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      Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment.

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          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.

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          Author and article information

          Journal
          Bone
          Bone
          1873-2763
          1873-2763
          Feb 2015
          : 71
          Affiliations
          [1 ] 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.
          [2 ] Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, United States.
          [3 ] Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States.
          [4 ] Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, United States.
          [5 ] 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.
          Article
          S8756-3282(14)00385-8 NIHMS637318
          10.1016/j.bone.2014.10.012
          25445450
          6fdcb047-e61e-4e48-939b-06b0de3b2676
          Copyright © 2014 Elsevier Inc. All rights reserved.
          History

          Anabolic therapy,Bone mass,Collagen,Dynamic histomorphometry,Osteogenesis imperfecta,Sclerostin antibody

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