Proton-Pump Inhibitors Versus H2-Receptor Antagonists on the Risk of Major Osteoporotic Fractures: A Global Propensity-Score-Matched Cohort Study

Background Long-term suppression of gastric acid is crucial for various conditions; however, proton-pump inhibitors (PPIs) may negatively impact skeletal health more than histamine-2 receptor antagonists (H2RAs). There is limited head-to-head data, particularly within Asian communities that have unique calcium consumption and drug metabolism patterns. Methods We conducted a retrospective cohort study that matched participants using propensity scores, utilizing the TriNetX integrated claims and electronic health-record database. Adults aged between 18 and 80 years who had at least 12 prescriptions for either a sole PPI or H2RA therapy from 2015 to 2025 were included. Following a 1:1 nearest-neighbor matching (caliper = 0.1), 131,698 individuals remained in each cohort. The outcomes measured included major osteoporotic fracture (MOF; primary), hip repair/arthroplasty, vertebral compression fracture, newly diagnosed osteoporosis, and malignant melanoma (negative control). The application of Cox proportional-hazards models allowed for the assessment of hazard ratios (HRs) and their linked 95% confidence intervals (CIs). Results Over a span of more than two million person-years, PPIs were linked to a higher incidence of MOF compared to H2RAs (HR 1.23, 95% CI 1.18–1.28; p < 0.0001). Significant dangers were pointed out regarding hip repair/arthroplasty (HR 1.46, 1.35–1.58) and vertebral compression fractures (HR 1.16, 1.09–1.23), while newly diagnosed osteoporosis showed no notable changes (HR 1.01, 0.98–1.03). The negative-control outcome indicated no correlation. In the Asia-Pacific subgroup, the risk of MOF increased by 77% (HR 1.77, 1.56–2.01). Consistent findings emerged from subgroup and sensitivity analyses. The increased fracture risk remained despite comparable demographics, comorbidities, and consistent acid suppression, suggesting that there may be drug-class-specific skeletal toxicity—potentially due to impaired mineral absorption, elevated gastrin levels, and increased bone turnover. The more pronounced effect in East-Asian populations highlights the interaction between dietary and genetic influences. Conclusions Ongoing PPI treatment, in contrast to H2RA therapy, leads to significant increases in the risk of fragility fractures. These findings advocate for a reduction in PPI usage duration, favoring H2RAs for patients at greater fracture risk, and call for proactive measures to safeguard bone health while future studies explore causality and effective strategies for mitigation.