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Scientific Articles   |    
Systemic Administration of Sclerostin Antibody Enhances Bone Repair in a Critical-Sized Femoral Defect in a Rat Model
Mandeep S. Virk, MBBS1; Farhang Alaee, MD1; Hezhen Tang, BS1; Michael S. Ominsky, PhD2; Hua Zhu Ke, PhD2; Jay R. Lieberman, MD3
1 New England Musculoskeletal Institute, Department of Orthopaedic Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030
2 Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320
3 Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, 1520 San Pablo Street, Suite 200, Los Angeles, CA 90033. E-mail address: jrlieber@usc.edu
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Investigation performed at the New England Musculoskeletal Institute, Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut



Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

Copyright © 2013 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2013 Apr 17;95(8):694-701. doi: 10.2106/JBJS.L.00285
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Abstract

Background: 

Systemic administration of sclerostin neutralizing antibody has led to increased bone formation in animal models of osteoporosis. The purpose of this study was to determine if systemic administration of sclerostin neutralizing antibody could increase the healing response in a critical-sized femoral defect in rats.

Methods: 

Critical-sized femoral defects were created in Lewis rats, and the rats were randomized into four groups. The sclerostin antibody (Scl-Ab) treatment groups included the continuous Scl-Ab group (twenty-one animals), the early Scl-Ab group (fifteen animals), and the delayed Scl-Ab group (fifteen animals), which received sclerostin antibody (25 mg/kg) twice weekly for weeks 0 through 12; weeks 0 through 2; and weeks 2 through 4; respectively. Twenty-one animals in the control group received vehicle from weeks 0 through 12. In a subsequent study, bone turnover markers were measured at zero, two, six, and twelve weeks after surgery in rats receiving vehicle or sclerostin neutralizing antibody for twelve weeks (fifteen rats per group). The quality of bone formed was evaluated with radiographs, microcomputed tomography, biomechanical testing, and histologic and histomorphometric analysis.

Results: 

In the primary study, four of fifteen defects in the continuous (zero to twelve-week) Scl-Ab group, three of fifteen defects in the early (zero to two-week) Scl-Ab group, and four of fifteen defects in the delayed (two to four-week) Scl-Ab group healed at twelve weeks, while none of the defects healed in the control group. In both studies, treatment with sclerostin antibody for twelve weeks demonstrated a significant increase in new bone formation (p < 0.05) compared with the control group. The three treatment groups did not differ significantly with respect to the healing rates and the quality of new bone formed in the defect. The serum markers of bone formation were significantly elevated in the animals in the continuous Scl-Ab group (p < 0.05) compared with the controls.

Conclusions: 

Administration of sclerostin neutralizing antibody led to increased bone formation, resulting in complete healing of femoral defects in a small subset of rats, with a majority of the animals not healing the defect by twelve weeks.

Clinical Relevance: 

Sclerostin neutralizing antibody is a systemically delivered agent that exerts an anabolic effect during fracture repair and has the potential to be used as an adjuvant to enhance bone-healing in difficult bone-repair scenarios.

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    References

    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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