OBJECTIVE: To understand if proton pump inhibitors (PPIs) usage associated with an increased risk of fractures among adult patients diagnosed with autoimmune rheumatic and gastrointestinal diseases, compared with H2 receptor antagonists (H2RAs) usage. METHODS: We used the TriNetX US collaborative database for the study, which includes detailed demographic information, diagnostic and procedural data, medication details, laboratory results, genomic information, and healthcare utilization metrics. We analyzed 61 healthcare organizations to compare fracture risks associated with PPIs and H2RAs in adults, particularly those diagnosed with autoimmune rheumatic and gastrointestinal diseases. Propensity score matching acted as a control for demographic and clinical variables. RESULTS: The study involved 1 717 598 patients, focusing on 16 299 who were new users of PPIs and 16 299 H2RAs users after propensity score matching. Over a 24-month follow-up period, no significant differences in fracture risks were observed between the PPI and H2RA groups in the overall cohort (hazard ratio, HR = 1.369, 95% confidence interval, CI = 0.933-2.009). However, subgroup analysis indicated that senior patients (≥ 65 years) who had been administered PPIs experienced a significantly higher risk of fractures (HR = 1.927 [1.153-3.221]), particularly non-vertebral fractures (HR = 2.379 [1.214-4.661]), when compared to their counterparts who had been prescribed H2RAs. Notably, the simultaneous use of PPIs and glucocorticoids further increased the fracture risk (HR = 4.273 [2.219-8.227]). CONCLUSIONS: The study demonstrates that patients diagnosed with autoimmune rheumatic and gastrointestinal diseases who were aged 65+ face increased fracture risks when using PPIs, particularly when there is a simultaneous intake of glucocorticoids.