Risk of bone fracture associated with sodium-glucose cotransporter-2 inhibitor treatment: A meta-analysis of randomized controlled trials.

AIM: To evaluate the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and risk of bone fractures in patients with type 2 diabetes mellitus (T2DM).

METHODS: A systematic literature search conducted of PubMed, Embase, the Cochrane Library and Web of Science from inception up to 31 August 2018 identified all eligible randomized controlled trials (RCTs). The following data were extracted from each study: first author; year of publication; sample size; patient characteristics; study design; intervention drug; control drug; follow-up durations; and incident bone-fracture events. A meta-analysis was performed using Review Manager 5.3 software to calculate odds ratios (ORs) and 95% confidence intervals (CI) for dichotomous variables.

RESULTS: A total of 30 studies involving 23,372 patients with T2DM were included in our analysis. There were 387 incident bone-fracture cases (245 in the SGLT2 inhibitor group, 142 in the control group). Compared with patients who received placebo, those receiving SGLT2 inhibitor treatment had a pooled OR of bone fracture of 0.86 (95% CI: 0.70-1.06). Also, there was no evidence that individual SGLT2 inhibitors across different doses were associated with any increased risk of bone fracture. After stratification by follow-up duration, an SGLT2 inhibitor treatment period of ≤ 52 weeks appeared to have beneficial effects against bone fracture; however, when the treatment period exceeded 52 weeks, these beneficial effects for preventing bone fracture disappeared.

CONCLUSION: Our meta-analysis has indicated that SGLT2 inhibitors do not increase risk of bone fracture compared with placebo in patients with T2DM. However, these findings now need to be confirmed in well-designed RCT studies.