Bone health, renal outcomes, and iron deficiency anaemia in proton pump inhibitor versus histamine-2 receptor antagonist users: a retrospective cohort study based on TriNetX global collaborative network data.

Objective: Proton pump inhibitors' (PPIs) widespread use raises concerns about bone health, renal outcomes, and iron deficiency anaemia (IDA). We aim to address these concerns via comprehensive matching.

Methods: Using TriNetX 1:1 propensity score matching (PSM), we compared PPI and histamine-2 receptor antagonist (H2RA) users in terms of renal outcomes (eg, estimated glomerular filtration rate and chronic kidney disease (CKD) stages), bone health (osteoporosis and fractures), and IDA (International Classification of Diseases codes and laboratory values).

Results: After 1:1 PSM, 126 155 matched patients (mean age 59 years, estimated glomerular filtration rate (eGFR) 84-86 mL/min/1.732 m²) with fewer comorbidities (24% diabetes, 18% ischaemic heart disease, 11% heart failure, 11% nicotine dependence, 4% osteoporosis) were included. After follow-up, patients in the PPI group had a significantly lower mean eGFR compared with those in the H2RA group (75.74 ± 37.56 vs 78.60 ± 35.23 mL/min/1.732 m², p<0.001). The PPI group also demonstrated significantly increased risk of CKD progression, with HR of 1.137 (95% CI 1.120 to 1.154) for stage 3a, 1.260 (95% CI 1.235 to 1.286) for stage 3b, 1.316 (95% CI 1.288 to 1.345) for stage 4, and 1.785 (95% CI 1.718 to 1.854) for stage 5. In addition, PPI users exhibited higher risks of osteoporosis (HR 1.119, 95% CI 1.071 to 1.169) and major bone fractures (HR 1.153, 95% CI 1.110 to 1.198). The risk of IDA was also significantly elevated in the PPI group (HR 1.761, 95% CI 1.691 to 1.835). Findings were consistent across all subgroups and regions.

Conclusion: In this large matched cohort, PPI use was associated with higher risks of CKD, osteoporosis, fractures, and IDA. Clinicians should monitor long-term PPI users for these potential adverse effects.