The Food and Drug Administration (FDA) has reviewed data from seven published epidemiologic studies and found that six of them indicated an increased risk of fractures with the use of proton pump inhibitors, particularly in patients over 50 years of age, prompting the agency to revise the labeling of these drugs to include a warning to that effect.

Prescription drugs in the class include esomeprazole (Nexium), dexlansoprazole (Dexilant), omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (Aciphex). Prescription proton pump inhibitors are used to treat conditions such as gastroesophageal reflux disease, stomach and small intestine ulcers, and inflammation of the esophagus. Over-the-counter formulations, used in the treatment of frequent heartburn, include omeprazole (Prilosec OTC, Zegerid OTC) and lansoprazole (Prevacid 24HR).

In the seven epidemiologic studies, researchers reviewed claims data from computerized administrative databases to evaluate the risk of fractures of the hip, wrist, and spine in patients treated with proton pump inhibitors (as compared with patients who weren't using proton pump inhibitors). Administrative claims databases don't typically contain all of the information on other factors that could affect fracture risk (such as a family history of osteoporosis; a history of smoking; dietary supplementation with vitamin D and calcium; or a recent history of immobility, dizziness, or falls), which would be considered in a clinical drug trial. Although this limited the FDA's ability to analyze the published research reports, the agency believes these studies to be credible and their findings to be strong enough to warrant label revisions.

The risk of fractures appears to be higher in patients who receive high doses of one of these drugs or receive the drug over a prolonged period of time, or both. (Currently, it's recommended that proton pump inhibitors not be used for longer than 14 days at a time and not more than three times in a year.) The FDA indicated that the data don't yet provide information sufficient to determine precisely how great the increase in risk is. There are currently no randomized clinical trial data indicating a heightened risk of fractures from proton pump inhibitor use, although relevant clinical trials have been short in duration.

The next phases of the investigation into this apparent increase in risk is to "analyze data from several large, long-term, placebo-controlled clinical trials of bisphosphonates (drugs used to prevent fractures) to assess the risk of fractures in women at risk for osteoporosis-related fractures" who use proton pump inhibitors, according to the FDA. In addition, the FDA is working with proton pump inhibitor manufacturers to further study the link between the drugs and fractures. "For example," writes the FDA, as part of the dexlansoprazole approval process, "the manufacturer was required to perform a postmarketing clinical trial to evaluate the effects of dexlansoprazole and esomeprazole on bone homeostasis, including changes in biomarkers of bone formation and bone resorption." Results of that trial are expected at the end of 2011.

Based on this information and the newly revised warning and precautions in the package insert, NPs who prescribe proton pump inhibitors should weigh the benefits of their use against risks in patients who require them for the prevention or treatment of gastric ulcer disease. Prescribers should consider using as low a dose as possible for as short a time as possible, to help minimize the risk of fracture. Nurses who work in hospital settings should carefully assess the discharge orders of patients being prescribed proton pump inhibitors. These drugs are often used in the hospital setting to decrease the risk of stress ulcers, and their use after discharge may not be warranted. To read the FDA Drug Safety Communication, go to http://bit.ly/a6p7sP.