Weighing the Benefits versus Potential Risks

Gastroesophageal reflux disease (GERD) occurs when the upper portion of the digestive tract is not functioning properly, causing stomach contents to flow back into the esophagus. Recurring heartburn is the most common symptom; others include the sensation of food or liquid coming up into the throat and a sour taste, as well as several less common symptoms. Recurring symptoms affect up to 29% of Canadians.

Proton pump inhibitors (PPIs) are a class of medications that have emerged as the most effective therapy for relieving symptoms, improving quality of life, and healing and preventing damage to the esophagus. Physicians also prescribe them for ulcer disease and functional dyspepsia. PPIs work by blocking an enzyme in the lining of the stomach that is necessary for acid secretion. Side effects that some patients report include headache, diarrhea, constipation, abdominal pain, and nausea. They usually resolve on their own and patients can usually carry on taking their PPI medication.1

With an increasing number of individuals in Canada taking PPI medications, sometimes on a long-term basis, studies have been focussing on potential risks associated with short- and long-term PPI use.1,2 Researchers have identified a range of potential issues that can arise over time, including bone fractures, vitamin B12 deficiency, low magnesium levels (hypomagnesemia), cardiovascular events, and C. difficile infection. While research is ongoing, this article will focus on the more common issues that you might have heard something about and want clarification.

Despite some alarming headlines, what most of the current research shows is that there are some statistically significant associations between PPI use and several health issues but the full importance of these associations is not yet well understood. Experts consider PPI medications to be generally safe, even for long-term use. They recommend that physicians use rigorous procedures to ensure accurate diagnosing of GERD, prescribe the lowest effective dose, and monitor patients regularly, especially if  they have risk factors for other health problems or are receiving treatment for other medical conditions (comorbidities). As with all prescribing decisions, physician and patient must discuss how the benefits of PPI therapy might or might not outweigh the potential risks.


Osteoporosis and Fractures

In 2013, at Health Canada’s request, PPI manufacturers added a warning to their product monographs regarding an association between PPI use and fracture risk.3 Current research suggests a small increased risk for fractures of the hip, wrist, or spine in patients on PPI therapy. The risk is slightly higher for patients taking multiple daily doses of PPIs and those using PPI therapy for a year or longer.

One frequently-cited study that included 1,211 postmenopausal women showed omeprazole, a type of PPI, to be an independent factor in increased spinal (vertebral) fractures.4 Many others studies have also found an association between some PPI medications and osteoporosis-related fractures (osteoporosis is a disease that causes weakening of the bones, often resulting in fractures) as well as non-osteoporosis-related fractures. However, results are inconsistent, the associations are not strong, some of the studies are of low quality, and researchers don’t yet know exactly how PPI medications could cause bone problems, although impaired intestinal absorption of calcium, folate, vitamin B12, and other nutrients is suspected.1 Some studies show a dose-related association, others show a duration-related association, and yet others show no association with PPI dose or duration and fracture risk. The evidence is conflicting.

The authors of a recent literature review, published in the Journal of Clinical Gastroenterology,1 say that most studies showing an association between PPIs and fractures are observational studies, which cannot alone indicate that PPIs are the cause. An observational study looks at available data (e.g., hospital admissions, diagnoses, prescriptions) and attempts to account for certain associations seen in that data. The review authors say that researchers might confuse patients’ risk factors with other known risk factors for fractures in some of the observational studies.1 For example, if a study is missing some important data that could create a more complete picture of a patient’s health (e.g., timing of PPI therapy or presence of other risk factors for fractures, such as smoking, age, family history), they might mistakenly put more emphasis on PPI use as a cause. The review authors suggest that nutritional deficiency, rather than PPI use, could be the real cause of these associated fractures in many cases.1

Experts don’t currently recommend that physicians monitor individuals on PPIs for bone mineral density or suggest they take calcium supplements. Continuing research will likely provide additional clarity.


Vitamin B12 Deficiency

A 2013 study, published in the Journal of the American Medical Association,5 compared 25,956 patients with a diagnosis of vitamin B12 deficiency to 184,199 patients without the deficiency. All subjects were patients of the Kaiser Permanente Medical Clinic in Northern California between 1997 and 2011. Patients who took PPIs for more than two years were 65% more likely to have a vitamin B12 deficiency. The risk was strongest for individuals on long-term PPI therapy, those taking stronger doses, and among women. The study authors say their results don’t suggest any other risk factors to account for the association. However, the risk is fairly low…. if 67 individuals take PPIs for two years, then 1 of them will have vitamin B12 deficiency.

A recent literature review describes several previous studies with comparable results,2 but this most recent study is the largest to date and the first study based on a broad community population rather than focussing on elderly individuals. Symptoms of vitamin B12 deficiency might include numbness or tingling in the hands, legs, or feet; balance problems; anemia; jaundice; cognitive difficulties, such as memory loss, paranoia, or hallucinations; and weakness or fatigue. If left untreated, some of these symptoms and complications can be irreversible. Treatment might include a simple B12 supplement.



Current scientific literature on this issue consists of several single case reports and a small case series.1,2 A number of these studies show that PPI-related hypomagnesemia is unlikely to occur until at least one year of PPI therapy and most studies show no dosing-related factors. The elderly and those on diuretic and/or digoxin therapy are at a further increased risk. The causal mechanism might have to do with impaired intestinal absorption. Physicians don’t routinely check for low magnesium in PPI users and some researchers think PPI-related hypomagnesemia could occur more often than is documented.

Symptoms of hypomagnesemia include loss of appetite, vomiting, tiredness, weakness, a change in personality, involuntary muscle contractions (tetany), or tremors. There are numerous conditions associated with hypomagnesemia, such as malnutrition, parathyroid gland disorders, alcoholism, diabetes, and others. Experts advise health care providers be aware of potential hypomagnesemia and take note of any presentations, especially among individuals with other risk factors.

Treatment is individualized. In many patients, a simple magnesium supplement will correct the problem.6 Discontinuing PPI therapy and switching to histamine-2 receptor antagonists (H2RAs) for GERD treatment can be helpful for some patients,7 but not if the reason the patient was on PPI therapy was to protect against ulcer-related bleeding (such as those taking NSAIDs), as H2RA medications do not provide the same protection.1


Cardiovascular Effects Related to Clopidogrel

Plavix® (clopidogrel) is a prescription blood thinner medication that helps prevent blood clots in individuals with a history of stroke or heart attack (cardiovascular illness). Many studies have emerged showing an increased risk of cardiovascular events in patients taking some PPI medications (specifically omeprazole) along with clopidogrel.1 The concern is that PPIs might make clopidogrel less effective, resulting in increased risk of cardiovascular events in already-vulnerable patients.1 In 2011, Health Canada advised physicians to avoid prescribing omeprazole and some other PPIs to patients taking clopidogrel. Previously, Health Canada had discouraged any PPI use with clopidogrel, but narrowed the recommendation to include only those PPIs for which there is significant evidence.8 It is likely these recommendations will continue to evolve with future research findings.

A recent randomized control trial (the most reliable type of study), which included 3,873 patients, showed no increase in adverse cardiovascular events with omeprazole and clopidogrel co-therapy.9 Unfortunately, the researchers had to halt this study before completion due to lack of funding. The study authors had intended to follow up with participants for two years or until 143 cardiovascular events occurred (whichever came first), much longer than the 180 days and 106 cardiovascular events covered in the final study. If they had been able to complete the study, they would have had additional cardiovascular events to consider in their analysis.

According to one recent literature review, the available studies are inconsistent, with some studies showing a weak association for only some PPIs.1 Further, research does not yet show a convincing cause/effect relationship. While researchers agree that it is theoretically possible for PPIs to interfere with clopidogrel, research thus far has failed to show such an interaction with any convincing evidence.1 Other studies have shown an increase in cardiovascular events associated with PPI use even without the use of clopidogrel. The review authors suggest that other cardiovascular risk factors that PPI users tend to have more than the average person are what likely puts them at a high risk of cardiovascular events and not the PPI medication itself.1

Additional, high-quality research is required in this area. Overall, experts recommend that patients with a history of cardiovascular problems, or risk factors for such events, should continue to receive PPI medications if they need them, at the lowest effective dose, and only for as long as needed.1,2


C. difficile Infection

In 2013, Health Canada released an advisory of a possible association between the use of PPIs and an increased risk of Clostridium difficile infection (CDI).10 C. difficile is a bacterium that can cause diarrhea and may lead to more serious intestinal conditions. Factors known to increase the risk of infection include advanced age, severe underlying illness, hospitalization, and antibiotic use.

A number of studies have suggested a possible link between PPIs and an increased risk of CDI, particularly in vulnerable patients and those taking higher doses.2,11 PPIs increase gastric pH, which allows any C. difficile that is present to proliferate. In a meta-analysis of 30 trials including 202,965 patients, CDI was significantly greater in patients who had received PPI therapy.2

Health Canada continues to monitor this issue, evaluating the scientific evidence as it emerges. Symptoms of CDI include severe watery or bloody diarrhea (at least three bowel movements per day for two or more days), fever, loss of appetite, nausea, and abdominal pain or tenderness. Persons taking a PPI who develop diarrhea that does not improve should speak to a health care professional immediately.



A growing body of research shows associations between PPI therapy and a number of health issues. While researchers are developing and testing theories, most studies do not yet demonstrate an obvious causal relationship with PPI medications and many do not account for all possible risk factors. Another challenge is that not all PPI medications have the same level of potential risk. Additional, high-quality research will expand our understanding of the associations researchers are observing.

Physicians must be prudent in their prescription decisions, especially among vulnerable patients. If you require a PPI to control GERD symptoms, and the benefits outweigh the potential risks, you should continue to take their medication as prescribed. If you notice any abnormal symptoms, such as those described in this article, then make an appointment to discuss them with your physician.

First published in the Inside Tract® newsletter issue 188 – 2013
1. Chen J et al. Recent Safety Concerns with Proton Pump Inhibitors. Journal of Clinical Gastroenterology. 2012;46(2):93-114.
2. Wilhelm SM et al. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Review of Clinical Pharmacology. 2013;6(4):443.
3. Health Canada. Media Release. Proton pump inhibitors: risk of bone fractures. 2013-04-04. Available at http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/26523a-eng.php. Accessed 2013-12-15.
4. Roux C et al. Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcified Tissue International. 2009;84(1):13-9.
5. Lam JR et al. Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 Deficiency. Journal of the American Medical Association. 2013; 310(22):2435-42.
6. Culpepper BL et al. Long-Term Consequences of Chronic Proton Pump Inhibitor Use. US Pharmacist. 2013;38(12):38-42.
7. Health Canada. Proton pump inhibitors: hypomagnesemia accompanied by hypocalcemia and hypokalemia. Canadian Adverse Reaction Newsletter. 2011;21(3). Available at http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v21n3-eng.php. Accessed 2013-12-15.
8. Health Canada. Media Release. Plavix (blood thinner): New recommendations for use with proton pump inhibitors (antacids). 2011-09-22. Available at http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2011/13545a-eng.ph. Accessed 2013-12-15.
9. Bhatt DL et al. Clopidogrel with or without Omeprazole in Coronary Artery Disease. New England Journal of Medicine. 2010;363(20): 1909-17.
10. Health Canada. Media Release. Proton pump inhibitors (antacids): possible risk of Clostridium difficile-associated diarrhea. 2012-02-16.
11. Howell MD et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Archives of Internal Medicine. 2010;170(9):784-90.