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Editorial: Non‐breaking news! High‐dose PPIs likely do not cause fractures

Proton pump inhibitors (PPIs) are the most effective medications for the treatment of gastro-oesophageal reflux disease and its complications. However, the long-term use of PPIs has recently been linked to a number of potentially serious adverse events, one being osteoporosis-related fractures. While the evidence from observational trials is conflicting, and the mechanism through which PPIs might cause fracture is uncertain, the FDA and other regulatory agencies have issued warnings of concern about this relationship. As there is unlikely to ever be a definitive trial which will convincingly prove their safety or demonstrate harm, we must rely on assessing PPI use in diverse cohorts in order to be more confident as to the presence or absence of a causal relationship between PPI use and fracture. With this in mind, Kumar and colleagues identified a cohort of persons with known Barrett’s oesophagus who were followed forward in time to determine their subsequent risk of osteoporosisrelated fracture. As persons with Barrett’s oesophagus may be required to use PPIs for years if not decades, and will frequently be prescribed PPIs at high doses, they would ostensibly be at high risk for complications like osteoporosis-relate fracture which have been linked to the cumulative exposure to PPIs. In other words, if PPI use is not associated with an increased risk of fracture among persons with Barrett’s oesophagus, there are unlikely to an association in other populations where PPI use is less prolonged and/or intense. Among 521 patients with Barrett’s oesophagus included in the study cohort, 46 eventually developed an osteoporosis-related fracture. The incidence of fracture was not significantly increased over the observed rate of osteoporosis-related fracture in an ageand sex-matched population. Furthermore, neither the duration of PPI use (HR 0.96; 95% CI 0.89-1.02) nor high-dose PPIs (HR 0.49; 95% CI 0.21-1.16) was associated with an increased risk of osteoporosis-related fracture. These results provide further evidence against PPIs being directly involved in the pathogenesis of fracture. However, this result comes with a few caveats. The population of persons with Barrett’s oesophagus had a mean BMI of approximately 30, whereas one of the strongest predictors of fracture is being underweight. Therefore, persons with Barrett’s may be less predisposed to developing fracture due to having a lower likelihood of being underweight. Also, the relatively small sample size and low rate of fractures limits the ability of this study to detect a small magnitude yet clinically significant increase in the risk of fracture among PPI users. In spite of these limitations, this study provides further support for the absence of any meaningful deleterious effects on bone health ascribable to PPI use. Given the ongoing lack of a biologically proven pathway through which PPIs negatively affect bone health and metabolism, clinicians should continue to feel comfortable in prescribing PPIs in patients with appropriate indication, irrespective of their history of fracture or underlying fracture risk.