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Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice

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Abstract

Sodium glucose cotransporter-2 inhibitors (SGLT2is) promote urinary glucose excretion and decrease plasma glucose levels independent of insulin. Canagliflozin (CANA) is an SGLT2i, which is widely prescribed, to reduce cardiovascular complications, and as a second-line therapy after metformin in the treatment of type 2 diabetes mellitus. Despite the robust metabolic benefits, reductions in bone mineral density (BMD) and cortical fractures were reported for CANA-treated subjects. In collaboration with the National Institute on Aging (NIA)–sponsored Interventions Testing Program (ITP), we tested skeletal integrity of UM-HET3 mice fed control (137 mice) or CANA-containing diet (180 ppm, 156 mice) from 7 to 22 months of age. Micro-computed tomography (micro-CT) revealed that CANA treatment caused significant thinning of the femur mid-diaphyseal cortex in both male and female mice, did not affect trabecular bone architecture in the distal femur or the lumbar vertebra-5 in male mice, but was associated with thinning of the trabeculae at the distal femur in CANA-treated female mice. In male mice, CANA treatment is associated with significant reductions in cortical bone volumetric BMD by micro-CT, and by quantitative backscattered scanning electron microscopy. Raman microspectroscopy, taken at the femur mid-diaphyseal posterior cortex, showed significant reductions in the mineral/matrix ratio and an increased carbonate/phosphate ratio in CANA-treated male mice. These data were supported by thermogravimetric assay (TGA) showing significantly decreased mineral and increased carbonate content in CANA-treated male mice. Finally, the sintered remains of TGA were subjected to X-ray diffraction and showed significantly higher fraction of whitlockite, a calcium orthophosphate mineral, which has higher resorbability than hydroxyapatite. Overall, long-term CANA treatment compromised bone morphology and mineral composition of bones, which likely contribute to increased fracture risk seen with this drug.

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Data availability

The datasets generated and analyzed during the current study are available upon request. Our studies do not include the use of custom code or mathematical algorithms. We have included citations for available data in the references section.

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Funding

Financial support is received from the National Institutes of Health Grant R01AG056397 to SY, U54GM115516 to CJR, U01-AG022303 to RAM, UO1-AG022308 to DEH, and U01-AG013319 to RS; RS is supported by a Senior Research Career Scientist Award from the Department of Veterans Affairs Office of Research and Development, S10 OD010751-01A1 for micro-computed tomography, S10 OD026989 for Zeiss Gemini 300 FE-SEM.

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Author notes

  1. Gozde Yildirim, Edmara T. P. Bergamo, and Sher Bahadur Poudel contributed equally to this work.

Authors and Affiliations

  1. David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, 345 East 24Th Street, New York, NY, 10010-4086, USA

    Gozde Yildirim, Sher Bahadur Poudel, Manisha Dixit, Bin Hu, Timothy G. Bromage & Shoshana Yakar

  2. David B. Kriser Dental Center, Biomaterials Division, Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, 10010-4086, USA

    Edmara T. P. Bergamo, Dindo Q. Mijares & Lukasz Witek

  3. David B. Kriser Dental Center, Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, NY, 10010-4086, USA

    Ryan R. Ruff

  4. Department of Biomedical Engineering, Tandon School of Engineering New York University, Brooklyn, NY, 11201, USA

    Lukasz Witek

  5. Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, USA

    Carolyn Chlebek & Clifford J. Rosen

  6. The Jackson Laboratory, Bar Harbor, ME, USA

    David E. Harrison

  7. Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA

    Randy Strong

  8. Barshop Institute for Longevity and Aging Studies and Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA

    Randy Strong

  9. Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA

    Richard A. Miller

  10. Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA

    Warren Ladiges

Authors
  1. Gozde Yildirim
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  2. Edmara T. P. Bergamo
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  3. Sher Bahadur Poudel
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  16. Shoshana Yakar
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Contributions

Conceptualization: Investigators of the ITP program RAM, RS, DEH, WL. Funding acquisition: SY. Formal analyses: SY, CJR. Investigation: GY, ETPB, SBP, MD, BH, DM, LW, CC, TGB. Statistical analyses: RRR. Resources: ITP centers (UM, UT, JL). Writing original draft: SY. Writing review and editing: SY, CJR.

Corresponding author

Correspondence to Shoshana Yakar.

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The project was reviewed and approved by the Institutional Animal Care and Use committees at the University of Michigan, University of Texas Health Science Center at San Antonio, and The Jackson Laboratory.

Conflict of interest

The authors declare no competing interests. All authors have discussed the results and approved the final version of the manuscript. SY is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Yildirim, G., Bergamo, E.T.P., Poudel, S.B. et al. Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice. GeroScience 45, 1933–1951 (2023). https://doi.org/10.1007/s11357-023-00803-8

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