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

Educational Objective
To evaluate the association between proton pump inhibitor use and risk of fracture in children.
1 Credit CME
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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Article Information

Accepted for Publication: December 4, 2019.

Corresponding Author: Yun-Han Wang, MSc, BPharm, Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Eugeniahemmet T2, 171 76 Stockholm, Sweden (yun-han.wang@ki.se).

Published Online: March 16, 2020. doi:10.1001/jamapediatrics.2020.0007

Author Contributions: Ms Wang and Dr Pasternak had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Wang, Wintzell, Pasternak.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wang.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Wang.

Obtained funding: Pasternak.

Administrative, technical, or material support: Wang, Wintzell, Pasternak.

Supervision: Pasternak.

Conflict of Interest Disclosures: Dr Svanström has received consulting fees from Celgene and is employed by IQVIA, outside of the submitted work. Dr Ludvigsson coordinates on behalf of the Swedish Inflammatory Bowel Disease Register (SWIBREG) a study that has received funding from Janssen Corporation. The other authors declare no conflicts of interest. No other disclosures were reported.

Funding/Support: Swedish Research Council and Frimurare Barnhuset Foundation supported this study, and Dr Pasternak was supported by an investigator grant from the Strategic Research Area Epidemiology program at Karolinska Institutet.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
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  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

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