PPIs, C. difficile, and bone fractures

Since H2 antagonists were introduced 30 years ago followed by proton pump inhibitors (PPIs) 20 years ago, there has been speculation whether long-term gastric acid suppression might have adverse effects. Billions of doses later, there is new evidence that chronic PPI use may lead to infections, especially Clostridium difficile infection (CDI), and may also contribute to bone fractures.

In the first of several studies published in the May 10 issue of Archives of Internal Medicine, researchers looked at more than 101,796 discharges from a tertiary care medical center during a five-year period, reviewing the level of acid suppression therapy and its relationship to CDI. As the level of acid suppression increased, the risk of CDI increased from 0.3% in patients not receiving acid suppressive therapy to 0.6% in those receiving H2 antagonists to 0.9% in those receiving daily PPIs and finally 1.4% in those receiving high-dose PPI therapy. After adjustment for a number of factors including comorbid conditions, age, and antibiotic use, the odds ratio for CDI infections were: 1 with no acid suppressing treatment, 1.53 (95% confidence interval [CI], 1.12-2.10) with H2 antagonist, 1.74 (95% CI, 1.39-2.13) with PPIs, and 2.36 (95% CI, 1.12-2.10) with high-dose PPI therapy. The authors conclude that increasing levels of pharmacologic acid suppression are associated with increased risk of nosocomial C. difficile infections, and the risk increases with more aggressive acid suppression (Arch Intern Med 2010;170:784-790).

In a second study from the same journal, researchers from the VA system in Massachusetts performed a retrospective, cohort study of 1166 inpatients and outpatients with CDI to determine if PPI use affected recurrence rates. During treatment for CDI, 45% of patients received a PPI while 55% did not. Recurrent CDI was more common in those exposed to PPIs than in those not exposed (25.2% vs 18.2%). The hazard ratio for recurrent CDI in those exposed to PPIs was 1.42 (95% CI, 1.11-1.82). The risk was higher in patients older than 80 years and in patients exposed to antibiotics not targeted to CDI infections The authors conclude that PPI use during treatment for CDI was associated with a 42% increased risk of recurrence (Arch Intern Med 2010;170:772-778).

It has also been postulated that suppressing gastric acid may affect digestion and absorption of certain nutrients, specifically calcium. Although this has never been definitively proven, multiple studies have shown that chronic PPI use is associated with bone fractures. The most recent study, also published in the May 10 issue of Archives of Internal Medicine, was a prospective analysis of more than 160,000 women enrolled in the Women's Health Initiative study. In more than 1 million person-years of follow-up, there were 1500 hip fractures, 4881 forearm or wrist fractures, 2315 clinical spine fractures, and more than 21,000 total fractures. The multivariate-adjusted hazard ratios for current PPI use was 1 for hip fracture, 1.47 (95% CI, 1.18-1.82) for clinical spine fracture, 1.26 (95% CI, 1.05-1.51) for forearm or wrist fractures, and 1.25 (95% CI, 1.15-1.36) for total fractures. Bone mineral density did not vary between PPI users and non-users. The authors conclude that use of PPIs in women was not associated with hip fractures but was modestly associated with clinical spine, forearm or wrist, and total fractures (Arch Intern Med 2010;170:765-771). This study confirms the findings of several large epidemiological studies that suggest that PPI use is associated with increased osteoporotic fracture risk. On May 25, the FDA issued a warning regarding the possible fracture risk associated with high-dose long-term use of PPIs. The Agency will require labeling changes to describe the possible risk.

As noted in these studies, PPI use is associated with risk of osteoporotic fractures and Clostridium difficile infections. Other studies have linked the PPIs to a higher risk of hospital- and community-acquired pneumonia, as well as enteric infection such as Salmonella and Campylobacter gastroenteritis. In an editorial in the May 10 issue of Archives of Internal Medicine, Mitchell Katz, MD, notes that of the more than 110 million prescriptions for proton pump inhibitors filled each year, many are for inappropriate indications, making PPIs one of the most overprescribed medication classes in the world. He suggests that "for most patients the adverse effects of PPIs outweigh the benefits" and urges physicians to offer other treatments for dyspepsia, prescribe shorter courses, and consider a trial of discontinuing PPIs in patients who are asymptomatic (Arch Intern Med 2010;170:747-748).