FDA Panel Waffles on Limiting Duration of Bisphosphonate Use

Spet. 9, 2011— -- ADELPHI, Md. -- A U.S. Food and Drug Administration advisory committee wants the agency to limit the duration of bisphosphonate therapy for treatment of osteoporosis, but the committee could not agree on what that time limit should be.

Earlier this year, the FDA required that all bisphosphonates used to prevent or treat osteoporosis warn on their labels that optimal duration of use hasn't been determined, and that all patients on bisphosphonate therapy should have their need for continued therapy re-evaluated periodically. The issue has become a hot potato for the FDA as reports have emerged linking long-time bisphosphonate therapy with increased risk of atypical fractures.

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The Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee met Friday to discuss whether emerging reports of adverse events should spur the FDA to change the label to indicate that the drug not be used long term, and the committee members voted 17-6 to endorse a label change -- but then backed away from setting a hard deadline, citing a lack of data to pinpoint an ideal therapeutic time limit.

Placebo-controlled trials typically provide data for only five years of therapy, but there is no strong clinical evidence that bisphosphonates work better after they're used for a long period of time, nor is there firm evidence that long-term use causes harm, the panel said.

Bisphosphonates are prescribed to some five million patients annually to stave off or treat osteoporosis and are highly effective at reducing the risk of osteoporotic fractures. The drugs, which include brand-names Actonel, Atelvia, Boniva, and Reclast, have been shown to reduce the risk of breaking a hip by 40 to 50 percent and fracturing a vertebra by between 40 and 70 percent by inhibiting bone resorption to prevent loss of bone mass.

In 2010, the FDA required makers of bisphosphonate drugs to add a warning to their labels about a small increased risk of atypical femur fractures after an American Society for Bone and Mineral Research task force concluded that the risk, although it is small, is real.

The panel heard from women who were taking bisphosphonates to prevent osteoporosis when suddenly and painfully, they broke their femurs. One woman was on a subway train that screeched to a halt, and as her weight was thrust onto one leg, her femur snapped and she collapsed. Other women had similar stories -- a teacher reaching something in front of her students, a grandmother taking a large step to walk toward her grandchild, a woman walking down a front stoop to pick up the morning newspaper -- and in each case the women collapsed to the ground as their femurs snapped.

The panel was also concerned with the drug's link to deterioration of the jawbone. In 2005, the FDA added a warning on bisphosphonates about osteonecrosis of the jaw, a rare disease in which the bone in the jaw dies. In data presented Friday, an FDA reviewer said the risk for osteonecrosis of the jaw appears more prevalent after four years or more of use.

There are also some data suggesting a link to long-term use of bisphosphonates and esophageal cancer, although solid evidence is lacking, the panel said. In 2009, a study in the New England Journal of Medicine used data from FDA's Adverse Event Reporting System to identify and describe 23 patients taking alendronate who were diagnosed with esophageal cancer.

Taken together, there's no clear answer on the long-term safety of bisphosphonate therapy for the prevention and treatment of osteoporosis, the panel said and called for more studies to hone in on the long-term risks and benefits of the drug.

"There's no doubt that these are very efficacious drugs that reduce fractures and mortality, and there are many women who should be on these drugs that aren't on them," said Dr. Sonia Hernandez Diaz, associate professor of epidemiology at Harvard School of Public Health. "But what we're talking about today is using these drugs for more than three years, and I'm not convinced at all that there are any good data that, even for subgroups of patients, they should be continued [past three years]."

The panel was also asked to discuss the idea of a "drug holiday" or taking a break for bisphosphonate treatment in order to minimize risks, but agreed there wasn't enough evidence to warrant recommending a drug holiday as a treatment plan.