SOURCE: From the Medical Letter on Drugs and Therapeutics. JAMA 2017;318:1177-1178.

Proton pump inhibitors (PPIs) are among the most widely used medications in the United States, thanks to a generally favorable combination of efficacy, tolerability, and safety. Because such a large portion of the adult population uses PPIs, even if a small fraction experiences an adverse effect, it becomes a potentially important issue.

Probably the most concerning adverse effect of PPIs is increased fracture risk. Although not all individual studies confirmed increased fracture risk from PPIs, a meta-analysis of 18 trials indicated a 26-33% increased risk. Since PPIs are not associated with osteoporosis, the mechanism by which PPIs incur increased fracture risk is unknown.

The FDA sent a warning letter to clinicians about another potentially serious adverse effect of PPIs: hypomagnesemia. To date, only long-term use has been associated with hypomagnesemia, and the mechanism is unknown. The severity of consequences ranges from simple fatigue to serious events like seizures and arrhythmias. Monitoring magnesium levels may be appropriate, especially in patients also receiving magnesium-depleting medications (e.g., diuretics).

Other rare but important adverse effects reported include acute kidney injury, chronic kidney disease, reduced vitamin B12 levels, iron deficiency, community-acquired pneumonia, and Clostridium difficile infection. The risk:benefit relationship of PPIs is favorable for most patients, but clinicians should remain vigilant for adversities noted above.