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Raloxifene Improves Bone Mechanical Properties in Mice Previously Treated with Zoledronate

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Abstract

Bisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment, femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest that the raloxifene treatment is enhancing mechanical material properties of the tissue.

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Acknowledgements

This work was supported by NIH Grants AR62002 (MRA), DK108554 (F32 support for EM), AR65971 (T32 support for MA), and AR067221 (JMW). The microCT utilized in this experiment was purchased through a NIH S10 Grant (OD 016208).

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Indiana University School of Medicine, MS 5035, 635 Barnhill Dr., Indianapolis, IN, 46202, USA

    Cory N. Meixner, Mohammad W. Aref, Aryaman Gupta, Erin M. B. McNerny, Drew Brown & Matthew R. Allen

  2. Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

    Joseph M. Wallace & Matthew R. Allen

  3. Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, USA

    Joseph M. Wallace & Matthew R. Allen

  4. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA

    Matthew R. Allen

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  1. Cory N. Meixner
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Correspondence to Matthew R. Allen.

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Cory N. Meixner, Mohammad W. Aref, Aryaman Gupta, Erin M. B. McNerny, Drew Brown, Joseph M. Wallace, Matthew R. Allen declare that they have no conflicts of interest related to the current work.

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All procedures were approved by the Indiana University School of Medicine Animal Care and Use Committee prior to initiating the study.

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Meixner, C.N., Aref, M.W., Gupta, A. et al. Raloxifene Improves Bone Mechanical Properties in Mice Previously Treated with Zoledronate. Calcif Tissue Int 101, 75–81 (2017). https://doi.org/10.1007/s00223-017-0257-4

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  • DOI: https://doi.org/10.1007/s00223-017-0257-4

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