[05-25-2010] The U.S. Food and Drug Administration (FDA) is revising the prescription and over-the-counter (OTC) labels for a class of drugs called proton pump inhibitors to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications.
Proton pump inhibitors work by reducing the amount of acid in the stomach. Nexium, Dexilant, Prilosec, Zegerid, Prevacid, Protonix, Aciphex, and Vimovo are available by prescription to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus. Prilosec OTC, Zegerid OTC, and Prevacid 24HR are sold over-the-counter (OTC) for the treatment of frequent heartburn.
The 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 (see Data Summary section).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 (indicated for 14 days of continuous use) also is being revised to include information about this risk.
Healthcare professionals and users of proton pump inhibitors should be aware of the possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors, and weigh the known benefits against the potential risks when deciding to use them.
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.1-7 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 (The findings from these studies are found in the Table below).
In these studies:
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 proton pump inhibitors 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 (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.
However, the exact mechanisms for an increased risk of fractures with proton pump inhibitor use are not known. Three epidemiologic studies found no consistent association between chronic proton pump inhibitor use and bone mineral density 6,7,8.
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 (drugs used to prevent fractures) 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 Dexilant (dexlansoprazole) approval, (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.
In summary, the available data, including findings from several epidemiological studies, suggest a possible increased risk of fractures of the hip, wrist, and spine in patients using proton pump inhibitors. The 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.
Data Source: 1. Denmark Health Database; 2. United Kingdom, General Practice Research Database; 3. Population Health Research Data Repository (Manitoba, Canada); 4. Kaiser Permanente Northern California; 5. Osteoporosis fractures in Men Study/Study of Osteoporotic Fractures; 6. Women's Health Initiative Observation Study/Women's Health Initiative Clinical Trials
± Adjusted for sex, age, body mass index, medication use (anxiolytics, antidepressants, NSAID/aspirin, thiazide diuretic, antipsychotic, antiparkinsonian, antiseizure, hormone therapy, corticosteroid, thyroxine), health condition (alcoholism, arthritis, stroke, asthma or COPD, dementia, diabetes mellitus, congestive heart failure, impaired mobility, myocardial infarction, peptic ulcer disease, seizure disorder, peripheral vascular disease, visual impairment, current smoker, prior fractures).
¥ Adjusted for income, region of residence, diagnoses (short or long-term diabetes, epilepsy, ischemic heart disease, myocardial infarction, hypertension, arthritis, solid organ transplant, chronic obstructive pulmonary disease, substance use, depression, schizophrenia, dementia), home care use and multiple medications.
£ Adjusted for age, clinic, race, body mass index, alcohol use, exercise, oral or inhaled corticosteroid use, NSAID use, calcium supplement use, osteoporosis medication use, and self-reported health, concurrent weight change, and initial total hip bone mineral density. SOF group is also adjusted for caffeine intake and estrogen use. MrOS group is also adjusted for smoking and history of stomach surgery.
≠Adjusted for age, race/ethnicity, body mass index, enrollment in clinical trial status, indicator for cohort, smoking, physical activity (metabolic equivalent tasks), self-reported health, having a parent who broke a hip after age 40 years, treated diabetes mellitus, history of fracture at 55 years or older, and corticosteroid use, physical function score, history of myocardial infarction or angina, asthma or emphysema, arthritis, stomach or duodenal ulcer, moderate or severe heartburn, osteoporosis, number of psychoactive medications, and use of hormone therapy and bisphosphonates.
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5. Corley, D.A., Kubo, A., Zhao, W., Quesenberry, C., Proton Pump Inhibitors and Histamine-2 Receptor Antagonists are Associated with Hip Fractures among At-Risk Patients, Gastroenterology (2009), doi:10.1053/j.gastro.2010.03.055.
6. Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z. Proton Pump Inhibitor Use, Hip Fracture, and Change in Bone Mineral Density in Postmenopausal Women. Arch Intern Med 2010;170 (9):765-771.
7. Yu EW, Blackwell T, Ensrud KE, Hillier TA, Lane NE, Orwoll E, Bauer DC, et al. Acid-Suppressive Medications and Risk of Bone Loss and Fracture in Older Adults. Calcif Tissue Int. 2008;83(4):251-259.
8. Targownik LE, Lix LM, Leung S, Leslie WD. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010;138:896-904.
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