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Long-term Consequences of Chronic Proton Pump Inhibitor Use

Here is the latest information regarding a subject which is of great concern to many of us :-

ACKNOWLEDGEMENT :- medscape.com

LeAnn W. O'Neill, PharmD, Benjamin L. Culpepper, PharmD, John A. Galdo, PharmD, BCPS


US Pharmacist. 2013;38(12):38-42.

Abstract and Introduction


Proton pump inhibitors (PPIs), available with or without a prescription, are commonly used for the treatment of acid-related

disorders. Despite their ease of availability and common use, PPIs can have severe side effects. The long-term

consequences of chronic PPI use include the potential increased risk of hypocalcemia, hypomagnesemia, Clostridium

difficile infections, and pneumonia. Community pharmacists are poised to provide evidence-based recommendations and

educate patients about the benefits and risks associated with chronic PPI use.


Proton pump inhibitor (PPIs) have been on the market since the late 1980s and have replaced the histamine2 receptorantagonists

(H2RAs) as the most potent class of drugs for the treatment of acid-related diseases.[1] Anti-ulcer medications

(therapeutic areas are based on proprietary IMS Health definitions) were the ninth largest class based on prescription

volume in the United States in 2012 and the 11th in sales.[2,3]

Medications in the PPI class are widely available with or without a prescription. Currently, the U.S. market contains six PPIs,

two of which are also available as OTC products ().[4–9] In the early 2000s, the FDA announced the availability of

omeprazole (Prilosec OTC) as the first OTC PPI.[10] It was soon followed by the approval of OTC lansoprazole (Prevacid


PPIs are used for the treatment of many gastric conditions including peptic ulcer disease, eradication of Helicobacter pylori

infections, treatment and prevention of nonsteroidal anti-inflammatory drug (NSAID) gastroduodenal ulcer, Zollinger-Ellison

syndrome, and gastroesophageal reflux disease (GERD).[1] Generally, these medications are prescribed because of the low

incidence of side effects and superior efficacy compared to other drugs used to treat the same conditions.[1]

Long-term use of any medication raises safety concerns, especially if that product is available OTC. The American

Gastroenterological Association (AGA) released guidelines on the management of GERD in 2008 that recommended against

routine monitoring for PPIs due to insufficient evidence.[12] However, since then studies have continued to show long-term

consequences from chronic PPI use including malabsorption consequences and infections. Subsequently, in March 2013,

the American College of Gastroenterology (ACG) released guidelines for the diagnosis and treatment of GERD.[13] These

guidelines do provide some insight into monitoring for long-term consequences of chronic PPI use. This article is a review of

the recent literature and guideline recommendations regarding the possible long-term consequences of chronic PPI

pharmacotherapy and opportunities to prevent these complications.

In animal studies, PPIs raised concerns about a potential for hypergastrinemia, but human studies failed to show an

association.[1] Therefore, long-term consequences of chronic PPI use can be grouped into two main categories,

malabsorption and infections.[1] Malabsorption secondary to PPI use affects calcium and magnesium, and the literature

specifies two infections most often associated with PPI use, Clostridium difficile and pneumonia. Unfortunately, a definition in

the literature for "long-term" is lacking; neither the AGA guidelines nor the ACG guidelines define what is considered

long-term. For the rest of this article, the authors use long-term to designate therapy greater than 14 days, the maximum

therapy for the OTC products.[10,11]


The first potential long-term consequence of chronic PPI use is malabsorption of key minerals in the body, namely calcium

and magnesium. The loss of these minerals could lead to bone fractures or cardiac abnormalities.

Decreased Calcium Absorption (Hypocalcemia)

Long-term PPI use has been associated with an increased risk of osteoporosis and decreased bone mineral density (BMD),

with a 35% increased risk of fractures.[14] Calcium serves an important role in bone health and formation, as it is a key

component of hydroxyapatite (the main structural element of bone). Bone material is a major reservoir for calcium and may

contain greater than 99% of a body's calcium.[15] The hypothesis for the mechanism of PPI-induced bone fractures is that

dietary calcium absorption is dependent upon an acidic environment in the gastrointestinal (GI) tract. Due to the decrease in

acidity from the pharmacologic effect of PPIs, a potential loss of calcium absorption occurs. This reduction in calcium

absorption leads to decreased osteoclastic activity and thus decreases in BMD, thereby increasing fracture risk.[1]

The 2013 ACG guidelines on GERD state that existing osteoporosis is not a contraindication to PPI therapy.[13] Patients with

osteoporosis may remain on PPI therapy unless another risk factor for hip fracture exists.[13] Furthermore, in March 2011,

the FDA modified its osteoporosis and fracture warning. It was concluded that OTC products do not warrant label changes to

include warnings of fracture risk.[16]

However, several studies have demonstrated an association between long-term PPI use and risk of fractures, but they

contain numerous confounders. Common risk factors for fractures such as a sedentary lifestyle and concomitant use of

certain medications (e.g., thiazide diuretics, hormone replacement therapy, corticosteroids) are often observed in patients

who routinely take PPIs.[14] Additionally, patients who take high doses of PPIs are at higher fracture risk versus patients who

take lower OTC doses.[17] Finally, patients who take PPIs for extended periods of time (>1 year) are more likely to

experience a fracture.[18]

An analysis of the data obtained from the Canadian Multicentre Osteoporosis Study revealed that the use of PPIs was

associated with lower BMD, particularly at the hip and femoral neck, when compared to non-PPI use.[19] However, long-term

PPI use was not associated with an accelerated decline in BMD. Targownik et al reported that patients using PPIs did have

lower BMD; however, these patients were significantly older (66.3 vs. 60.9 years; P <.001) and had a higher mean body

mass index (BMI) (28.3 vs. 26.9; P <.001).[19]

Data remain relatively inconclusive and conflicting regarding the magnitude of the PPI and fracture association in the

absence of additional risk factors. According to the 2013 ACG guidelines, there is insufficient evidence to warrant routine

BMD tests, calcium supplementation, or other routine precautions because of PPI use.[13] In contrast, Health Canada issued

an alert in April 2013 stating that patients with existing risk factors for osteoporosis should be monitored closely and should

also receive short-term PPI therapy at the lowest effective dose.[20] This is parallel to current recommendations from the

FDA despite the lack of recommendations from the ACG.[16] If calcium supplementation is indicated, use of calcium citrate is

the preferred calcium supplement in patients taking PPIs, as it can be absorbed in the absence of an acidic environment.[1]

Decreased Magnesium Absorption (Hypomagnesemia)

In March 2011, the FDA released a warning regarding low serum magnesium levels associated with long-term use of

PPIs.[21] An analysis of reports from the FDA's Adverse Event Reporting System (AERS) states that approximately 1% of

patients who experienced an adverse effect while on a PPI experienced hypomagnesemia.[21] The mechanism behind the

changes in absorption is unknown. Symptoms of hypomagnesemia include seizures, arrhythmias, hypotension, and tetany.

Hypomagnesemia is also potentially fatal.[22] Hypomagnesemia related to chronic PPI use was not addressed in the 2013

ACG guidelines.[13]

All PPIs are associated with decreased magnesium absorption.[21] Hypomagnesemia was more common in older patients

taking a PPI (mean age 64.4 years).[21] Mean time to onset of hypomagnesemia was 5.5 years after initiation of therapy.[21]

Similarly, a systematic review of case reports found that patients who presented with hypomagnesemia in association with

PPI use also presented with other electrolyte disturbances, specifically hypokalemia and hypocalcemia.[23]

Hypomagnesemia generally resolved with the discontinuation of the PPI and recurred soon after the PPI was


Concurrent use of medications that also decrease magnesium increases the risk of significant hypomagnesemia. Danziger

et al reported that patients who take a PPI with a diuretic have nearly a 55% greater risk of hypomagnesemia than patients

who take only a PPI.[22]

An FDA Drug Safety Communication warns of the risks of hypomagnesemia and recommends that providers monitor serum

magnesium levels in patients taking PPIs.[21] The FDA suggests that providers obtain serum magnesium levels prior to

initiation of therapy and periodically thereafter for patients who will continue prolonged treatment and for patients who take

medications that also cause hypo-magnesemia. Patients who present with clinically significant hypomagnesemia may

require discontinuation of PPI therapy, magnesium replacement via oral or IV methods, and treatment with an alternative

class of drugs for GI conditions such as an H2RA.[1]


In addition to decreased magnesium and calcium absorption, patients on long-term PPIs may be at an increased risk of

infection. The hypothesis for the mechanism of action is that the gastric acid secretions act as a defense mechanism against

enteric bacteria, and the increased gastric pH during PPI use allows for colonization of opportunistic microbes.[1] The 2013

ACG guidelines warned about the risk of increased infections of C difficile and community-acquired pneumonia (CAP).[13]

Clostridium difficile

In a 2005 retrospective study, researchers found that patients who were taking PPIs had a hazard ratio (HR) of 2.9 (95% CI,

2.4–3.4); i.e., patients had a 2.9-fold increase in the risk of acquiring C difficile than patients who were not on a PPI.[25]

Seventy-five percent of the patients with reported cases were over the age of 65 years. Not only does long-term use of PPIs

cause an increased incidence of C difficile, but patients who received a PPI during treatment of C difficile were also 42%

(95% CI, 1.11–1.82) more likely to have a recurrent infection after finishing therapy.[25]

A 2010 study by Linsky et al looked at the association of PPI use and recurrent C difficile. [26] The authors determined

whether or not the patient had an infection with recurrent C difficile, 15 to 90 days after initial C difficile infection, if the patient

received a PPI within 14 days of initial C difficle infection. The HR for patients exposed to PPIs during treatment was 1.42

(95% CI, 1.11–1.82). For patients over the age of 80 years, the HR increases from 1.42 to 1.86 (95% CI, 1.15–3.01).[26]

In 2012, the FDA issued a statement detailing the relationship between C difficile–associated diarrhea (CDAD) with the use

of a PPI.[27] The FDA safety alert warns patients and healthcare professionals to consider CDAD if a patient takes a PPI and

experiences persistent diarrhea.[27] The FDA also recommends that patients be on the lowest dose for the shortest period of

time to treat their current condition.[27] The 2013 ACG guidelines recommend use of PPIs with caution in patients with a risk

of C difficile infections.[13]

Community-Acquired Pneumonia

Patients taking PPIs may potentially be at an increased risk for CAP. However, the degree of association is unclear due to

conflicting data.[28–30] The 2013 ACG guidelines state that short-term PPI use may increase the risk of CAP, but the risk

does not seem to be elevated in long-term use.[13]

A 2012 cohort study by de Jagar et al showed that patients on PPIs were 2.23 times (95% CI, 1.28–3.75) more likely to

develop a CAP infection compared to patients not on PPIs.[31] Unfortunately, the duration of time that patients were

prescribed was not included in the study design.[31] In a meta-analysis completed in 2004, researchers discovered that

patients who were on an acid-suppressing agent, either a PPI or an H2RA, were 4.5 (95% CI, 3.8–5.1) times more likely to

develop pneumonia.[30] Mean duration of use for H2RAs was 2.8 months; for PPIs the mean duration was 5 months.[30]

Conversely, a 2008 study conducted by Sarkar et al showed that current PPI use was not associated with an increased risk

of CAP (odds ratio [OR] 1.02, 95% CI 0.97–1.08).[29] However, the study did observe an increased risk of acquiring an

infection in patients initiated on a PPI within the past 14 days (adjusted OR 3.21, 95% CI 2.46–4.18).[29]

The data support a short-term increase risk of pneumonia infections, but they are conflicting regarding long-term

consequences. Despite the conflicting data, this risk is important to consider, especially because of the new Centers for

Medicare & Medicaid (CMS) regulations on hospital readmissions.[32] Laheij et al determined that the incidence rate of

pneumonia was 2.5 per 100 patient-years for patients on PPIs.[30] With 65.7 million prescriptions of omeprazole alone and

an increased $15,682 cost to Medicare beneficiaries due to pneumonia hospitalizations, the risk of PPI use-associated

infections warrants vigilance and evidence-based medicine on the part of the pharmacist.[33,34]


PPIs are an efficacious and safe drug class. They offer relief to patients in a patient-centered healthcare system.

Unfortunately, these agents do potentially have some long-term consequences from continued use, including malabsorption

issues and increased risk of infections. The pharmacist can be an advocate for the patient in the hospital system or in the

community by understanding these risks and fostering patient-centered care by empowering a well-informed patient in

healthcare decisions.


Wolfe M. Overview and comparison of proton pump inhibitors for the treatment of acid-related disorders. In: Basow

DW, ed. UpToDate. Waltham, MA: UpToDate; 2013.


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/Top_Therapeutic_Classes_Dispensed_Prescriptions_2012.pdf. Accessed November 4, 2013.


Top therapeutic classes by non-discounted spending (US). IMS Health. Updated February 17, 2013.


/Top_Therapeutic_Classes_by_Non-Discounted_Spending.U.S.pdf. Accessed November 4 2013.


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5. Esomeprazole. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc. online.lexi.com. Accessed August 15, 2013.

6. Lansoprazole. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc. online.lexi.com. Accessed August 15, 2013.

7. Omeprazole. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc. online.lexi.com. Accessed August 15, 2013.

8. Pantoprazole. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc. online.lexi.com. Accessed August 15, 2013.

9. Rabeprazole. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc. online.lexi.com. Accessed August 15, 2013.

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/OfficeofMedicalProductsandTobacco/CDER/ucm220944.htm. Accessed June 5, 2013.


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12. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association Institute technical review on the

management of gastroesophageal reflux disease. Gastroenterology. 2008;135:1392–1413.

Katz P, Gerson L, Vela, M. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J

Gastroenterol. 2013;108:308–328.


Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary

and lifestyle factors: a prospective cohort study. BMJ. 2012;344:e372.


Flynn A. The role of dietary calcium in bone health. Proc Nutr Soc. 15. 2003;62:851–858.

FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of

proton pump inhibitors. FDA. March 28, 2011. fda.gov/drugs/drugsafety

/postmarketdrugsafetyinformationforpatientsandproviders/ucm213206.htm. Accessed June 11, 2013.


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3 Replies

Hi Gutless Wonder, How long have you been on a PPI? Did you smoke? Are you overweight or were you at one time? Are you having difficulty taking a PPI Longterm? Are you still on a PPI?


All medications are likely to have side effects. The PPIs do reduce the stomach acid, and some of the long term effects of PPIs are consequences of not having the benefit of this acid in the digestive system (eg some bugs thrive better when the acid does not kill them off). It can have an effect on calcium absorption so you may need to watch out for bone density issues like osteoporosis, but the answer to that may be to have a bone density scan and to take calcium supplements if it is a problem. The trouble is that acid in the wrong place is a (probably larger) problem too, and taking PPIs are often a necessity and a sensible judgement of risks and benefits. They are, I believe, available over the counter in the USA and perhaps in the UK also.

If you stop taking PPIs you may get a 'bounce' effect of extra reflux whilst the body is adapting to life without them. During this period of a couple of weeks or so, taking an alginate like Gaviscon can help.

PPIs are used when patients have had an oesophagectomy and no longer have the lower oesophageal sphincter valve that should keep the acid in the stomach rather than in the remains of the oesophagus, and the people reading this are likely to be in that very specialised category which the study probably does not really address. PPIs are used for many different situations, and were not developed specifically to address the post-oesophagectomy issues, but nevertheless are often effective.

I know some people who have had an oesophagectomy who have been able to manage without them, and many more who have tried to do without them and gone back on them because of the reflux effects.

If you do feel that you are adversely affected by the PPI you are taking, and this does happen from time to time, you can always discuss this with your doctor. The solution may be altering the dose, trying another PPI, finding a supplement or another medication to counter the adverse effect, or trying to give them up completely or partially and see what happens. But if your situation has reached a position of long awaited stability, do not get panicked into leaving them off without a good deal of thought! Reviewing medication periodically is never a bad thing.


Excellent reply. For those of us who have had an esophagectomy, regular monitoring of both the health of the esophageal remnant (remaining portion of esophagus used to make anastamosis) and the transposed stomach (fundus used in gastic pull-up surgery) is prudent. My opinion is that if you discover a non-PPI alternative to keeping your "new" esophagus healthy, then that is wonderful. There are so many choices and ways to accomplish this. If, however, you have reached the point of mucosal changes, then PPI is warranted. The side effects of long term PPI use are severe and require a great deal of thought. Please see my book Living with Achalasia at livingwithachalasia.org for a free download. I cover this issue in great detail. Any comments and personal experiences are most welcomed! Thank you.