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Sclerostin-Antibody Treatment Decreases Fracture Rates in Axial Skeleton and Improves the Skeletal Phenotype in Growing oim/oim Mice

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Abstract

In osteogenesis imperfecta (OI), vertebrae brittleness causes thorax deformations and leads to cardiopulmonary failure. As sclerostin-neutralizing antibodies increase bone mass and strength in animal models of osteoporosis, their administration in two murine models of severe OI enhanced the strength of vertebrae in growing female Crtap−/− mice but not in growing male Col1a1Jrt/+ mice. However, these two studies ignored the impact of antibodies on spine growth, fracture rates, and compressive mechanical properties. Here, we conducted a randomized controlled trial in oim/oim mice, an established model of human severe OI type III due to a mutation in Col1a2. Five-week-old female WT and oim/oim mice received either PBS or sclerostin antibody (Scl-Ab) for 9 weeks. Analyses included radiography, histomorphometry, pQCT, microcomputed tomography, and biomechanical testing. Though it did not modify vertebral axial growth, Scl-Ab treatment markedly reduced the fracture prevalence in the pelvis and caudal vertebrae, enhanced osteoblast activity (L4), increased cervico-sacral spine BMD, and improved the lumbosacral spine bone cross-sectional area. Scl-Ab did not impact vertebral height and body size but enhanced the cortical thickness and trabecular bone volume significantly in the two Scl-Ab groups. At lumbar vertebrae and tibial metaphysis, the absolute increase in cortical and trabecular bone mass was higher in Scl-Ab WT than in Scl-Ab oim/oim. The effects on trabecular bone mass were mainly due to changes in trabecular number at vertebrae and in trabecular thickness at metaphyses. Additionally, Scl-Ab did not restore a standard trabecular network, but improved bone compressive ultimate load with more robust effects at vertebrae than at metaphysis. Overall, Scl-Ab treatment may be beneficial for reducing vertebral fractures and spine deformities in patients with severe OI.

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Acknowledgements

The authors thank the Amgen-UCB consortium for providing the anti-sclerostin antibody (DHM). They are grateful to Isabelle Badoud, Jennifer Siebenaler and Walter Hudders for their expertise and assistance.

Funding

This research is supported by the Medical Scientific Research Fund (FRSM-IREC88A6, DHM) and by the French-speaking Belgian Association of the Osteogenesis Imperfecta (www.fetealavie.be, www.afboi.be/).

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Author notes

  1. Catherine Nyssen-Behets and Daniel H. Manicourt contributed equally to this work.

Authors and Affiliations

  1. Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium

    Mickaël Cardinal, Alicia Dessain, Thomas Roels, Sébastien Lafont & Catherine Nyssen-Behets

  2. Pole of Rheumatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium

    Jean-Pierre Devogelaer & Daniel H. Manicourt

  3. Radius Health, Inc. (Formerly at Amgen Inc, Thousand Oaks, CA, USA), Waltham, MA, USA

    Michael S. Ominsky

  4. GEROM, Groupe d′Etudes sur le Remodelage Osseux et les bioMatériaux, University of Angers, 49933, Angers, France

    Daniel Chappard & Guillaume Mabilleau

  5. Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital, Geneva, Switzerland

    Patrick Ammann

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  1. Mickaël Cardinal
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Correspondence to Mickaël Cardinal.

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Conflict of interest

Michael S. Ominsky is a former employee and stockholder of Amgen. Mickaël Cardinal, Alicia Dessain, Thomas Roels, Sébastien Lafont, Jean-Pierre Devogelaer, Daniel Chappard, Guillaume Mabilleau, Patrick Ammann, Catherine Nyssen-Behets and Daniel H. Manicourt declare that they have no other conflict of interest.

Human and Animal Rights and Informed Consent

This study was approved by the Ethics Committee for Animal Care of the Université Catholique de Louvain under the reference number: 2014/UCL/MD/021, and conformed to the Belgian federal law for animal care.

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Cardinal, M., Dessain, A., Roels, T. et al. Sclerostin-Antibody Treatment Decreases Fracture Rates in Axial Skeleton and Improves the Skeletal Phenotype in Growing oim/oim Mice. Calcif Tissue Int 106, 494–508 (2020). https://doi.org/10.1007/s00223-019-00655-5

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