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Original Investigation
March 16, 2020

Association Between Proton Pump Inhibitor Use and Risk of Fracture in Children

Author Affiliations
  • 1Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
  • 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 3Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
  • 4School of Medicine, Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom
  • 5Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York
  • 6Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
JAMA Pediatr. Published online March 16, 2020. doi:10.1001/jamapediatrics.2020.0007
Key Points

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.

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