Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice.
Document Type
Article
Publication Date
6-1-2023
Original Citation
Yildirim G,
Bergamo E,
Poudel S,
Ruff R,
Dixit M,
Hu B,
Mijares D,
Witek L,
Chlebek C,
Harrison D,
Strong R,
Miller R,
Ladiges W,
Bromage T,
Rosen C,
Yakar S.
Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice. Geroscience. 2023; 45(3):1933
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.