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

Gozde Yildirim, Edmara T.P. Bergamo, Sher Bahadur Poudel, Ryan R. Ruff, Manisha Dixit, Bin Hu, Dindo Q. Mijares, Lukasz Witek, Carolyn Chlebek, David E. Harrison, Randy Strong, Richard A. Miller, Warren Ladiges, Timothy G. Bromage, Clifford J. Rosen, Shoshana Yakar

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1933-1951
Number of pages19
JournalGeroScience
Volume45
Issue number3
DOIs
StatePublished - Jun 2023
Externally publishedYes

Keywords

  • BMD
  • Bone
  • Canagliflozin
  • Micro-CT
  • SGLT2i

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine
  • Aging
  • Complementary and alternative medicine
  • veterinary (miscalleneous)

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