Differential fracture risk among proton pump inhibitors in older adults: evidence network and pharmacovigilance validation.

BACKGROUND

Proton pump inhibitors (PPIs) are the first-line therapy for acid-related disorders, with particularly high rates of chronic use in adults aged ≥65 years. Nearly all existing studies treat PPIs as a uniform drug class, overlooking potential heterogeneity in fracture risk across individual agents. This study aimed to evaluate the relative fracture risk of individual PPIs in elderly adults, using a complementary dual-method approach of network meta-analysis (NMA) and disproportionality analysis.

METHODS

First, we performed a NMA to compare the relative risk of any-site fracture associated with individual PPIs. Second, we performed a complementary disproportionality analysis using data from the US FDA Adverse Event Reporting System (FAERS) database, with additional analysis of osteoporosis/osteopenia events defined by the Standardised Medical Dictionary for Regulatory Activities (MedDRA) Standardised Query (SMQ).

RESULTS

The NMA included 9 eligible studies, enrolling a total of 257,445 participants. Compared with non-PPI users, omeprazole (OR 1.51, 95%CI 1.36-1.67), rabeprazole (OR 1.47, 95%CI 1.22-1.78), pantoprazole (OR 1.44, 95%CI 1.28-1.62), and lansoprazole (OR 1.32, 95%CI 1.14-1.53) were associated with a significantly increased risk of any-site fracture. In contrast, esomeprazole showed no significant association with overall fracture risk (OR 1.16, 95%CI 0.97-1.38). Pairwise comparisons from the NMA showed that esomeprazole had a lower relative fracture risk compared with other individual PPIs. In the FAERS analysis, we identified 16,908 PPI-related fracture adverse events. Consistent with NMA findings, omeprazole exhibited a significant fracture risk signal (ROR 1.25, 95%CI 1.03-1.51), while esomeprazole showed no significant signal for overall fracture (ROR 0.89, 95%CI 0.66-1.20). However, esomeprazole presented a strong positive risk signal in the narrow-scope MedDRA SMQ analysis for Osteoporosis/Osteopenia (ROR 2.44, 95%CI 1.41-4.20).

CONCLUSION

Long-term PPI use is associated with increased fracture risk in elderly adults, with significant heterogeneity in bone safety profiles across individual PPI agents. Although esomeprazole was not significantly associated with fracture risk in NMA or FAERS fracture analyses, it showed a strong narrow-scope osteoporosis/osteopenia SMQ signal. This discordance indicates that absence of a fracture signal should not imply skeletal safety. These findings provide evidence-based guidance for individualized PPI prescribing in elderly patients, with careful benefit-risk assessment for those requiring extended-duration PPI regimens.