Diabetes and Bone Fragility: SGLT2 Inhibitor Use in the Context of Renal and Cardiovascular Benefits

Type 2 diabetes mellitus (T2DM) has been shown to negatively impact bone quality and increase fracture risk. While the pathophysiology of bone fragility in T2DM is not clear and likely multifactorial, medications used to treat T2DM are increasingly scrutinized for their potential role in aberrant bone metabolism. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are gaining popularity in patients with T2DM. In addition to lowering blood glucose, there is evidence that these drugs offer cardiac and renal benefit to individuals with T2DM, leading to FDA-approved indications for use in at-risk individuals. At the same time, there remain concerns that SGLT2 inhibitors, specifically canagliflozin, have adverse effects on bone metabolism and increase fracture risk in T2DM. This review seeks to further clarify the impact of these agents on the skeleton.

SGLT2 inhibitors may indirectly disrupt calcium and phosphate homeostasis, contribute to weight loss, and cause hypotension, resulting in bone mineral density (BMD) losses and increased falls. The true long-term impact of SGLT2 inhibitors on the diabetic skeleton is still unclear; this review summarizes the results in studies investigating the impact of SGLT2 inhibitors on fracture risk in T2DM. Whereas studies performed with dapagliflozin and empagliflozin have not shown an increased risk of bone fractures compared with placebo, some studies have shown increased markers of bone turnover and reduced bone mineral density with canagliflozin treatment. While an increased fracture risk was observed with canagliflozin in the CANVAS trial (HR 1.26; 95% CI 1.04, 1.52), an increased risk was not seen in the CANVAS-R (HR 0.86) or CREDENCE (HR 0.98) trials.

There is substantial evidence of the cardiac and renal protective benefits of SGLT2 inhibitors. There does not appear to be an increased fracture risk with the use of dapagliflozin or empagliflozin. Given the possible association between canagliflozin and adverse bone outcomes described in CANVAS, canagliflozin use should be pursued in individuals with T2DM only after careful consideration of the individual’s skeletal risk.