To Örebro University

Background: Proton pump inhibitor (PPI) use has been linked to increased risk of fracture in adults. Despite an increasing trend in prescription of PPIs in children, there is scarce evidence regarding this safety concern in pediatric patients.

Objectives: To evaluate the association between PPI use and risk of fracture in children.

Methods: We conducted a nationwide register-based cohort study of children aged <18 years in Sweden between July, 2006 to December, 2016. The analyzed cohort included 115,933 pairs of PPI initiators and non-initiators matched on propensity score and age. Cox regression was used to estimate hazard ratios (HRs) for a first fracture of any type and 5 subtypes of fracture with follow-up up to 5 years. To address potential residual confounding, high-dimensional propensity score-matching and a direct comparison with histamine-2-receptorant agonists (H2RA) were performed.

Results: During mean 2.2 (standard deviation 1.6) years of follow-up, 5,354 and 4,568 cases of any fracture occurred among PPI initiators and non-initiators, respectively (20.2 versus 18.3 events per 1000 person-years; HR, 1.11; 95%CI, 1.06-1.15). PPI was associated with increased risk of upper limb fracture (HR, 1.08; 95%CI, 1.03-1.13), lower limb fracture (HR, 1.19; 95%CI, 1.10-1.29), other fracture (HR, 1.51; 95%CI, 1.16-1.97) but not head fracture (HR, 0.93; 95%CI, 0.76-1.13) and spine fracture (HR, 1.31; 95%CI, 0.95-1.81). The HRs for fracture according to cumulative duration of PPI use were 1.08 (95%CI, 1.03-1.13) for ≤30 days, 1.14 (95% CI, 1.09-1.20) for31-364 days and 1.34 (95% CI, 1.13-1.58) ≥365 days. The association was consistent in most sensitivity analyses, including high-dimensional propensity score-matching (HR, 1.10; 95% CI, 1.06-1.15), although the analysis of PPI vs H2RA did not reach statistical significance (HR,1.06; 95%CI, 0.97-1.15).

Conclusions: In this large pediatric cohort, PPI use was associated with a small but statistically significant increased risk of any fracture. Risk of fracture should be taken into account when weighing the benefits and risks of PPI treatment in children.