title: Systemic Administration of Sclerostin Antibody Enhances Bone Morphogenetic Protein-Induced Femoral Defect Repair in a Rat Model.
abstract: BACKGROUND
  Recombinant human bone morphogenetic protein (rhBMP)-2 is a potent osteoinductive agent; however, its clinical use has been reduced because of safety and efficacy concerns. In preclinical studies involving a critical-sized defect in a rat model, sclerostin antibody (Scl-Ab) treatment increased bone formation within the defect but did not result in reliable healing. The purpose of the current study was to evaluate bone repair of a critical-sized femoral defect in a rat model with use of local implantation of rhBMP-2 combined with systemic administration of Scl-Ab.
  
  
  METHODS
  A critical-sized femoral defect was created in rats randomized into three treatment groups: local rhBMP-2 and systemic Scl-Ab (Scl + BMP), local rhBMP-2 alone, and collagen sponge alone (operative control). The Scl + BMP group received local rhBMP-2 (10 μg) on a collagen sponge placed within the defect intraoperatively and then twice weekly injections of Scl-Ab (25 mg/kg) administered postoperatively. The femora were evaluated at twelve weeks with use of radiography, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing.
  
  
  RESULTS
  At twelve weeks, all Scl + BMP and rhBMP-2 only samples were healed. No femora healed in the operative control group. Histomorphometric analysis demonstrated more bone in the Scl + BMP samples than in the samples treated with rhBMP-2 alone (p = 0.029) and the control samples (p = 0.003). MicroCT revealed that the Scl + BMP group had a 90% greater bone volume within the defect region compared with the rhBMP-2 group and a 350% greater bone volume compared with the operative control group (p < 0.001). Biomechanical testing showed that the group treated with Scl + BMP had greater torsional strength and rigidity compared with the rhBMP-2 group (p < 0.001 and p = 0.047) and the intact femoral control group (p < 0.001). Torque to failure was lower in the rhBMP-2 group compared with the intact femoral control group (p < 0.002). Mean energy to failure was higher in the Scl + BMP samples compared with the rhBMP-2 only samples (p = 0.001).
  
  
  CONCLUSIONS
  In a critical-sized femoral defect in a rat model, local rhBMP-2 combined with systemic administration of Scl-Ab resulted in more robust healing that was stronger and more rigid than results for rhBMP-2 alone and intact nonoperative femora.
  
  
  CONCLUSIONS
  Our study demonstrated that combining an osteoinductive agent with a systemically administered antibody that promotes bone formation can enhance bone repair and has potential as a therapeutic regimen in humans.
authors.affiliation: Department of Orthopaedic Surgery, University of Connecticut Health Center, MARB 4th floor, 263 Farmington Avenue, Farmington, CT 06030. E-mail address for B.A. Tinsley: btinsley@uchc.edu.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Tinsley
authors.affiliation: Department of Orthopaedic Surgery, University of Connecticut Health Center, MARB 4th floor, 263 Farmington Avenue, Farmington, CT 06030. E-mail address for B.A. Tinsley: btinsley@uchc.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Dukas
authors.affiliation: Department of Orthopaedic Surgery, University of Connecticut Health Center, MARB 4th floor, 263 Farmington Avenue, Farmington, CT 06030. E-mail address for B.A. Tinsley: btinsley@uchc.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pensak
authors.affiliation: Department of Orthopaedic Surgery, University of Connecticut Health Center, MARB 4th floor, 263 Farmington Avenue, Farmington, CT 06030. E-mail address for B.A. Tinsley: btinsley@uchc.edu.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1520 San Pablo Street, Los Angeles, CA 90033.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Tang
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., 1 Amgen Center Drive, Thousand Oaks, CA 91320.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.affiliation: Bone Research, UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, United Kingdom.
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.affiliation: Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1520 San Pablo Street, Los Angeles, CA 90033.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Lieberman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D055396:Bone Morphogenetic Protein 2 / Q000627:therapeutic use*; D019485:Bone Morphogenetic Proteins / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D005593:Fracture Fixation, Internal; D017102:Fracture Healing; D005819:Genetic Markers; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D011859:Radiography; D011897:Random Allocation; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000627:therapeutic use*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D011994:Recombinant Proteins; C422903:SOST protein, human; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2