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

Abstract

To investigate the association between proton pump inhibitor (PPI) use and fracture nonunion risk across different anatomical fracture locations and patient age groups. Design: Retrospective cohort study utilizing propensity score matching to control for confounding variables. Multicenter database analysis (TriNetX). 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). 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). 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). 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 III.