Insulin Use and Fracture Risk in Patients with Type 2 Diabetes: A Meta-analysis of 138,690 Patients

Patients with type 2 diabetes mellitus (T2DM) have been reported to have an enhanced risk of bone fracture, however the association between insulin treatment and risk of fracture in patients with T2DM remains to be fully elucidated. The aim of the present meta-analysis was to examine the possible association between insulin treatment and risk of fracture in patients with T2DM. Relevant studies published prior to and including April 2018 were identified by literature searches in PubMed, Embase and Cochrane Library databases. A meta-analysis was performed, which included relevant trials of patients with T2DM comparing insulin to oral anti-diabetic drugs. The combined effect was expressed as a pooled risk ratio (RR) with 95% confidence interval (CI), using a random-effects model. Subgroup analysis was performed to consolidate the results. A total of 7 studies comprising 138,690 patients were eligible for inclusion in the present meta-analysis. After exclusion of one study that introduced major heterogeneity, treatment with, insulin was associated with a significantly increased risk of fracture among patients with T2DM (RR=1.24, 95% CI, 1.07-1.44; P=0.004). Subgroup analysis by sex indicated that the RR for men was 1.04 (95% CI, 0.76-1.44, P=0.801) and that for women was 1.22 (95% CI, 0.92-1.62, P=0.175). Subgroup analysis by fracture site indicated that the RR for hip was 1.18 (95% CI, 0.83-1.68, P=0.363), that for vertebrae was 1.28 (95% CI, 0.90-1.81, P=0.169) and that for non-vertebrae was 1.06 (95% CI, 0.80-1.41, P=0.686). Subgroup analysis by study design suggested that the RR for prospective and retrospective studies was 1.35 (95% CI, 1.06-1.71, P=0.014) and 1.16 (95% CI, 0.99-1.35, P=0.059), respectively. Subgroup analysis by region indicated that the RR for Europe was 1.16 (95% CI, 0.91-1.48, P=0.220), that for North America was 1.24 (95% CI, 0.81-1.90, P=0.333) and that for Asia was 1.34 (95% CI, 0.91-1.98, P=0.141). In conclusion, treatment with insulin increased the risk of fractures among patients with T2DM compared with oral anti-diabetic drugs; however, the association was influenced by various factors, including sex, fracture site, study design and geographical region.