Proton Pump Inhibitors Associated With Increased Risks of Fractures and Asthma in Children

Recently published research found a link between use of proton pump inhibitors (PPIs) and an increased risk of developing fractures and asthma in children and adolescents.

Proton pump inhibitors (PPIs) are approved by the Food and Drug Administration (FDA) for treating several stomach-acid–related disorders, including gastroesophageal reflux disease (GERD) and intestinal and stomach ulcers.[1] PPIs include dexlansoprazole (DEXILANT), esomeprazole (NEXIUM), lansoprazole (PREVACID), omeprazole (PRILOSEC, ZEGERID), pantoprazole (PROTONIX) and rabeprazole (ACIPHEX). All are approved by the FDA for treating GERD in children, including infants in some cases.[2],[3],[4],[5],[6],[7]

PPIs act by completely inhibiting the secretion of stomach acid. By comparison, histamine-2 (H2) blockers, such as cimetidine (TAGAMET), famotidine (PEPCID) and ranitidine (ZANTAC), only partially prevent such acid production. Over-the-counter (OTC) antacids, such as calcium carbonate (TUMS), act by neutralizing stomach acid after it is secreted.

Public Citizen’s Health Research Group has classified PPIs as Limited Use for GERD because behavioral modifications (such as reducing intake of fatty foods, caffeine and alcohol; quitting smoking; wearing loose clothing; and avoiding late-night eating) should be the first-choice therapy. Antacids and H2 blockers are safe and fast-acting second-line options. Additionally, PPIs, particularly with long-term use, are associated with an increased risk of a severe type of diarrhea caused by Clostridium difficile infection, low blood magnesium levels, vitamin B12 deficiency and osteoporosis-related fractures.

New fracture study

A study published in the June 2020 issue of the Journal of the American Medical Association (JAMA) Pediatrics found that PPI use in children was associated with a small increased risk of fractures.[8]

The researchers studied fracture risk associated with PPIs in children because PPI-induced gastric-acid changes may lead to impairment in calcium absorption. They further note that a previously published analysis of 32 observational studies in the elderly at high risk of fracture indicated that PPI use increased fracture risk by a statistically significant 30%.[9] The few prior observational studies in children that examined use of PPIs and fracture risk provided conflicting results.[10],[11]

Accordingly, to better understand the risks of PPI use in children, the new JAMA Pediatrics study utilized Sweden’s National Patient Register database combined with national pharmacy and vital records. For the period from July 2006 to December 2016, researchers identified approximately 117,000 children (age 0 to 17 years) who used PPIs and 2.3 million who did not. Statistical one-to-one matching techniques were used to create two groups of about 116,000 children each, one of PPI users and one of non-PPI users. The groups were matched for age, sex, parental education and income, and various medical factors including cardiovascular disease, inflammatory disease, psychiatric disorders, falls and the use of various types of medical services, including specific drugs.

The researchers found that for each 1,000 person-years studied there were 20.2 fractures in the children exposed to PPIs and 18.3 in those not exposed to PPIs, corresponding to a significant 11% increase in the risk of fractures. A further analysis comparing children who used PPIs for 1 to 30 days, 31 to 364 days, or more than 364 days with children who never used PPIs revealed that increasing duration of PPI use was associated with gradually increasing risk of fracture (8%, 14% and 34%, respectively).

The researchers concluded that the increased risk of fracture should be considered when weighing the risks and benefits of PPI therapy in children.

New asthma study

The same group of researchers who published the study on fracture risk with PPI use also published a separate study on PPI use and asthma in the April 2021 issue of JAMA Pediatrics.[12] The second study found that PPI use in children was associated with an increased risk of asthma.

The researchers noted that understanding the factors that contribute to the development of asthma is of great public health importance because it affects about 14% of children globally.[13] They further remarked that PPI inhibition of stomach acid is known to alter bacteria in the gut and lungs, changes that have been linked to asthma flares. The one previous study of this topic found that PPI use in infants up to age six months was associated with a 41% increase in asthma risk.

The asthma study used data and analytic methods nearly identical to those of the fracture study. Data was obtained from the same Swedish registries for the period from January 2007 to June 2016. The researchers created two similarly matched groups of approximately 81,000 children (age 0 to 17 years), one treated with PPIs and the other never treated with PPIs.

The researchers found that for every 1,000 person-years of follow-up, 22 new cases of asthma were diagnosed in children treated with PPIs compared with only 14 new asthma cases in children never treated with PPIs. This difference corresponded to a significant 57% increase in the risk of asthma. Interestingly, in contrast to the fracture study, a further analysis comparing children who used PPIs for 1 to 30 days, 31 to 364 days, or more than 364 days with children who never used PPIs found a similar level of increased risk of asthma regardless of the cumulative duration of PPI use (52%, 51% and 59%, respectively).

The researchers concluded that given the increased risk of asthma, PPIs should only be prescribed to children when they are clearly indicated and only after weighing the potential benefits against the potential risks.

What You Can Do

If you have a child or adolescent experiencing gastroesophageal reflux disease, first try non-drug remedies such as reducing exacerbating foods or late-night meals. If these measures do not work, talk to your child’s doctor about OTC medications such as simple antacids or H2 blockers. If short-term use of those medications fails, then consult with your physician about other remedies that might include the limited use of PPIs. Finally, if PPIs are prescribed, work with your child’s doctor to mitigate the risks of such medications, including the risks of sustaining a bone fracture or of developing asthma.
 

References

[1] Review of the popular stomach-acid suppressant proton pump inhibitor drugs. Worst Pills, Best Pills News. July 2019. https://www.worstpills.org/newsletters/view/1272. Accessed April 12, 2021.

[2] Takeda Pharmaceuticals America, Inc. Label: dexlansoprazole (DEXILANT). November 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022287s034lbl.pdf. Accessed April 13, 2021.

[3] AstraZeneca Pharmaceuticals LP. Label: esomeprazole (NEXIUM). November 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021153s057,021957s024,022101s021lbl.pdf. Accessed April 13, 2021.

[4] Takeda Pharmaceuticals America, Inc. Label: lansoprazole (PREVACID). November 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020406s092,021428s039lbl.pdf. Accessed April 14, 2021.

[5] Covis Pharma. Label: omeprazole (PRILOSEC). November 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022056s023lbl.pdf. Accessed April 14, 2021

[6] Pfizer. Label: pantoprazole (PROTONIX). November 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020987s056,022020s018lbl.pdf. Accessed April 15, 2021.

[7] Eisai Inc. Label: rabeprazole (ACIPHEX). November 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020973s041lbl.pdf. Accessed April 12, 2021. [See “Label_ACIPHEX.pdf,” PDF page 1, INDICATIONS AND USAGE]

[8] Wang YH, Wintzell V, Ludvigsson JF, et al. Association between proton pump inhibitor use and risk of fracture in children. JAMA Pediatr. 2020;174(6):543-551.

[9] Liu J, Li X, Fan L, et al. Proton pump inhibitors therapy and risk of bone diseases: An update meta-analysis. Life Sci. 2019 Feb 1;218:213-223.

[10] Wagner K, Wagner S, Susi A, et al. Prematurity does not increase early childhood fracture risk. J Pediatr. 2019 Apr;207:148-153.

[11] Freedberg DE, Haynes K, Denburg MR, et al. Use of proton pump inhibitors is associated with fractures in young adults: a population-based study. Osteoporos Int. 2015;26(10):2501-2507.

[12] Wang YH, Wintzell V, Ludvigsson JF, et al. Association between proton pump inhibitor use and risk of asthma in children. JAMA Pediatr. 2021;175(4):394-403.

[13] Pearce N, Aït-Khaled N, Beasley R, et al; ISAAC Phase Three Study Group. Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax. 2007;62(9):758-766.