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Association Between Proton Pump Inhibitor Use and Risk of Fracture in Children
Yun-Han Wang1, Viktor Wintzell1, Jonas F Ludvigsson2,3,4,5
1Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
Insights
Proton pump inhibitor (PPI) use in children is linked to a small but significant increase in fracture risk. Healthcare providers should consider this when prescribing PPIs to pediatric patients.
Area of Science:
- Pediatric Gastroenterology
- Pharmacovigilance
- Bone Health
Background:
- Proton pump inhibitor (PPI) use is increasing in children.
- Evidence linking PPIs to fracture risk in adults exists.
- Safety data on PPIs and fracture risk in pediatric populations is limited.
Purpose of the Study:
- To investigate the association between PPI use and fracture risk in children.
- To evaluate the risk of various fracture types in pediatric PPI users.
Main Methods:
- Nationwide, register-based cohort study in Sweden (2006-2016).
- Propensity score matching of children initiating PPI use with non-users.
- Cox regression analysis to determine hazard ratios (HRs) for fractures over up to 5 years follow-up.
Main Results:
- Over 115,000 child pairs were analyzed.
- PPI use was associated with an increased risk of any fracture (HR, 1.11).
- Increased risk observed for upper-limb, lower-limb, and other fractures; no significant association with head or spine fractures.
Conclusions:
- PPI use in children is associated with a small but statistically significant increase in fracture risk.
- The risk of fracture should be considered when evaluating the benefits and risks of PPI therapy in 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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