Title

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

Document Type

Article

Publication Date

6-1-2023

Keywords

JMG, Male, Female, Animals, Mice, Canagliflozin, Diabetes Mellitus, Type 2, Sodium-Glucose Transporter 2 Inhibitors, X-Ray Microtomography, Skeleton

ISSN

2509-2723

PMID

37166526

DOI

https://doi.org/10.1007/s11357-023-00803-8

Grant

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 sup- ported by a Senior Research Career Scientist Award from the Department of Veterans Affairs Office of Research and Devel- opment, S10 OD010751-01A1 for micro-computed tomogra- phy, S10 OD026989 for Zeiss Gemini 300 FE-SEM.

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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