The first indication that SGLT2 inhibitors could possibly influence bone health came from animal studies 38. Rats exposed to high doses of dapagliflozin (the first developed drug of this class) were observed to have disturbances in calcium homeostasis, tissue mineralization, increased trabecular bone and renal medullary tubular degeneration. The proposed mechanism was thought to be due to the high dose of dapagliflozin causing non-selective inhibition of SGLT1 in the gut, thereby altering the pH balance in the intestinal lumen and increasing calcium reabsorption. These findings are not thought to be relevant to human pharmacology when SGLT2 inhibitors are administered at approved doses. Nevertheless, given these findings, special attention was paid to bone mineralization and changes during clinical development.