This study assessed the effects of SGLT2 inhibitor canagliflozin (CANA) on the bone health of genetically heterogeneous mice, UM-HET3. It does help lowering blood glucose levels independently of insulin while also inducing a chain of metabolic adjustments including loss of weight and impaired bone integrity. This study will consider the effects of CANA on bone metabolism inasmuch as SGLT2 is neither expressed in osteoblasts nor in osteocytes, which are of great importance for bone remodeling.
CANA was given to mice for three different periods: 1 month, 3 months, and 6 months. Metabolic adaptations were seen at 1.5 months, especially in male mice. Male mice treated with CANA showed significant body weight loss and a decrease in proinflammatory and bone-remodeling markers, indicating decreased cortical bone remodeling. Metabolome profiling in bone tissues of these mice showed enrichment in metabolites involved in amino acid transport and tryptophan catabolism. Meanwhile, female mice treated with CANA showed increases in nucleic acid metabolism.
IntegrOmics, combining bone tissue metabolome and bone-marrow RNAseq findings, showed a positive correlation of the datasets in male mice. Such analysis revealed three clusters of transcripts and metabolites associated with energy metabolism, oxidative stress response, and cellular proliferation and differentiation, all reduced in male mice receiving CANA treatment. This suggests that the effect of CANA on bone metabolism is mostly exercised through induction of a ‘glucose restriction state’ that acts on bone cell proliferation and differentiation.
The study concludes that SGLT2i drugs like CANA have significant effects on bone health, highlighting the need to consider sex-specific responses when developing clinical treatments that alter substrate availability. The detailed supplementary data provided in the PDFs, including RNAseq analysis, metabolome profiles, and mechanical testing results, further support these conclusions, offering a comprehensive view of CANA’s impact on bone metabolism.
