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Supplements with Chronic PPI Use?

Darrell Hulisz, RPh, PharmD
Marissa Wagner,

May 4, 2015

A recent study is casting some doubt on whether patients on long-term proton pump inhibitors (PPI) require additional supplementation, such as calcium, vitamin D, vitamin B12, and iron. Data from two prospective trials, one of five years, the other of 12 years of continuous PPI use in over 800 patient showed no clinically relevant changes in vitamin D, vitamin B12 , folate and homocysteine levels over time.

PPIs inhibit the secretion of hydrochloric acid which mediates small intestinal absorption of calcium. Additionally, PPIs may lead to reduced bone resorption of calcium since osteoclasts possess proton pumps that may be affected by PPI therapy. To date, data linking PPI use to increased bone fracture are from retrospective observational studies. The data from these studies have been inconsistent. However, data from the Women's Health Initiative has led to the recommendation that older patients on long-term or high-dose PPI therapy should consider increased dietary or supplementary calcium and vitamin D intake to minimize the risk of fracture. If calcium supplementation is indicated, calcium citrate should be used since it can be absorbed without an acidic environment. The FDA requires that labeling for PPIs include information about a possible increased risk of fractures of the hip, wrist, and spine. An FDA review of several studies found that the patients with the highest risk for these fractures received a high dose of PPI or had duration of therapy longer than one year.

The first step in cobalamin (B12) absorption requires gastric acid and pepsin in order to release cobalamin from dietary proteins. Malabsorption of vitamin B12 may result from atrophic gastritis and achlorhydria. However, the clinical correlation of adverse effects on nutritional status have yet to be determined. In recent reviews, there was no supporting clinical evidence to document the development of B12 deficiency in chronic PPI users. There are currently no guidelines to support routine screening of vitamin B12 levels in patients on PPI therapy.

Gastric acid is necessary to allow absorption of non-heme iron and also enhances iron salt dissociation from ingested food. Theoretically, chronic PPI therapy may result in iron malabsorption due to reduced gastric acid secretion and achlorhydria; and patients with a history of atrophic gastritis have been shown to have iron-deficiency anemia. There are no current recommendations to monitor patients on PPI therapy for iron-deficiency anemia.

The FDA released a warning that hypomagnesemia may occur with PPI use of longer than one year. Magnesium deficiency has been associated with PPI use and does not appear to be dose-related, and has reappeared upon PPI rechallenge. The FDA recommends that a magnesium level be obtained prior to initiation of therapy and periodically thereafter as clinically indicated. It has also been suggested to screen patients with history of cardiac arrhythmias and patients on antiarrhythmic agents for hypomagnesemia if on chronic PPI therapy.

Until evidence-based guidelines become available, it seems prudent to advise patients on chronic PPI therapy to consume a well-rounded diet rich in natural B complex, iron, calcium and magnesium. Concerned patients, or those with malabsorption states and the elderly, can be screened for these deficiencies and supplemented when clinically indicated.

Attwood SE, Ell C, Galmiche JP, Fiocca R, et al. Long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the SOPRAN and LOTUS studies. Aliment Pharmacol Ther. 2015 Apr 10. doi: 10.1111/apt.13194.

Heidelbaugh JJ. Proton pump inhibitors and risk of vitamin and mineral deficiency. Ther Adv in Drug Safe 2013;4(3):125-133.

O'Neill LW, Culpepper BL, Galdo JA. Long-term consequences of chronic proton pump Inhibitor Use. US Pharm 2013;38(12):38-42.

Katz PO, Gerson LB, Vela MF. Diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308-328.

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