Risks of proton-pump inhibitors: what every doctor should know.

A low level of gastric acid promotes the growth of swallowed and enteric flora in the proximal gut, and these bacteria may be aspirated during episodes of physiological reflux. In this issue of the Journal, Roughead and colleagues assess the risk of pneumonia in Australian veterans taking PPIs (page 114); they identified a 16% increase in risk, equating to four extra hospitalisations for pneumonia each year for every 1000 people prescribed a PPI. 1 A study from Denmark found current use of PPIs was associated with a 1.5-fold (or 50%) increase in the risk of community-acquired pneumonia (95% CI, 1.3–1.7); the attributable proportion (ie, the fraction of pneumonia potentially caused by PPIs) was calculated to be 4%. 3 Similarly, a Netherlands study reported an adjusted relative risk for pneumonia among those using PPIs versus those who stopped using the drugs of 1.89 (95% CI, 1.36–2.62). 4 There is, therefore, a small increased risk of pneumonia, and this may be further increased in those who have recently begun taking PPIs. However, no preventive strategies are available to reduce this risk, and a causal association has not been established. Indeed, the increase could still be caused by unidentified confounders. For example, many patients in these studies had multiple comorbid conditions that might have given rise to an increased risk of pneumonia in the first place, such as alcoholism, previous stroke, or immune compromise secondary to chronic disease. 3,4 A case–control study reported a significantly increased risk of Clostridium difficile infection in those who were exposed to PPIs in the 90 days before the infection, with an odds ratio (OR) of 3.5 (95% CI, 2.3–5.2). 5 As expected, previous exposure to antibiotics was also a significant risk factor for C. difficile infection in this study. An association with H 2 -receptor antagonists, as well as nonsteroidal anti-inflammatory drugs (but not aspirin), was also reported. 5 An increased risk of other enteric infections has similarly been observed with PPI use (OR, 2.55; 95% CI, 1.53–4.26), although combining data in this meta-analysis was problematic because of significant study heterogeneity. 6 Whether other comorbid conditions in patients taking these drugs account for the association remains to be clarified, and any causal link is still speculative. An acid environment is needed for insoluble calcium absorption, but the effects of PPI on dietary calcium absorption are uncertain. Increasing dietary calcium intake and taking calcium citrate as a supplement (which does not require gastric acid for absorption) is not established practice for patients who are prescribed acid-suppressing medications. A large retrospective study from the United Kingdom General Practice Research Database suggested that there was an increased risk of hip fracture in patients taking PPIs, with an adjusted odds ratio of 1.44 (95% CI, 1.30–1.59). 7 Importantly, the calculated excess risk was small (about 1263 patients over the age of 50 would need to be treated with PPIs for a year to identify one excess hip fracture). A weaker effect was seen with H 2 -receptor antagonists. A recent Canadian case–control study in an administrative claims database examined longer-term PPI use and osteoporosis-related fractures; exposure of 7 years or more was modestly associated with an increased fracture risk (OR, 1.92; 95% CI, 1.16–3.18). 8 A causal association has not been established, but it may be worth considering increasing calcium intake for prevention and assessing bone mineral density in those requiring a daily PPI for more than 5 years. 9 Carpopedal spasm secondary to low serum magnesium and calcium levels that reversed with withdrawal of PPI therapy in two patients has also been reported. 10