High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice.

Abstract

BACKGROUND:

Receptor activator of nuclear factor-κB 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 OI, the col1α2-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.

• Authors: Renee Bargman, Ram Posham, Adele Boskey, Erin Carter, Edward DiCarlo, Kostas Verdelis, Cathleen Raggio, Nancy Pleshko
• Journal: Pediatric research (Pediatr Res) Vol. 72 Issue 5 Pg. 495-501 (Nov 2012) ISSN: 1530-0447 [Electronic] United States
• PMID: 22926546 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Collagen Type I
• Immunoconjugates
• Immunoglobulin Fc Fragments
• Isoenzymes
• Osteoprotegerin
• RANK Ligand
• Tnfsf11 protein, mouse
• Acid Phosphatase
• Tartrate-Resistant Acid Phosphatase

Topics

• Acid Phosphatase (blood)
• Age Factors
• Animals
• Biomarkers (blood)
• Bone Remodeling (drug effects)
• Collagen Type I (deficiency, genetics)
• Dentin (drug effects, metabolism, pathology)
• Disease Models, Animal
• Female
• Immunoconjugates (toxicity)
• Immunoglobulin Fc Fragments (toxicity)
• Isoenzymes (blood)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteoclasts (drug effects, metabolism)
• Osteogenesis Imperfecta (diagnostic imaging, drug therapy, genetics, metabolism, pathology)
• Osteopetrosis (chemically induced, diagnostic imaging, metabolism, pathology)
• Osteoprotegerin (toxicity)
• RANK Ligand (antagonists & inhibitors, metabolism)
• Radiography
• Risk Assessment
• Tartrate-Resistant Acid Phosphatase
• Time Factors
• Tooth Eruption (drug effects)
• Weight Gain (drug effects)