Question
Is proton pump inhibitor (PPI) use associated with increased risk of fracture in children?
Findings
This pediatric cohort compared 115 933 patients who initiated PPI use with 115 933 matched individuals who did not initiate use and found that PPI use was associated with an 11% increased risk of fracture, a significant difference.
Meaning
These data suggest that PPI use is associated with a small increased risk of fracture in children; the findings inform safety considerations when these drugs are prescribed to pediatric patients.
Importance
Proton pump inhibitor (PPI) use has been linked to increased risk of fracture in adults. Despite a trend in prescription of PPIs in children, there is scarce evidence regarding this safety concern in pediatric patients.
Objective
To evaluate the association between PPI use and risk of fracture in children.
Design
This nationwide register-based cohort study included data from Sweden from July 2006 to December 2016. Children younger than 18 years who initiated PPI use were matched on propensity score and age with those who did not initiate PPI use.
Exposure
Initiation of PPI use.
Main Outcomes and Measures
Cox regression was adopted to estimate hazard ratios (HRs) for a first fracture of any type and 5 subtypes of fracture, with follow-up for up to 5 years. To address potential residual confounding, high-dimensional propensity score matching and a direct comparison with histamine-2 receptor antagonists were performed.
Results
There were a total of 115 933 pairs of children included. During a mean (SD) of 2.2 (1.6) years of follow-up, 5354 and 4568 cases of any fracture occurred among those who initiated PPIs vs those who did not, respectively (20.2 vs 18.3 events per 1000 person-years; hazard ratio [HR], 1.11 [95% CI, 1.06-1.15]). Use of PPIs 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]), and other fractures (HR, 1.51 [95% CI, 1.16-1.97]) but not head fracture (HR, 0.93 [95% CI, 0.76-1.13]) or 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 or less, 1.14 (95% CI, 1.09-1.20) for 31 to 364 days, and 1.34 (95% CI, 1.13-1.58) for 365 days or more. 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 histamine-2 receptor antagonist did not reach statistical significance (HR, 1.06 [95% CI, 0.97-1.15]).
Conclusions and Relevance
In this large pediatric cohort, PPI use was associated with a small but 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.