Alendronate Treatment of the Brtl Osteogenesis Imperfecta Mouse Improves Femoral Geometry and Load Response Before Fracture but Decreases Predicted Material Properties and Has Detrimental Effects on Osteoblasts and Bone Formation

Authors

  • Thomas E Uveges,

    1. Bone and Extracellular Matrix Branch, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland, USA
    2. Current address: Trevigen, Gaithersburg, Maryland, USA
    3. These authors contributed equally to this work and are co-first authors
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  • Kenneth M Kozloff,

    1. These authors contributed equally to this work and are co-first authors
    2. Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA
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  • Jennifer M Ty,

    1. Bone and Extracellular Matrix Branch, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland, USA
    2. Current address: Department of Orthopaedic Surgery, duPont Hospital for Children, Wilmington, Delaware, USA
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  • Felicia Ledgard,

    1. Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA
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  • Cathleen L Raggio,

    1. Center for Skeletal Dysplasias, Hospital for Special Surgery, New York, New York, USA
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  • Gloria Gronowicz,

    1. Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA
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  • Steven A Goldstein,

    1. Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA
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  • Joan C Marini

    Corresponding author
    1. Bone and Extracellular Matrix Branch, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland, USA
    • Address correspondence to: Joan C. Marini, MD, PhD, Chief, Bone and Extracellular Matrix Branch, NICHD, NIH Building 10, Room 10N260, 9000 Rockville Pike, Bethesda, MD 20892, USA
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  • Dr. Ty owns stock in Merck. All other authors state that they have no conflicts of interest.

Abstract

Long courses of bisphosphonates are widely administered to children with osteogenesis imperfecta (OI), although bisphosphonates do not block mutant collagen secretion and may affect bone matrix composition or structure. The Brtl mouse has a glycine substitution in col1a1 and is ideal for modeling the effects of bisphosphonate in classical OI. We treated Brtl and wildtype mice with alendronate (Aln; 0.219 mg/kg/wk, SC) for 6 or 12 wk and compared treated and untreated femora of both genotypes. Mutant and wildtype bone had similar responses to Aln treatment. Femoral areal BMD and cortical volumetric BMD increased significantly after 12 wk, but femoral length and growth curves were unaltered. Aln improved Brtl diaphyseal cortical thickness and trabecular number after 6 wk and cross-sectional shape after 12 wk. Mechanically, Aln significantly increased stiffness in wildtype femora and load to fracture in both genotypes after 12 wk. However, predicted material strength and elastic modulus were negatively impacted by 12 wk of Aln in both genotypes, and metaphyseal remnants of mineralized cartilage also increased. Brtl femoral brittleness was unimproved. Brtl osteoclast and osteoblast surface were unchanged by treatment. However, decreased mineral apposition rate and bone formation rate/bone surface and the flattened morphology of Brtl osteoblasts suggested that Aln impaired osteoblast function and matrix synthesis. We conclude that Aln treatment improves Brtl femoral geometry and load to fracture but decreases bone matrix synthesis and predicted material modulus and strength, with striking retention of mineralized cartilage. Beneficial and detrimental changes appear concomitantly. Limiting cumulative bisphosphonate exposure of OI bone will minimize detrimental effects.

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