Safety of proton pump inhibitors: current evidence for osteoporosis and interaction with antiplatelet agents.

Proton pump inhibitors (PPIs) are commonly used in millions of patients. Despite the widespread usage and favorable safety profile, much attention has focused recently on potential adverse events associated with use. One area of particular concern is the reported potential adverse effects on bone density, causing possible osteoporosis and related bone fractures. The low magnitude of the association (OR < 2), lack of experimental evidence documenting a mechanism, and inability to assess potential confounding factors limit statements regarding causality. The other area of particular concern has been the combined use with antiplatelet agents, in particular with clopidogrel. Several retrospective studies suggested an adverse cardiovascular outcome if clopidogrel was combined with PPIs. The theoretic concern was raised to a possible interference with the bioactivation of the prodrug via competitive interference for both drugs at the cytochrome P450 pathway. Although ex vitro studies suggested a possible effect and several retrospective analyses were supportive of an adverse clinical outcome, the more recent prospective controlled trial data do not support an adverse cardiovascular outcome. This report reviews the scientific hypothesis, biologic plausibility, and the most recent clinical trial data for both areas of controversy.