title: Recombinant human bone morphogenetic protein-2-induced craniosynostosis and growth restriction in the immature skeleton.
abstract: BACKGROUND
  Recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered on an absorbable collagen sponge is a U.S. Food and Drug Administration-approved therapy effective at generating bone formation. In pediatric patients for whom other therapeutic options have been exhausted, rhBMP-2 is used off-label to address problematic bony defects. In the skeletally immature patient, the safety of rhBMP-2 therapy remains uncertain. Experiments are needed that investigate the effect of rhBMP-2 on growth and development in clinically relevant models.
  
  
  METHODS
  Ten juvenile rabbits underwent creation of a parietal skull defect that was treated with either 0.2 mg/cc rhBMP-2/absorbable collagen sponge or a neutral buffer solution/absorbable collagen sponge. Amalgam markers were placed at suture confluences to track suture separation and skull growth. Cranial growth was assessed radiographically at 10, 25, 42, and 84 days of age. Means and standard deviations for the various craniofacial growth variables were calculated and compared. Mean differences were considered significant for values of p < 0.05. At 84 days, sutures were analyzed by means of micro-computed tomographic scanning and histologic staining.
  
  
  RESULTS
  Treatment with rhBMP-2 resulted in fusion of the coronal sutures bilaterally, with variable fusion of the sagittal suture by cephalometric, radiographic, and histologic analysis. There were statistically significant changes to coronal suture growth, sagittal suture growth, skull height, craniofacial length, and intracranial volume (p < 0.05).
  
  
  CONCLUSIONS
  The use of rhBMP-2 in this juvenile animal model resulted in skeletal changes that may be undesirable in a clinical setting. The appearance of these fused sutures suggested a direct effect of rhBMP-2. Further work is required to limit the effect of rhBMP-2 to the target defect when used in the immature skeleton.
authors.affiliation: Pittsburgh, Pa. From the Division of Plastic Surgery and the Departments of Anthropology, Oral Biology, Orthodontics, and Bioengineering, University of Pittsburgh, and the Department of Physical Therapy, Duquesne University.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Kinsella
authors.forename: James J
authors.initials: JJ
authors.lastname: Cray
authors.forename: Emily L
authors.initials: EL
authors.lastname: Durham
authors.forename: Anne M
authors.initials: AM
authors.lastname: Burrows
authors.forename: Lisa
authors.initials: L
authors.lastname: Vecchione
authors.forename: Darren M
authors.initials: DM
authors.lastname: Smith
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mooney
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cooper
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Losee
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000009:adverse effects*; D001861:Bone Regeneration / Q000187:drug effects*; D003398:Craniosynostoses / Q000139:chemically induced* / Q000473:pathology; D004195:Disease Models, Animal; D005781:Gelatin Sponge, Absorbable; D006801:Humans; D010012:Osteogenesis / Q000187:drug effects*; D010294:Parietal Bone / Q000187:drug effects / Q000254:growth & development; D011817:Rabbits; D011994:Recombinant Proteins / Q000009:adverse effects*; D016212:Transforming Growth Factor beta / Q000009:adverse effects*
chemical_list: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2