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Pre-treatment with Pamidronate Improves Bone Mechanical Properties in Mdx Mice Treated with Glucocorticoids

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Abstract

Duchenne muscular dystrophy (DMD) is an X-linked disease of progressive muscle deterioration and weakness. Patients with DMD have poor bone health which is partly due to treatment with glucocorticoids, a standard therapy to prolong muscle function that also induces bone loss. Bisphosphonates are used to treat adults at risk of glucocorticoid-induced osteoporosis but are not currently used in DMD patients until after they sustain fractures. In this study, C57BL/10ScSn-mdx mice, a commonly used DMD animal model, received continuous glucocorticoid, prednisone treatment (0.083 mg/day) from 5 to 10 weeks of age. Pre-treatment with the bisphosphonate pamidronate started at 4 weeks of age over a period of 2 weeks or 6 weeks (cumulative dose 8 mg/kg for both) to assess the effectiveness of the two dosing regimens in ameliorating glucocorticoid-induced bone loss. Mdx mice treated with prednisone had improved muscle function that was not changed by pamidronate treatment. Glucocorticoid treatment caused cortical bone loss and decreased cortical bone strength. Both 2 and 6 week pamidronate treatment increased cortical thickness and bone area compared to prednisone-treated Mdx mice, however, only 2 week pamidronate treatment improved the strength of cortical bone compared to that of glucocorticoid-treated Mdx mice. In the trabecular bone, both pamidronate treatments significantly increased the amount of bone, and increased the ultimate load but not the energy to fail. These results highlight the importance of when and how much bisphosphonate is administered prior to glucocorticoid exposure.

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Acknowledgements

This work was supported by a grant to MDG and JM from the Canadian Institutes of Health Research (CIHR MOP-123265), JC received support from a Canada Graduate Scholarship-Master’s from CIHR, S-HY received support from the Ontario Student Opportunity Trust Funds.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Jinghan Chen, Sung-Hee Yoon & Jane Mitchell

  2. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Health System, Toronto, ON, Canada

    Jinghan Chen, Sung-Hee Yoon & Marc D. Grynpas

  3. Department of Pharmacology and Toxicology, University of Toronto, 1 King’s College Circle, Room 4342, Toronto, ON, M5S 1A8, Canada

    Jane Mitchell

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  1. Jinghan Chen
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  2. Sung-Hee Yoon
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Correspondence to Jane Mitchell.

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Conflict of interest

Jinghan Chen, Sung-Hee Yoon, Marc D. Grynpas, Jane Mitchell declare they have no conflicts of interest.

Human and Animal Rights and Informed Consent

All animal care procedures were reviewed and approved by the Animal Care Committee of the University of Toronto. Human informed consent statements are not applicable since this is an animal study.

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Chen, J., Yoon, SH., Grynpas, M.D. et al. Pre-treatment with Pamidronate Improves Bone Mechanical Properties in Mdx Mice Treated with Glucocorticoids. Calcif Tissue Int 104, 182–192 (2019). https://doi.org/10.1007/s00223-018-0482-5

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  • DOI: https://doi.org/10.1007/s00223-018-0482-5

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