rhBMP-2 induces transient bone resorption followed by bone formation in a nonhuman primate core-defect model.
BACKGROUND
Bone resorption preceding bone formation has been reported following the administration of recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered in an absorbable collagen sponge (ACS) in metaphyseal bone. This study characterizes treatment with rhBMP-2/ACS in metaphyseal bone with use of a nonhuman primate core-defect model.


METHODS
Unilateral proximal femoral core defects were treated with 360 microg of rhBMP-2/ACS or ACS alone or were left untreated in seven, five, and five adult male cynomolgus monkeys, respectively. Distal femoral core defects in seven of the above animals were treated with 360 microg of rhBMP-2/ACS in one limb and ACS alone in the contralateral limb. Retention of rhBMP-2 in the proximal part of the femora was determined with use of tracer amounts of (125)I-rhBMP-2 imaged with a gamma camera. The distal part of the femora was evaluated with in vivo computed tomography. Computed tomography and histological evaluation were performed on harvested segments in all animals at twenty-four weeks. The histological response in the proximal and distal parts of the femora containing core defects treated with 360 microg of rhBMP-2/ACS in one limb and ACS alone in the contralateral limb was evaluated at one, two, and four weeks in three animals per time point.


RESULTS
Approximately 39.9%, 24.2%, 3.4%, and 0.5% of the rhBMP-2 was retained in the proximal part of the femora at one, seven, fourteen, and twenty-one days, respectively. The mineral density and trabecular volume fraction of the core defects treated with rhBMP-2/ACS, those treated with ACS alone, and untreated core defects in the proximal part of the femora were 81%, 54%, and 20%, respectively, and 94%, 36%, and 31%, respectively, of the corresponding region in the contralateral limbs at twenty-four weeks. The mineral density and trabecular volume fraction of the region surrounding the core defects treated with rhBMP-2/ACS, those treated with ACS alone, and untreated core defects were 112%, 105%, and 104%, respectively, and 117%, 108%, and 107%, respectively, of the corresponding region in the contralateral limbs. Treatment with rhBMP-2/ACS increased the size of the proximal and distal core defects compared with treatment with ACS alone. Histological evaluation of the rhBMP-2/ACS-treated limbs demonstrated that bone resorption was initiated at one week in association with osteoclasts and receptor activator of nuclear factor-kappaB ligand-positive stained spindle-shaped cells and peaked at two weeks. Bone formation was observed at two weeks and was ongoing at twenty-four weeks.


CONCLUSIONS
Treatment of metaphyseal core defects with rhBMP-2/ACS resulted in bone resorption followed by bone formation in nonhuman primates.
Seeherman
Howard J
HJ
Musculoskeletal Therapies, Wyeth Discovery Research, Cambridge, MA 02140, USA. hseeherman@wyeth.com
Li
X Jian
XJ
Bouxsein
Mary L
ML
Wozney
John M
JM
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage* / Q000009:adverse effects*; D001862:Bone Resorption / Q000139:chemically induced*; D005272:Femur Neck / Q000000981:diagnostic imaging / Q000601:surgery; D005781:Gelatin Sponge, Absorbable; D008252:Macaca fascicularis; D008297:Male; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects*; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000009:adverse effects*
D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2