title: Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment.
abstract: Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown that bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical Wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly→Cys substitution on col1a1, for 5weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI.
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Sinder
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Salemi
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Caird
authors.affiliation: Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, United States.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States. Electronic address: kenkoz@umich.edu.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kozloff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D006023:Glycoproteins / Q000276:immunology*; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009929:Organ Size / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010013:Osteogenesis Imperfecta / Q000097:blood / Q000473:pathology* / Q000503:physiopathology*; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D015675:Osteocalcin
keywords: Anabolic therapy; Bone mass; Collagen; Dynamic histomorphometry; Osteogenesis imperfecta; Sclerostin antibody