title: rhBMP-2/calcium phosphate matrix accelerates osteotomy-site healing in a nonhuman primate model at multiple treatment times and concentrations.
abstract: 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.
authors.affiliation: Women's Health and Musculoskeletal Biology, Wyeth Discovery Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. hseeherman@wyeth.com
authors.forename: Howard
authors.initials: H
authors.lastname: Seeherman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Li
authors.forename: Mary
authors.initials: M
authors.lastname: Bouxsein
authors.forename: Hyun
authors.initials: H
authors.lastname: Kim
authors.forename: X Jian
authors.initials: XJ
authors.lastname: Li
authors.forename: Erica A
authors.initials: EA
authors.lastname: Smith-Adaline
authors.forename: Maria
authors.initials: M
authors.lastname: Aiolova
authors.forename: John M
authors.initials: JM
authors.lastname: Wozney
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001843:Bone Cements / Q000627:therapeutic use*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D002146:Bony Callus / Q000187:drug effects; D002130:Calcium Phosphates / Q000008:administration & dosage / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D005360:Fibula / Q000187:drug effects / Q000473:pathology / Q000601:surgery*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects; D010027:Osteotomy / Q000379:methods*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D012399:Rotation; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects
chemical_list: D001843:Bone Cements; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002130:Calcium Phosphates; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; C020243:calcium phosphate