title: Efficacy and safety of recombinant human bone morphogenetic protein-2/calcium phosphate matrix for closed tibial diaphyseal fracture: a double-blind, randomized, controlled phase-II/III trial.
abstract: BACKGROUND
  Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new, injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation.
  
  
  METHODS
  Patients were randomized (1:2:2:1) to receive standard of care, which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM, to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone.
  
  
  RESULTS
  Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis, the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks), 1.0-mg/mL rhBMP-2/CPM (13.0 weeks), 2.0-mg/mL rhBMP-2/CPM (15.9 weeks), or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks), 1.0-mg/mL rhBMP-2/CPM (13.4 weeks), 2.0-mg/mL rhBMP-2/CPM (14.3 weeks), and buffer/CPM (16.4 weeks) treatment groups.
  
  
  CONCLUSIONS
  In patients with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone. 24306696
authors.affiliation: Department of Trauma Services, Lutheran Medical Center, 150 55th Street, Brooklyn, NY 11220. E-mail address for T. Lyon: TLyon@lmcmc.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lyon
authors.forename: Wim
authors.initials: W
authors.lastname: Scheele
authors.forename: Mohit
authors.initials: M
authors.lastname: Bhandari
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Koval
authors.forename: Eduardo Gomez
authors.initials: EG
authors.lastname: Sanchez
authors.forename: Jared
authors.initials: J
authors.lastname: Christensen
authors.forename: Alexandre
authors.initials: A
authors.lastname: Valentin
authors.forename: Francois
authors.initials: F
authors.lastname: Huard
mesh_terms: D000328:Adult; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000009:adverse effects; D001858:Bone Nails; D002130:Calcium Phosphates / Q000008:administration & dosage* / Q000009:adverse effects; D018483:Diaphyses / Q000293:injuries; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D005594:Fracture Fixation, Intramedullary / Q000379:methods; D017102:Fracture Healing / Q000187:drug effects; D005596:Fractures, Closed / Q000188:drug therapy* / Q000601:surgery; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D011183:Postoperative Complications / Q000209:etiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013978:Tibial Fractures / Q000188:drug therapy* / Q000601:surgery; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D002130:Calcium Phosphates; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; C020243:calcium phosphate