FDA panel unclear on osteoporosis drug labels

Labels on bisphosphonates, a type of medication used to treat and prevent osteoporosis, should further clarify how long patients can take them, an FDA advisory panel voted today.

But the panel backed off giving any specific time limits.

Bisphosphonates include Aclasta, Actonel, Altevia, Boniva, Fosamax, and Reclast. Four million to 5 million Americans fill prescriptions for the drugs every year, according to the FDA

The FDA convened the meeting because of emerging safety concerns related to long-term use -- generally considered more than three to five years -- of bisphosphonates.

In particular, the agency has received reports of osteonecrosis, or bone death, of the jaw and unusual fractures of the femur, or thigh bone, in women who had taken the drugs for several years or more.

Meanwhile, some research suggests that because bisphosphonates remain in bone for years, women could still benefit after they stop taking them.

More Information Needed on Labels

The panel, made up of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee, voted 17 to 6 in favor of recommending additional labeling information about the drugs' long-term safety and effectiveness.

The FDA usually but not always follows its advisory committee's recommendations.

The agency's own analysis concluded that in women who continue bisphosphonate therapy after five years of use there's no clear benefit or evidence of harm and no subset of patients who have a "clear and consistent" reduced fracture risk, FDA scientist Theresa Kehoe, MD, told the panel.

Bisphosphonate labels mention that safety and effectiveness information is based on one to four years -- depending on the drug -- of clinical trial data, Kehoe said, but optimal length of use is unknown.

"This is really an issue that's front and center in primary care," said Douglas Bauer, MD, a University of California, San Francisco, primary care doctor invited by the FDA to address the advisory panel.

While not an ideal study to examine long-term use, the only published study to do so involved Fosamax, Bauer said. That study randomly assigned women who'd taken Fosamax daily for five years in a clinical trial to either continue taking the drug for another five years or stop.

For fractures other than those of the spine, there was no evidence overall of continued benefit after five years, Bauer said.

But there was a 55% reduction in spine fracture risk in women who continued taking Fosamax for the extra five years, said Arthur Santora, executive director of clinical research for diabetes and endocrinology drugs at Merck, which makes the drug.

And in studies of up to 10 years of use, Santora said, there were no reports of jawbone death and no difference in the risk of unusual thigh fractures between women who took the drug and those who didn't.

Long-Term Use of Bisphosphonates

Panelists noted that it's difficult to predict which women will benefit from long-term bisphosphonate use. The Fosamax study did find that women's bone mineral density at the time they discontinued the drug was strongly related to their fracture risk over the next five years, Bauer told panel members.

The findings probably can be generalized to weekly dosing of Fosamax, he said, but it's unclear how they relate to other bisphosphonates.

Paul Miller, MD, medical director of the Colorado Center for Bone Research, noted that long-term use wasn't an issue when bisphosphonates first came on the market. At that time, "we didn't treat a lot of women in their 50s or early 60s with bisphosphonates," said Miller, who was representing Warner Chilcott, maker of Actonel. "We treated sicker women in their 70s and 80s."

In July 2002, the first published results from the Women's Health Initiative changed all that, he said. The study found that Premarin, the top-selling brand of postmenopausal estrogen, increased heart attack, stroke, and breast cancer risk. Postmenopausal women who had been on hormone therapy to protect their bones flooded doctors' offices in search of an alternative, Miller said.

Most of the bisphosphonate patients who testified before the panel about their unusual thigh fractures said they had started taking the drugs in their 50s or 60s. Some of the women said they'd been prescribed the drugs for osteopenia, which means their bone mineral density was lower than normal but not low enough to be classified as osteoporosis.

Advisory committee member Clifford Rosen, MD, director of the Center for Clinical and translational Research at the Maine Medical Center Research Institute in Scarborough, questioned the wisdom of prescribing bisphosphonates simply to prevent osteoporosis, as opposed to treating it.

"A prevention indication, I think, is being revisited all the way around, including by the FDA," Kehoe said in response. "Certainly it's something we're struggling with and dealing with."