Safety of Long-Term PPI Use Save

The current issue of JAMA reviews the safety of long-term use of proton pump inhibitors (PPI). The following is a collection of the evidence about these purported risks.

Fractures

• Thought to occur because reduced gastric acidity might interfere with calcium absorption.
• One meta-analysis of 18 trials involving a total of 244,109 fracture cases found that PPI use was associated with a modest increase in the risk of hip (RR 1.26), spine (RR 1.58), and any-site fractures (RR 1.33).
• A prospective cohort study including 79,899 postmenopausal women from the Nurses’ Health Study found no significant association between PPI use and fracture risk.
• No association between PPI use and osteoporosis has been demonstrated.

Renal Disease

• PPIs are rarely associated with acute interstitial nephritis and subsequent progression to chronic kidney disease (CKD). The mechanism by which PPIs might cause CKD is unknown.
• A prospective cohort study in 10,482 patients followed for 14 years found that the risk of CKD was higher (HR 1.45) with PPI use.
• A retrospective analysis of 114,833 new PPI and H2-receptor antagonist (H2RA) users found that patients taking a PPI were more likely to have a doubling of serum creatinine levels, a ≥30% decrease in eGFR, end-stage renal disease, and acute kidney injury than those taking an H2RA.21.
• Another retrospective analysis of 144,032 PPI and H2RA users reported similar results, but found that 50% of cases of CKD were preceded by acute kidney injury.

Community-Acquired Pneumonia (CAP)

• The mechanism by which PPIs might increase the risk of CAP is not known. 
• Meta-analysis of 9 trials involving a total of 120,863 pneumonia cases found that short-term PPI use (30 days) or high-dose PPI therapy was associated with an increased risk of CAP.
• A case-control review of 80,066 patients and 79,881 controls found no significant association between PPI use and CAP.
• A retrospective cohort study compared the incidence of hospitalization for CAP among new NSAID users who also started a PPI with those who did not take a PPI; there was no difference between the two groups in the 6-month incidence of CAP.

 Clostridium difficile infection (CDI) 

• PPI and CDI risk is controversial. Reduced gastric acidity may promote bacterial colonization and increase C difficile colonization of the GI tract.
• A population-based study in 385 patients, use of PPIs and H2RAs showed no association with an increased incidence or recurrence of the infection.
• A case-control study in 137 hospitalized patients, the duration or dose of PPI did not increase the risk of CDI.
• Analysis of observational studies found that PPI use increased the risk of developing CDI by 75% and the risk of recurrent infection 2.5-fold.