The drugs are Aciphex, Nexium, Prevacid, Prilosec (called Losec in Europe), and Protonix. The drugs shut down the chemical "pump" needed by stomach cells to make acid. They are very effective for treating GERD (gastrointestinal reflux disease).
That makes the acid-fighting drugs very popular. Together they rang up nearly $13 billion in U.S. sales in 2005 -- a year in which American doctors wrote more than 95 million prescriptions for the drugs. Prilosec is now available over the counter.
Now a new study shows that when taken long term the drugs may have a side effect: hip fracture. People over age 50 who take the drugs for more than one year have a 44% increased risk of breaking a hip, find University of Pennsylvania researchers Yu-Xiao Yang, MD, and colleagues.
Taking proton-pump inhibitors at higher doses -- and for longer periods -- dramatically increases the risk. Long-term, high-dose use of the drugs ups the risk of hip fracture by 245%.
"Proton-pump inhibitor therapy is associated with a significantly higher risk of hip fractures, with the highest risk seen among those receiving high-dose proton-pump-inhibitor therapy," Yang and colleagues conclude.
The findings appear in the Dec. 27 issue of The Journal of the American Medical Association.
Proton Pump Inhibitors and Calcium
Yang and colleagues analyzed medical records on patients treated in the U.K. between 1987 and 2003. The study included 13,556 patients with hip fractures and 135,386 patients without fractures.
After controlling for all variables -- including a diagnosis of GERD -- hip fractures were strongly associated with use of proton-pump inhibitors.
It's not entirely clear why this happens. Stomach acid helps the body absorb calcium, which is needed for healthy bones. But it only takes a little bit of acid to do this. That may be why Yang's team finds only a "modest" fracture risk with low doses of proton-pump inhibitors and a "much higher magnitude" risk with high doses.
It may also explain why they found no link between other types of GERD drugs and hip fracture. Other GERD treatments include histamine blockers -- referred to as H2 antagonists; they specifically block the histamine type 2 receptor, preventing histamine from stimulating acid-producing cells. H2 antagonists include Tagamet, Zantac, Axid, and Pepcid.
The researchers suggest that proton-pump inhibitors may have "an exaggerated effect" among people already at risk of osteoporosis. They urge doctors to prescribe the drugs at the lowest effective dose.
They also urge elderly patients who need high-dose, long-term treatment with proton-pump inhibitors to get more calcium. This calcium, Yang and colleagues suggest, should be consumed in the form of dairy foods. If patients take calcium supplements, they should remember to take them with a meal.
WebMD asked the drug companies that make proton-pump inhibitors to comment on the study.
Wyeth Pharmaceuticals makes Protonix. Wyeth notes that clinical trials of Protonix extended for up to 12 months. In that period, fewer than 1% of patients suffered bone disorders.
"Wyeth is aware of the study on PPIs and risk of hip fracture," the company tells WebMD. "As always, we are continuing to monitor our safety database. Wyeth places patient safety at the center of our activities worldwide."
The recommended adult daily dose of Protonix is one 40 milligram delayed-release tablet.
AstraZeneca makes Nexium and Prilosec. Doug Levine, MD, clinical development leader for AstraZeneca, tells WebMD in a written statement that the Yang study provides important information that must be interpreted in the context of other data.
"This study does not establish a direct causal relationship between hip fractures, which were assumed to be secondary to osteoporosis, and either proton-pump inhibitors or other acid suppressive medications," Levine writes. "This study does suggest a 'potential association,' as characterized by the authors of the study."
Levine notes that "hip fractures and osteoporosis are attributable to many other well-established medical and circumstantial risk factors" other than proton-pump inhibitors. He stresses that "oversight of at-risk patients by physicians and other health care professionals is very important to help define and employ interventional clinical management strategies that may help prevent hip fractures and treat or prevent osteoporosis."
TAP Pharmaceutical Products Inc. makes Prevacid. Amy Allen, TAP's associate director for public affairs, provided a written statement to WebMD.
"For more than 10 years, proton pump inhibitors (PPIs) have been used to treat millions of patients suffering from acid-related disorders, and the safety and efficacy of PPIs have been well established through many randomized, controlled clinical trials, which are considered to be the gold standard for evaluating the risks and benefits of medicines," Allen writes. "The study discussed in this article is a retrospective analysis which is usually not sufficient to prove or disprove potential hypotheses."
Allen notes that TAP conducts postmarketing surveillance and has not yet seen any "safety signal for bone fractures related to Prevacid." She stresses that the company remains committed to patient safety.
Eisai Inc. makes Aciphex. Eisai provided WebMD with written comments.
"These preliminary results warrant further study, as hip fractures are an important medical issue that can occur for a variety of reasons," Eisai tells WebMD. "Our clinical trials and postmarketing data have not shown an increased risk of hip fractures in patients taking Aciphex, but we will continue to monitor our adverse event database."
Wyeth, AstraZeneca, and TAP are WebMD sponsors.