What question did this study set out to answer?

To assess the connection between proton pump inhibitors and nonunion risk across various fracture locations and ages.

December 9, 2025

Proton Pump Inhibitors Are Associated With Increased Risk of Site-Specific Nonunion After Open Reduction Internal Fixation

Key Points

To assess the connection between proton pump inhibitors and nonunion risk across various fracture locations and ages.
Retrospective cohort study design
Analyzed data from a multicenter database (TriNetX)
Patients included those with operative fixation of fractures in specific sites
PPI users had higher nonunion rates in tibia/fibula (4.44% vs 2.21%) and radius/ulna (3.36% vs 1.88%)
Significant hazard ratios indicate increased risk associated with PPI use
Younger patients (ages 18-44) showed the highest vulnerability for tibia/fibula nonunion

Abstract

OBJECTIVES: To investigate the association between proton pump inhibitor (PPI) use and fracture nonunion risk across different anatomical fracture locations and patient age groups. METHODS: Design : Retrospective cohort study utilizing propensity score matching to control for confounding variables. Setting: Multicenter database analysis (TriNetX). Patient Selection Criteria: This study included patients who underwent operative fixation of a fracture of the humerus, radius/ulna, femur, or tibia/fibula corresponding to OTA/AO fracture types 11-13, 21-23, 31-33, and 41-43, respectively. Fractures that occurred between 2015 and 2023 were identified using ICD and CPT codes. Propensity matching balanced cohorts by age, sex, race/ethnicity, comorbidities (e.g., obesity, chronic kidney disease, hypertension), bone health conditions (osteoporosis, osteopenia), and medication use affecting fracture healing (NSAIDs, Denosumab, Alendronate, Vitamin D). Outcome Measures and Comparisons: The primary outcome was rate of fracture nonunion. Comparisons included anatomical fracture site (humerus, radius/ulna, femur, tibia/fibula), and patient age groups (18-44, 45-64, ≥65 years). RESULTS: 410,433 patients were analyzed, with balanced cohorts of PPI users and non-users. PPI use significantly increased nonunion risk in tibia/fibula (4.44% vs 2.21%; HR: 2.08, 95% CI: 1.86-2.31, p <0.0001) and radius/ulna fractures (3.36% vs. 1.88%; HR: 1.85, 95% CI: 1.56-2.20, p <0.0001). The highest vulnerability was among younger patients (ages 18-44) with tibia/fibula fractures (HR: 10.87, 95% CI: 6.95-16.99). Nonunion rates were higher, though not statistically significant for femur (4.34% vs. 3.88%; HR: 1.11, 95% CI: 0.97-1.27, p =0.0958) and humerus fractures (6.06% vs. 5.21%; HR: 1.21, 95% CI: 1.01-1.44, p =0.0802). CONCLUSIONS: Proton pump inhibitor (PPI) use was associated with increased nonunion risk, particularly in tibia/fibula and radius/ulna fractures. Younger patients demonstrated greater susceptibility to PPI-associated nonunion. The findings indicated that PPI exposure may have adversely affected fracture healing in specific anatomical or demographic subgroups and warranted further investigation. LEVEL OF EVIDENCE: Level III.

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