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

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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.

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Acknowledgments

The authors thank Bonnie Nolan, Kathy Sweet and Marry Eddy for their contributions. Scl-Ab was provided by Amgen and UCB Pharma. Funding support from NIH to KMK (R01AR062522) is gratefully acknowledged. Study designed and conducted by BPS and KMK. Data collected by BPS, LEW, and JDS. Data analyzed and interpreted by BPS, LEW, JDS, MSO, MSC, JCM, and KMK. The manuscript was written by BPS and KMK and revised and approved by all authors. KMK takes responsibility for the integrity of the data analysis.

Conflicts of interest

Michael S. Ominsky is an employee and stock owner of Amgen Inc. Benjamin P. Sinder, Logan E. White, Joseph D. Salemi, Michelle S. Caird, Joan C. Marini, and Kenneth M. Kozloff declare no conflict of interest.

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Authors and Affiliations

  1. Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, 2015 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA

    B. P. Sinder, L. E. White, J. D. Salemi, M. S. Caird & K. M. Kozloff

  2. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA

    B. P. Sinder, J. D. Salemi & K. M. Kozloff

  3. Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, USA

    M. S. Ominsky

  4. Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    J. C. Marini

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  1. B. P. Sinder
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  2. L. E. White
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  7. K. M. Kozloff
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Correspondence to K. M. Kozloff.

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Sinder, B.P., White, L.E., Salemi, J.D. et al. Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength. Osteoporos Int 25, 2097–2107 (2014). https://doi.org/10.1007/s00198-014-2737-y

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