Canagliflozin-Induced Adaptive Metabolism in Bone

Sodium–glucose transporter-2 inhibitor (SGLT2i) drugs are widely used for lowering blood glucose levels independent of insulin. Beyond this, these drugs induce various metabolic changes, including weight loss and impaired bone integrity. A significant gap exists in understanding SGLT2i-induced skeletal changes, as SGLT2 is not expressed in osteoblasts or osteocytes, which use glucose to remodel the bone matrix. We studied the impact of 1, 3, or 6 months of canagliflozin (CANA), an SGLT2i treatment, on the skeleton of 6-month-old genetically heterogeneous UM-HET3 mice. Significant metabolic adaptations to CANA were evident as early as 1.5 months after treatment, specifically in male mice. CANA-treated male mice exhibited notable re-ductions in body weight and decreased proinflammatory and bone remodeling markers associated with reduced cortical bone remodeling indices. Bone tissue metabo-lome indicated enrichment in metabolites related to amino acid transport and tryptophan catabolism in CANA-treated male mice. In contrast, CANA-treated female mice showed increases in nucleic acid metabolism. An integrOmics ap-proach of source-matched bone tissue metabolome and bone marrow RNA sequencing indicated a positive correlation between the two omics data sets in male mice. Three clusters of transcripts and metabolites involved in energy metabolism, oxidative stress response, and cellular proliferation and differentiation were reduced in CANA-treated male mice. In conclusion, CANA affects bone metabolism mainly via the “glucose restriction state” it induces and impacts bone cell proliferation and differen-tiation. These findings underline the effects of SGLT2i on bone health and highlight the need to consider sex-specific responses when developing clinical treatments that alter substrate availability.