Proton Pump Inhibitors May Increase Fracture Risk, FDA Warns

May 25, 2010 — The US Food and Drug Administration (FDA) today recommended that physicians exercise more caution in prescribing proton pump inhibitors (PPIs) in light of evidence suggesting that high doses or long-term administration of the medications may increase the risk for hip, wrist, and spine fractures.

"Consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition," the FDA advised in a safety communication. The agency also advised that patients should continue taking PPIs unless their physicians instructed them to stop.

The FDA announced that it would add safety information about the possible increased risk for hip, wrist, and spine fractures to the prescription and over-the-counter (OTC) labels for PPIs, which include esomeprazole (Nexium), omeprazole (Prilosec, Zegerid), and lansoprazole (Prevacid). PPIs treat conditions such as gastroesophageal reflux disease, stomach and small intestine ulcers, and inflammation of the esophagus.

Epidemiologic Studies Are Not Conclusive

The FDA noted in its announcement today that randomized clinical trials of PPIs have yet to find an increased risk for hip, wrist, or spine fractures. Instead, the FDA based its decision to revise the Warnings and Precautions section of PPI prescription labeling and the Drug Facts label on OTC PPIs on an agency review of 7 published epidemiologic studies.

The studies rely on claims data to evaluate the risk for hip, wrist, and spine fractures in patients taking PPIs from 1 to 12 years, depending on the study compared with patients who were not taking such medications. Six studies reported an increased risk for fracture with PPI use. In addition, 2 studies showed such an increased risk with a higher PPI dose, while 2 studies reported a greater risk with longer duration of use.

"The majority of the studies evaluated individuals 50 years of age and older and the increased risk of fracture primarily was observed in this group," the FDA stated.

However, the 7 epidemiologic studies come with limitations that cast uncertainty on their findings, according to the FDA. The claims databases used in these studies usually do not include information on all potential risk factors such as family history of osteoporosis, smoking history, and alcohol use "that could influence the relationship between [PPI] use and fracture risk." In most studies reporting a possible link between PPIs and fracture risk, no information was gathered about the timing of PPI therapy in relation to the onset or worsening of osteoporosis. Furthermore, 3 epidemiologic studies did not show a consistent association between long-term PPI therapy and bone mineral density.

Accordingly, the FDA said it was not clear if PPIs accounted for the higher risk for fracture in the epidemiologic studies. To seek more clarity, the agency intends to analyze data from several large, long-term, placebo-controlled clinical trials of bisphosphonates — prescribed to prevent bone fractures — to determine the fracture risk of women at risk for osteoporosis-related fractures, some of them taking PPIs and some of them not. The FDA also is working with PPI manufacturers to further study the issue of fracture risk.

More information on the FDA announcement is available on the agency's Web site.

To report adverse events related to PPIs, contact MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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