Reported Side Effects and Complications of Long-term Proton Pump Inhibitor Use

Dissecting the Evidence

David A. Johnson; Edward C. Oldfield IV


Clin Gastroenterol Hepatol. 2013;11(5):458-464. 

In This Article

Effects on Vitamin and Mineral Absorption


Nonheme iron (ferric, Fe 3+) constitutes the majority of dietary iron consumed. To be absorbed by duodenal enterocytes, this iron subsequently must undergo a reduction into the ferrous state (Fe 2+), mediated by hydrochloric acid released from the stomach. In vivo data have shown that this absorption is related directly to the release of ferric iron by gastric juice.[2] There also is evidence suggesting that this process is related more specifically to the vitamin C released in gastric secretions, which acts as a reducing agent and prevents the formation of insoluble compounds.[3] Although there is concern regarding evidence that PPIs may reduce the bioavailability of ingested vitamin C, long-term follow-up evaluation of patients taking chronic daily PPIs for up to 7 years has not shown iron absorption to be clinically apparent.[4,5] Further, most cases of iron malabsorption can be managed clinically with the use of medicinal iron supplements that are absorbed independent of gastric acid and vitamin C.[6]

To date, only one study has addressed the association between PPI use and the development of iron-deficiency anemia. This study found that among patients receiving chronic PPI therapy there was a significant decrease in all hematologic indexes from baseline.[7] Despite these findings, the study suffered from a number of drawbacks including small sample size, limited serial ferritin levels to properly determine iron-deficiency anemia, and the inability to exclude a number of potential confounders. Given these limitations, this study did not offer a definitive answer on the topic.

Bottom Line. Although it is conceivable that PPI therapy may reduce absorption of nonheme iron and retard iron pool replenishment, this effect has not been well studied or evident from widespread use in clinical practice.


The absorption of dietary calcium is believed to be mediated by gastric acid release of ionized calcium from insoluble calcium salts. Hence, there have been concerns that hypochlorhydric states, in particular those induced by PPIs, may impair calcium absorption; however, there are limited data to support this claim; in fact 2 high-quality studies showed no adverse effect.[8,9] Overall, the studies suggested that calcium absorption potentially was affected negatively only in the setting of reduced acid secretion when ingested calcium carbonate was provided in the fasting state. Despite this, in 2010 the FDA issued a product label warning for all PPIs because of clinical reports inferring increased risk for bone fractures. The FDA revised this warning in March of 2011 to release over-the-counter PPIs, which are intended for short-term use (ie, 2 weeks) for up to 3 cycles per year.[10]

Literature analysis of PPI use and bone fractures revealed conflicting results. The earlier published reports linking PPI use to the development of hip fractures were observational case-control studies and thereby have greater potential for bias and therefore less accurate estimates. In addition, the strength of association in the PPI studies has been of low magnitude. Given that the estimates and even the upper bounds of most of the 95% confidence intervals (CIs) of the odds ratios (ORs) were well below 2, there is a strong possibility these differences could have been related to the channeling bias inherent in observational studies.[11] For example, a prospective study including 79,899 postmenopausal women from the US Nurse's Health Study showed that despite an OR of 1.36 (95% CI, 1.13–1.63) for PPI use, when accounting for a history of smoking, there was no significant association between PPI use and fracture risk (OR, 1.06; 95% CI, 0.77–1.46).[12] More recent studies have shown an association between PPI use and hip fracture risk, yet there was no evidence to suggest a duration effect from long-term PPI use (OR, 1.30; 95% CI, 0.98–1.70) as compared with short-term use (OR, 1.24; 95% CI, 1.19–1.28).[13] This suggests that the observed association likely was owing to confounding factors. In addition, other recent cross-sectional, longitudinal, and prospective observational reports did not support the prior reported association.[14,15] Even more convincing evidence supporting the lack of harm comes from a recently published population-based sample of Canadians who underwent bone mineral density (BMD) testing of the femoral neck, total hip, and lumbar spine at baseline, and then again at 5 and 10 years. In all, 8340 subjects were included in the baseline analysis, with 4512 (55%) undergoing year 10 BMD testing. After adjusting for potential confounders, PPI use was associated with significantly lower baseline BMD at the femoral neck and total hip. By multivariate linear regression, however, there was no evidence of any acceleration in covariate-adjusted BMD loss at any measurement site after 5 and 10 years of follow-up evaluation. Therefore, PPI users had lower BMD at baseline than PPI nonusers, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. It would be paradoxic that there would be an element of risk at entry and that longer duration of exposure would not amplify any risk effect.[16]

Contrary to their purported role in increasing the risk for fractures, PPIs actually may increase bone density through their impairment of osteoclast activity. Osteoclasts contain vacuolar proton pumps necessary for acidification at the ruffled border, which facilitates dissolution of the bone matrix and its subsequent resorption.[17] Patients on PPIs have decreased levels of urinary calcium and hydroxyproline, suggesting decreased osteoclast activity and bone resorption. In addition, these patients have increased levels of the osteoblast precursors, osteocalcin and tissue-resistant alkaline phosphatase, suggesting new bone formation.[18]

Bottom Line. There is no good evidence to establish that PPI use has a significant risk for bone density loss or osteoporotic-related fractures. Accordingly, the data on bone density loss and osteoporotic fractures would not support that PPI therapy be discontinued in patients taking PPIs for appropriate indications at appropriate doses. Supplemental calcium is not recommended or justified solely because of PPI use.


There have been several (total, <50) cases of hypomagnesemia that were associated with long-term PPI use.[19–21] The patients generally presented with profound hypomagnesemia and typically required hospitalization. In approximately 25% of these cases, the patients had persistent hypomagnesemia despite supplements. Prompt resolution of magnesium levels was evident after discontinuance of the PPIs, and in a few cases in which the patients were rechallenged with a PPI, the hypomagnesemia recurred, suggesting a PPI-related effect. None of the patients had identifiable GI wasting or renal loss etiologies. A recent systematic review on this association concluded that there was no typical patient profile that was unique for PPI-related hypomagnesemia and the final attribution to the symptoms and electrolyte abnormalities sometimes took years; in the absence of symptoms, identification of PPI-related hypomagnesemia was purely dependent on chance.[22] In addition, data from this review further support a PPI class effect because there is evidence that subsequent treatment with H2RAs prevents the recurrence of hypomagnesemia. Together, these case reports prompted a recent alert by the FDA about PPI use and hypomagnesemia.[23] Although it originally only was cited for omeprazole and esomeprazole, it was later revised to cover PPIs as a class. This alert suggested that health care providers should consider checking magnesium levels in patients who are anticipated to be on long-term PPIs.

The mechanism for the magnesium depletion is not known. The primary absorption of magnesium is through a passive pathway in the small intestine. There is some identifiable active transport, however, via transport channels (transient receptor potential and magnesium transporter 6 and 7).[24] It is not known if PPIs may have some effect on this pathway, but there are familial cases with mutations at this pathway who develop hypomagnesemia.

Bottom Line. The FDA recommendation to consider checking magnesium levels before starting is not practical, in particular for the over-the-counter market. In patients who may be predisposed to present or ongoing magnesium loss from intestinal malabsorption or renal excretion and wasting, it may be reasonable to follow up magnesium levels more closely and consider this association, particularly if profound hypomagnesemia develops. Given the extreme rarity of the reports and no controlled studies to delineate the mechanisms, it is important for health care providers to be aware of this, but keep PPIs where clinically justified.

Vitamin B12

Gastric acid is involved in the absorption of B12 by facilitating its release from dietary protein, such that B12 can bind to R proteins. This B12–R protein complex is broken down in the duodenum and, subsequently, B12 can be absorbed in the terminal ileum once bound to intrinsic factor. Because B12 absorption is dependent on gastric acid, theoretically, long-term PPI use may impair an individual's absorptive ability.

Bottom Line. Studies examining the potential relationship between PPIs and B12 have shown conflicting results, and a prospective trial is needed to conclude any causative effect.[25,26,27,28,29] In addition, to date no studies have provided a longitudinal evaluation showing alterations of specific metabolic intermediates (eg, methylmalonate and homocysteine), which can accumulate with this deficiency. Further, because hypochlorhydria would only impair the release of B12 from dietary protein, absorption of oral B12 supplements should be unimpaired.[26]

Alteration of Pharmacodynamics: Clopidogrel

PPIs are metabolized by the cytochrome P450 pathway, specifically CYP2C19 and CYP3A4. As a prodrug, clopidogrel requires a biotransformation to be converted into its active form, a process also mediated by the CYP2C19 and CYP3A4 enzymes.[27] This reliance on the same pathway has led to the hypothesis that competition at CYP2C19 may reduce the biological activity of clopidogrel. This is supported by in vitro studies that showed a pharmacodynamic interaction, which was an attenuated antiplatelet effect as measured by adenosine diphosphate–induced platelet aggregation and increased platelet activity.[28] More recent evidence has suggested that this effect is related more closely to the reduced function of CYP2C19*2 and *3 alleles.[29,30] This is an important consideration when analyzing potential competition between PPIs and clopidogrel because these polymorphisms are quite prevalent, affecting 30% of whites, 40% of blacks, and 55% of East Asians.[31]

In January 2009, the FDA issued a recommendation against the combined use of clopidogrel and all PPIs, subsequently revising their statement to recommend against potent CYP2C19 inhibitors, naming omeprazole, esomeprazole, and cimetidine.[32,33] This recommendation was based on several high-profile retrospective database evaluations that found higher cardiac event rates (stent thrombosis, myocardial infarct, and death) in patients who were taking clopidogrel with any PPI vs those on clopidogrel alone.[34,35] In stark contrast, around this same time the leading clinical gastroenterology and cardiology national societies issued consensus recommendations supporting the combined use for patients at increased risk for GI bleeding.[36]

Despite the FDA's recommendation against specific PPIs, the most recent meta-analysis on the subject found no consistent evidence for intraclass differences among PPIs when used with clopidogrel.[37] Early studies suggested that pantoprazole, a less-potent inhibitor of CYP2C19, would have less of an effect on clopidogrel, and the current product labeling indicates no reduction of effect on concomitant dosing with clopidogrel; however, a recent placebo-controlled randomized trial showed a significant reduction on the antiplatelet effect.[38] Despite this, combination therapy did not significantly increase the risk of adverse cardiovascular events. Another recent study comparing the potential antiplatelet interference effect on co-therapy of dexlansoprazole with clopidogrel showed bioequivalence to placebo and a product label change was made in May 2012 indicating that there was no physiological reduction in clopidogrel effect when these drugs were used concomitantly.[39]

A literature review suggests that the original reasons for the perceived intraclass differences most likely arose from a channeling bias—the tendency among physicians to prescribe certain medications for certain patient populations.[40,41] A cohort of 23,000 patients from the Veterans Administration Pharmacy Benefits Management Database showed that omeprazole was the most commonly prescribed PPI (88%), with esomeprazole, lansoprazole, rabeprazole, and pantoprazole accounting for the remainder.[42] In fact, the most recent post hoc database assessment (using the Veterans Administration database) did suggest an apparent cardiovascular harm for combined use, but when the investigators used propensity-matched evaluations to correct for covariate cardiovascular risks and medication compliance, they found no significant association between major cardiovascular events and use of clopidogrel with continuous, switched, or discontinued PPIs.[40] In addition, a systematic review of 19 studies showed that considerable heterogeneity among the studies did not allow for the demonstration of a clear interaction between clopidogrel and PPIs in platelet function studies.[43]

Bottom Line. The current literature questions the exact relationship between ex vivo platelet assays and clinical outcomes, especially with regard to the assessment of drug interactions. Although the platelet assays and observational data may be factual, they are not always appropriate for extrapolation into clinical care. Given the lack of concise randomized controlled trial data, appropriate assessment of the patient is the key consideration. For patients showing signs and symptoms of acid-related disease or patients meeting risk criteria for GI nonsteroidal anti-inflammatory drug injury prophylaxis, there is evidence to support the concomitant use of PPIs.