachusetts Avenue, Cambridge, MA 02139
View Disclosures and Other Information
The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. One or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from commercial entities (Wyeth [H.S., R.L., M.B., H.K., X.J.L., E.A.S.-A., and J.M.W.] and ETEX [M.A.]). 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.
Investigation performed at Women's Health and Musculoskeletal Biology, Wyeth Discovery Research, Cambridge, Massachusetts

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Jan 01;88(1):144-160. doi: 10.2106/JBJS.D.02453
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Background: While recombinant human bone morphogenetic protein-2 (rhBMP-2) administered in a calcium phosphate cement accelerates osteotomy-site healing in animal models when administered three hours after surgery, definitive fracture treatment is often delayed. The present study evaluated the ability of rhBMP-2, administered in a new particulating calcium phosphate matrix, to accelerate nonhuman primate fibular osteotomy-site healing following treatment at multiple treatment times and concentrations.

Methods: The ability of 1.5-mg/mL rhBMP-2/calcium phosphate matrix to accelerate osteotomy-site healing when administered three hours, one day, one week, or two weeks after surgery was first evaluated with use of bilateral proximal and distal fibular osteotomy sites in adult male monkeys. In a second study, the healing of osteotomy sites that had been treated with the administration of calcium phosphate matrix alone and with different concentrations of rhBMP-2/calcium phosphate matrix (0.5 mg/mL, 1.5 mg/mL, or 4.5 mg/mL) seven days after surgery was compared with that of contralateral, untreated osteotomy sites. In a third study, the histologic progression of osteotomy-site healing following treatment with 1.5-mg/mL rhBMP-2/calcium phosphate matrix or calcium phosphate matrix alone, administered three hours or one week after surgery to the osteotomy site, was assessed at multiple time points for as long as twenty-four months after surgery.

Results: Radiographs demonstrated increased callus area and more rapid healing in response to 1.5-mg/mL rhBMP-2/calcium phosphate matrix administered over the range of treatment times after surgery as compared with the findings of previous reports on untreated osteotomy sites. Bone formation appeared at the osteotomy sites sooner following treatment at one and two weeks as compared with the findings at the earlier time-points. Scintigraphic imaging at one day and one week after surgery showed prolonged retention of rhBMP-2 at the osteotomy site following an initial burst release. In the second study, radiographic, peripheral quantitative computed tomographic, biomechanical, and microscopic evaluation demonstrated that administration of 1.5 and 4.5-mg/mL rhBMP-2/calcium phosphate matrix one week after surgery accelerated osteotomy-site healing by 40% to 50% compared with the findings in untreated controls. The magnitude of acceleration was less in response to 0.5-mg/mL rhBMP-2/calcium phosphate matrix, and calcium phosphate matrix alone did not accelerate osteotomy-site healing. Histological evaluation indicated that an increased cellular infiltrate and increased direct bone formation contributed to the accelerated osteotomy-site healing following administration of rhBMP-2/calcium phosphate matrix at one week compared with three hours after surgery.

Conclusions: A single percutaneous injection of rhBMP-2/calcium phosphate matrix accelerated healing in nonhuman primate fibular osteotomy sites over a wide range of treatment times. Efficacy was optimized in association with the administration of 1.5-mg/mL rhBMP-2/calcium phosphate matrix. Delaying treatment for one week further accelerated healing because of an increase in the number of responding cells and an increase in direct bone formation.

Clinical Relevance: The results of the present study provide a rationale for evaluating rhBMP-2/calcium phosphate matrix to accelerate healing of fractures in humans.

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    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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