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

  • Wang, Yun-Han1
  • Wintzell, Viktor1
  • Ludvigsson, Jonas F2, 3, 4, 5
  • Svanström, Henrik1, 6
  • Pasternak, Björn1, 6
  • 1 Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 2 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 3 Department of Pediatrics, Örebro University Hospital, Örebro, Sweden. , (Sweden)
  • 4 School of Medicine, Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom. , (United Kingdom)
  • 5 Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York.
  • 6 Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. , (Denmark)
Published Article
JAMA pediatrics
Publication Date
Jun 01, 2020
DOI: 10.1001/jamapediatrics.2020.0007
PMID: 32176276


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. To evaluate the association between PPI use and risk of fracture in children. 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. Initiation of PPI use. 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. 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]). 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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