Proton pump inhibitors and fracture risk: true effect or residual confounding?

Fracture is a major contributor to human morbidity and mortality, especially in the elderly. It has been discussed in the literature that conditions associated with decreased stomach acidity may lead to a decrease in intestinal calcium absorption and, consequently, to an increased fracture risk. In recent years, several observational studies reported a slightly increased fracture risk in association with the use of proton pump inhibitors (PPIs) and/or histamine H(2) receptor antagonists. It was the objective of this review to critically assess the available evidence linking PPI use to an increased fracture risk. A MEDLINE and EMBASE search from 1960 to June 2010 was performed to identify the relevant articles using predefined search terms. Because (i) there is no proven mechanism, (ii) the reported magnitude of the risk elevation associated with the use of PPIs was only weak, and (iii) the likelihood of residual confounding despite adjustment for known co-morbidities and drug use cannot be ruled out, we conclude that the currently available literature does not support the notion that the use of PPIs is causally related to a materially increased fracture risk in humans.