Proton Pump Inhibitor Use in Infants and Children

A Review of the Recent Literature

Marcia L. Buck, PharmD, FCCP, FPPAG, BCPPS


Pediatr Pharm. 2019;25(7) 

In This Article


The association between PPIs and hip, wrist, or spine fractures has been established in nearly a dozen studies.[10] The increased fracture risk appears to be the result of the effects of both increased gastrin production and gastric acid suppression. Hypergastrinemia caused by PPI exposure produces significant elevations in histamine secretion from enterochromaffin-like cells (ECLCs). Higher circulating levels of histamine have been suggested as a mechanism for increased differentiation of osteoclast precursors. Hypergastrinemia may also spur the development of hyperparathyroidism, resulting in increased levels of osteocalcin and alkaline phosphatase, markers of increased bone turnover. Reduction in gastric acid production also results in clinically significant reductions in the absorption of several micronutrients, including vitamin B12, magnesium, and calcium. While not consistent among the studies, the most commonly reported risk factors for fractures include patient age (elderly patients are known to be at higher risk), extended use (1 year or longer), or use of high-dose therapy.[1,3,10] Comorbidities such as osteoporosis or chronic kidney disease, further compound the risk.

A study published by Malchodi and colleagues in the June 2019 issue of Pediatrics is the first to have identified an association between PPI use and fractures in children.[11] The authors conducted a retrospective cohort study of 851,631 children born between 2001 and 2013 who were followed for at least 2 years. Eleven percent received gastric acid suppression in the first year of life: 7,998 (0.9%) received a PPI, 71,578 (8%) were given an H2RA, and 17,710 (2%) received both. Infants given acid suppression therapies had an earlier median age at first fracture (3.9 years versus 4.5 years in the untreated group). The use of a PPI increased fracture hazard by 21% (HR 1.23, 95% CI 1.15–1.32) and the use of an H2RA with a PPI increased it by 30% (HR 1.31, 95% CI 1.25–1.37). There was no significant impact of H2 blocker use alone (HR 1.04, 95% CI 0.99–1.09). Length of treatment with a PPI, with or without an H2RA, and earlier age at initiation of treatment were both positively correlated with increased risk for fractures.