Association Between the Use of Proton Pump Inhibitors and Osteoporosis/Fracture: Nested Case-Control Studies Using a...

Background/Objectives: Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related disorders. However, there are concerns that PPI use may be associated with an increased risk of osteoporosis and fractures. This study aimed to investigate the association between PPI use and the risk of osteoporosis and fractures using national data. Methods: Two nested case-control studies using Korean National Health Insurance Service-Health Screening Cohort (514,866 participants, 2002-2019). Study I: 68,719 osteoporosis patients matched 1:1 with 68,719 controls by age, sex, income, region. Study II: 72,456 fracture patients matched 1:1 with 72,456 controls, stratified by fracture site (distal radius [n = 25,882], hip [n = 7753], spine [n = 38,821]). PPI use defined as prescription 1-year preceding index date: current users (≤30 days) and exposed group (31-365 days). Associations were analyzed using propensity score overlap-weighted logistic regression. Results: For osteoporosis, current PPI use showed odds ratio (OR) = 37.4 (95% confidence interval [CI] 33.3-42.1, p < 0.001); exposed group OR = 2.62 (95% CI 2.32-2.96, p < 0.001). Duration-dependent relationship observed: <30 days OR = 8.67, 30-180 days OR = 29.9, ≥180 days OR = 25.0. For fractures, current use associated with distal radius (OR = 37.4, 95% CI 28.8-48.7), hip (OR = 20.3, 95% CI 13.7-30.3), and spine (OR = 29.8, 95% CI 23.7-37.4). However, the exposed group showed no significant associations (distal radius OR = 1.24 p = 0.125; hip OR = 1.34 p = 0.174; spine OR = 1.26 p = 0.057). Conclusions: Current PPI use is strongly associated with increased odds of osteoporosis and fracture in the Asian population, with prominent duration-response relationship. Past PPI exposure showed no significant fracture risk. Healthcare providers should carefully assess bone health risks and consider lowest effective PPI doses.