title: Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta.
abstract: Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Symptoms are most prominent during childhood. Although antiresorptive bisphosphonates have been widely used to treat pediatric OI, controlled trials show improved vertebral parameters but equivocal effects on long-bone fracture rates. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin antibody (Scl-Ab) therapy is potently anabolic in the skeleton by stimulating osteoblasts via the canonical wnt signaling pathway, and may be beneficial for treating OI. In this study, Scl-Ab therapy was investigated in mice heterozygous for a typical OI-causing Gly→Cys substitution in col1a1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in a knock-in model for moderately severe OI (Brtl/+) and in WT mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. In conclusion, short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in pediatric OI.
authors: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA.
authors: Benjamin P
authors: BP
authors: Sinder
authors: Mary M
authors: MM
authors: Eddy
authors: Michael S
authors: MS
authors: Ominsky
authors: Michelle S
authors: MS
authors: Caird
authors: Joan C
authors: JC
authors: Marini
authors: Kenneth M
authors: KM
authors: Kozloff
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002113:Calcification, Physiologic / Q000187:drug effects; D004195:Disease Models, Animal; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D005452:Fluoresceins / Q000378:metabolism; D006023:Glycoproteins / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D036103:Nanotechnology; D009929:Organ Size / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects; D010013:Osteogenesis Imperfecta / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D000071681:Tartrate-Resistant Acid Phosphatase; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D015415:Biomarkers; D005452:Fluoresceins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; C486030:Sost protein, mouse; D015675:Osteocalcin; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C007740:fluorexon