rhBMP-2/Calcium Phosphate Matrix Induces Bone Formation While Limiting Transient Bone Resorption in a Nonhuman Primate Core Defect Model

• Published in: Journal of bone and joint surgery. American volume Vol. 94; no. 19; pp. 1765 - 1776
• Main Authors: Seeherman, Howard J, Li, X Jian, Smith, Erica, Wozney, John M
• Format: Journal Article
• Language: English
• Published: Boston, MA Copyright by The Journal of Bone and Joint Surgery, Incorporated 03-10-2012; Journal of Bone and Joint Surgery Incorporated
• Subjects: Animals; Biological and medical sciences; Biopsy, Needle; Bone and Bones - drug effects; Bone and Bones - pathology; Bone and Bones - surgery; Bone Morphogenetic Protein 2 - adverse effects; Bone Morphogenetic Protein 2 - pharmacology; Bone Resorption; Disease Models, Animal; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Drug Administration Schedule; Femur - diagnostic imaging; Femur - drug effects; Femur - surgery; Fundamental and applied biological sciences. Psychology; Haplorhini; Immunohistochemistry; Male; Medical sciences; Orthopedic surgery; Osteogenesis - drug effects; Radiography; Radius - drug effects; Radius - pathology; Radius - surgery; Random Allocation; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacology; Reference Values; Sensitivity and Specificity; Skeleton and joints; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tibia - diagnostic imaging; Tibia - drug effects; Tibia - surgery; Transforming Growth Factor beta - adverse effects; Transforming Growth Factor beta - pharmacology; Vertebrates: osteoarticular system, musculoskeletal system; Bone resorption; Orthopedic surgery; Treatment; Calcium phosphate; Models; Bone; Transitory
• ISSN: 0021-9355; 1535-1386
• DOI: 10.2106/JBJS.K.00523

BACKGROUND:Transient bone resorption limits the use of recombinant human bone morphogenetic protein-2 (rhBMP-2)/absorbable collagen sponge in metaphyseal bone. The purpose of the present study was to evaluate the efficacy of rhBMP-2/calcium phosphate matrix (CPM) to induce bone formation while limiting transient bone resorption in nonhuman primate core defects.
METHODS:Metaphyseal core defects were created in eighteen cynomolgus monkeys. rhBMP-2 retention was evaluated in the distal part of the radius. Bone formation was evaluated at eight weeks following treatment with 1.5 or 4.5-mg/mL rhBMP-2/CPM, CPM alone, or no treatment in the distal part of the radius, the proximal part of the tibia, and the proximal part of the femur; at twenty-four weeks following treatment with 1.5-mg/mL rhBMP-2/CPM or CPM alone in the proximal part of the tibia; and at one, two, and four weeks following treatment with 1.5-mg/mL rhBMP-2/CPM or no treatment in the distal part of the radius. Bone resorption was evaluated at four weeks following treatment with 1.5, 2.0, 3.0, and 4.5-mg/mL rhBMP-2/CPM or CPM alone in the distal part of the femur. Evaluations were performed with use of scintigraphy, radiographs, histological analysis, and computed tomography.
RESULTS:Seventy-eight percent, 64%, 50%, 35%, and 12% of the rhBMP-2 was retained in the distal part of the radius at one, seven, fourteen, twenty-one, and forty-nine days after surgery. rhBMP-2/CPM increased bone formation within core defects and surrounding trabeculae compared with CPM alone or no treatment at all anatomic locations at eight weeks, and bone formation was ongoing in the rhBMP-2/CPM-treated proximal tibial sites at twenty-four weeks. Bone formation began in the trabeculae surrounding the core defects at one week and was observed adjacent to the resorbing CPM within the core defects and in the surrounding trabecular bone at two and four weeks in the rhBMP-2/CPM-treated distal radial sites. Bone formation was confined to the region immediately surrounding the core defects in the untreated distal radial sites at all time points. Transient bone resorption was only observed in the distal femoral sites treated with 4.5 mg/mL of rhBMP-2/CPM at two weeks.
CONCLUSIONS:Treatment of nonhuman primate metaphyseal core defects with 1.5 to 3.0-mg/mL rhBMP-2/CPM resulted in bone formation without transient bone resorption.
CLINICAL RELEVANCE:rhBMP-2/CPM may be useful to accelerate healing of metaphyseal bone defects in humans.