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Podcast for Healthcare Professionals: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors

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Welcome, my name is Mary Kremzner, a pharmacist in the Division of Drug Information. I am updating you on the possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors.

FDA is revising the prescription and over-the-counter labels for proton pump inhibitors, or PPIs, to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications.

Nexium, Dexilant, Prilosec, Zegerid, Prevacid, Protonix, Aciphex, and Vimovo are available by prescription to treat conditions such as GERD, stomach and small intestine ulcers, and inflammation of the esophagus. Additionally, Prilosec OTC, Zegerid OTC, and Prevacid 24HR are sold over-the-counter, or OTC, for the treatment of frequent heartburn.

This new safety information is based on FDA's review of several epidemiological studies that reported an increased risk of fractures of the hip, wrist, and spine with proton pump inhibitor use. Some studies found that those at greatest risk for these fractures received high doses of proton pump inhibitors or used them for one year or more. The majority of the studies evaluated individuals 50 years of age or older and the increased risk of fracture primarily was observed in this age group.

While the greatest increased risk for fractures in these studies involved people who had been taking prescription proton pump inhibitors for at least one year or who had been taking high doses of the prescription medications (not available over-the-counter), as a precaution, the "Drug Facts" label on the OTC proton pump inhibitors, which are indicated for 14 days of continuous use, is also is being revised to include information about this risk.

To date, randomized clinical trials of proton pump inhibitors have not found an increased risk of fractures of the hip, wrist, or spine. These studies are generally six months in duration and there is limited information on effects of higher than recommended doses.

The decision to revise the Warnings and Precautions section of the prescription labeling as well as the OTC Drug Facts label for proton pump inhibitors is based on FDA's review of the findings from seven published epidemiological studies. These studies used 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 compared to individuals who were not using proton pump inhibitors. A Table summarizing the epidemiological studies evaluating fracture risk with Proton pump inhibitors is available in the full drug safety communication at: www.fda.gov/drugs.

In these studies:

  • Six reported an increased risk of fractures with the use of proton pump inhibitors.
  • Exposure to proton pump inhibitors ranged from a period of 1 to 12 years, depending on the study.
  • The emergence of fractures varied among studies; with one study reporting an increase in fractures with use of proton pump inhibitors in the previous year and another study finding an increase after 5 to 7 years of proton pump inhibitor use.
  • The increased risk of fractures was primarily observed in older individuals.
  • Two studies reported an increase in fractures with higher doses of proton pump inhibitors.
  • Two studies reported an increase in fractures with longer duration of use.
  • One study did not find a relationship between proton pump inhibitor use and fractures . This study limited the study population to those without major risk factors for fracture.

FDA does not have access to the data or the protocols for these studies, so our ability to verify that the studies were conducted as described in the original publications is limited. Based on our review of the published articles, the key strengths of these studies are that they appear well-designed, considered the effects of both dose and duration of use of proton pump inhibitors on fracture risk, and used appropriate statistical methods to reduce bias by adjusting for potential factors that are known to be associated with the occurrence of fractures such as age, gender, presence of co-existing conditions and use of co-prescribed medications.

Several study limitations, however, make understanding the clinical relevance of the reported findings difficult to determine. Administrative claims databases do not typically contain information on all potential factors that could influence the relationship between PPI use and fracture risk. These studies were not able to account for missing or incomplete information on family history of osteoporosis, smoking history, weight and height measurements, alcohol use, history of dietary and supplement use such as calcium and vitamin D, OTC medication use, presence of digestive diseases, such as ulcers, reasons for proton pump inhibitor use, and recent history of immobility, dizziness, or falls. In addition, in most studies where a possible link with osteoporotic fracture was reported, no information was collected about the timing of proton pump inhibitor use in relation to onset or worsening of osteoporosis.

The exact mechanisms for an increased risk of fractures with proton pump inhibitor use is not known. Three epidemiologic studies found no consistent association between chronic proton pump inhibitor use and bone mineral density.

Based on the available data, at this time it is not clear if the use of proton pump inhibitors is the cause of the increased risk of fractures seen in some epidemiologic studies.

To further investigate this issue, the FDA plans to analyze data from several large, long-term, placebo-controlled clinical trials of bisphosphonates to assess the risk of fractures in women at risk for osteoporosis-related fractures who used or did not use proton pump inhibitors.

FDA is also working with the manufacturers of these products to further study this possible risk. For example, as part of the dexlansoprazole approval, in January 2009, 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. The results from this trial are expected at the end of 2011.

The available data suggest that the increased risk may be dependent upon dose, duration of use, or both. At the present time, there is uncertainty about the magnitude of this risk. In light of this uncertainty, when prescribing proton pump inhibitors, healthcare professionals should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition.

In summary, Healthcare Professionals considerations are:

  1. Proton pump inhibitors provide important benefits for many patients in treating or preventing conditions such as erosive esophagitis, nonsteroidal anti-inflammatory drug-induced ulcers and gastroesophageal reflux disease.
  2. When prescribing proton pump inhibitors, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition.
  3. Follow the recommendations in the product labeling when prescribing proton pump inhibitors.
  4. Individuals at risk for osteoporosis should have their bone status managed according to current clinical practice, and should take adequate vitamin D and calcium supplementation.
  5. Report any adverse events with proton pump inhibitors to FDA's MedWatch program at www.fda.gov/medwatch.

Thank you for listening. The FDA is committed to keeping healthcare professionals informed of the latest safety information. If you have questions about this safety communication, you can reach the Division of Drug Information at the following email address: druginfo@fda.hhs.gov.