Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice.
Gozde YildirimEdmara T P BergamoSher Bahadur PoudelRyan R RuffManisha DixitBin HuDindo Q MijaresLukasz WitekCarolyn ChlebekDavid E HarrisonRandy StrongRichard A MillerWarren LadigesTimothy G BromageClifford J RosenShoshana YakarPublished in: GeroScience (2023)
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.
Keyphrases
- bone mineral density
- computed tomography
- postmenopausal women
- high fat diet induced
- type diabetes
- electron microscopy
- minimally invasive
- body composition
- physical activity
- magnetic resonance
- risk factors
- magnetic resonance imaging
- insulin resistance
- weight loss
- electronic health record
- blood pressure
- skeletal muscle
- blood glucose
- metabolic syndrome
- soft tissue
- high throughput
- cell therapy
- machine learning
- big data
- single cell