Journal
PEDIATRIC RESEARCH
Volume 72, Issue 5, Pages 495-501Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/pr.2012.118
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Funding
- Amgen [2008-2009]
- National Institutes of Health (NIH) [AR48337]
- Musculoskeletal Repair and Regeneration Core Center [AR046121]
- Osteogenesis Imperfecta Foundation
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BACKGROUND: Receptor activator of nuclear factor-kappa B ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin immunoglobulin Fc segment complex (OPG-Fc), in a growing animal model of 01, the colla2-deficient mouse (oim/oim) and its wild-type controls (+/+). METHODS: Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b,TRACP-5b) until 25 wk of age. RESULTS:Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate-resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4-8 wk post-treatment. CONCLUSION: Both high- and low-dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK immunoglobulin Fc segment complex (RANK-Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children.
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