Osteoporosis International

, Volume 25, Issue 8, pp 2097–2107

Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength

  • B. P. Sinder
  • L. E. White
  • J. D. Salemi
  • M. S. Ominsky
  • M. S. Caird
  • J. C. Marini
  • K. M. Kozloff
Original Article

DOI: 10.1007/s00198-014-2737-y

Cite this article as:
Sinder, B.P., White, L.E., Salemi, J.D. et al. Osteoporos Int (2014) 25: 2097. doi:10.1007/s00198-014-2737-y

Abstract

Summary

Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect.

Introduction

Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1.

Methods

Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2×/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed.

Results

Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength.

Conclusion

Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI.

Keywords

Mouse modelOsteogenesis imperfectaOsteoporosisSclerostin antibody

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2014

Authors and Affiliations

  • B. P. Sinder
    • 1
    • 2
  • L. E. White
    • 1
  • J. D. Salemi
    • 1
    • 2
  • M. S. Ominsky
    • 3
  • M. S. Caird
    • 1
  • J. C. Marini
    • 4
  • K. M. Kozloff
    • 1
    • 2
  1. 1.Orthopaedic Research Laboratories, Department of Orthopaedic SurgeryUniversity of MichiganAnn ArborUSA
  2. 2.Department of Biomedical EngineeringUniversity of MichiganAnn ArborUSA
  3. 3.Department of Metabolic DisordersAmgen, Inc.Thousand OaksUSA
  4. 4.Bone and Extracellular Matrix BranchNational Institute of Child Health and Human Development, NIHBethesdaUSA