title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pediatrics, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Bargman
authors.forename: Ram
authors.initials: R
authors.lastname: Posham
authors.forename: Adele
authors.initials: A
authors.lastname: Boskey
authors.forename: Erin
authors.initials: E
authors.lastname: Carter
authors.forename: Edward
authors.initials: E
authors.lastname: DiCarlo
authors.forename: Kostas
authors.initials: K
authors.lastname: Verdelis
authors.forename: Cathleen
authors.initials: C
authors.lastname: Raggio
authors.forename: Nancy
authors.initials: N
authors.lastname: Pleshko
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016723:Bone Remodeling / Q000187:drug effects; D024042:Collagen Type I / Q000172:deficiency / Q000235:genetics; D003804:Dentin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018796:Immunoconjugates / Q000633:toxicity*; D007141:Immunoglobulin Fc Fragments / Q000633:toxicity*; D007527:Isoenzymes / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010022:Osteopetrosis / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000633:toxicity*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011859:Radiography; D018570:Risk Assessment; D000071681:Tartrate-Resistant Acid Phosphatase; D013997:Time Factors; D014078:Tooth Eruption / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007527:Isoenzymes; D053244:Osteoprotegerin; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase