Systemic Administration of Sclerostin Antibody Enhances Bone Morphogenetic Protein-Induced Femoral Defect Repair in a Rat Model

J Bone Joint Surg Am. 2015 Nov 18;97(22):1852-9. doi: 10.2106/JBJS.O.00171.


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.

Clinical relevance: 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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Bone Density Conservation Agents / therapeutic use*
  • Bone Morphogenetic Protein 2 / therapeutic use*
  • Bone Morphogenetic Proteins / therapeutic use*
  • Chemotherapy, Adjuvant
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Femoral Fractures / diagnostic imaging
  • Femoral Fractures / drug therapy*
  • Femoral Fractures / pathology
  • Femoral Fractures / surgery
  • Fracture Fixation, Internal*
  • Fracture Healing
  • Genetic Markers
  • Humans
  • Injections, Subcutaneous
  • Male
  • Radiography
  • Random Allocation
  • Rats
  • Recombinant Proteins / therapeutic use
  • Transforming Growth Factor beta / therapeutic use*


  • Adaptor Proteins, Signal Transducing
  • Bone Density Conservation Agents
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Genetic Markers
  • Recombinant Proteins
  • SOST protein, human
  • Transforming Growth Factor beta
  • recombinant human bone morphogenetic protein-2