Abstract
INTRODUCTION: Pioglitazone, a thiazolidinedione, effectively reduces stroke and cardiovascular events in individuals with type 2 diabetes, insulin resistance, and/or stroke. However, its potential to increase fracture risk, particularly among women and those with pre-existing skeletal conditions, has not yet been completely understood. This meta-analysis aims to clarify fracture risk associated with pioglitazone, thereby focusing on individuals with a history of stroke. METHODS: A systematic review was performed for clinical trials conducted up to March 2024, focusing on trials comparing pioglitazone to placebo or other antihyperglycemic drugs that reported fracture outcomes. RESULTS: From 860 trials identified, 78 satisfied the inclusion criteria: 34 with a high risk of bias, 8 with unclear risk, and 36 with low risk. The meta-analysis revealed an association between pioglitazone and a significant increase in fracture risk (risk ratio [RR] 1.21; 95% CI 1.01-1.45; P = 0.04), including non-serious (RR 1.25; 95% CI 1.03-1.51; P = 0.02) and serious fractures (RR 1.48; 95% CI 1.10-1.98; P = 0.01). Notably, the risk was exacerbated for low-energy fractures, particularly resulting from falls (RR 1.49; 95% CI 1.20-1.87; P = 0.0004), in insulin resistance individuals (RR 0.87; 95% CI 0.43-1.76; P = 0.69), and stroke survivors (RR 1.41; 95% CI 1.09-1.83; P = 0.008). Fractures were most frequently observed in lower extremities (RR 1.85; 95% CI 1.33-2.56; P = 0.0002), with women at a greater risk (RR 1.56; 95% CI 1.20-2.02; P = 0.0008). When compared with other antihyperglycemic drugs, no significant difference in fracture risk was noted (RR 1.08; 95% CI 0.73-1.59; P = 0.70), except rosiglitazone, which showed higher fracture risk (RR 1.42; 95% CI 1.23-1.64; P < 0.00001). Fracture risk was significant in the fixed-effect model but not in the random-effects model. DISCUSSION: Though pioglitazone offers several cardiovascular benefits, its association with increased fracture risk, especially among women and non-diabetic individuals post-stroke, warrants careful consideration. Individualized treatment interventions balancing cardiovascular and skeletal outcomes are essential, and further research is needed to optimize therapeutic strategies in this population. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016038242, identifier CRD42016038242.