March 3, 2021

F.D.A. to Review Safety of Popular Bone Drugs

The panels and F.D.A. staff members are also expected to conduct a comprehensive safety review of the medical evidence to date, after 16 years of growing use of the drugs, to determine whether they have proved to be safe and effective in use longer than three to five years. The recommendation could affect many of the estimated four million women in the United States who take the drugs, called biphosphonates. Biphosphonates inhibit a bone renewal process called resorption, adding bone mass, but possibly causing brittleness as well.

Fosamax was first approved in 1995 to treat postmenopausal osteoporosis and Paget’s disease of the bone, conditions that weaken bones. It has also been marketed, controversially, for a pre-osteoporosis condition called osteopenia. The Fosamax patent expired in 2008 and generics have flooded the market.

The F.D.A. announced in July that it would convene a joint meeting of advisory committees on drug safety and reproductive health to reconsider osteoporosis drugs after evidence surfaced linking long-term use with unusual breaks of the femur or thigh bone, bone death in the jaw, and possibly esophageal cancer.

This summer, the F.D.A. has formulated the questions it will ask the panels of scientific advisers, which are often central to shaping the debate and outcome. The panels meet Friday in Adelphi, Md. The agency usually follows its advisory panels’ advice.

Biphosphonates reduce hip and spine fractures in some postmenopausal women. They include Fosamax from Merck, Boniva from Roche Therapeutics, Actonel and Atelvia from Warner Chilcott, and growing numbers of generic copies.

Worldwide sales of biphosphonates were $7.6 billion last year, down from a peak of $8.8 billion in 2007, with more than 75 percent of sales aimed at osteoporosis and the remainder at tumor-related calcium disorders, according to the data firm IMS Health. Dollar sales fell after Fosamax faced generic competition in 2008.

Ronald Rogers, a spokesman for Merck, said the company was responding to two questions from the F.D.A. One is whether the drugs have been proved to be safe and effective for longer term use, he said, while the other is whether to restrict that use or require “drug holidays.” Most research on the drugs is for three to five years, but many women take them indefinitely. Merck is planning to issue its report later this week, Mr. Rogers said.

His account of the questions was confirmed by a bone expert briefed on the F.D.A. plan, who declined to be identified because the F.D.A. is trying to keep it quiet until later this week.

Jeff Ventura, an F.D.A. spokesman, said the agency would disclose its questions and a staff report possibly on Wednesday. He declined further comment.

Last October, the F.D.A. ordered the makers of biphosphonate drugs to add a warning to their labels about a small increased risk of atypical femur fractures. In 2005, it added a warning about the rare jaw disease called osteonecrosis.

Because the risks may increase with the length of time the drug is taken, whether to impose a stronger warning or even a ban on long-term use is the chief issue facing the advisory panels and the government. There is not a consensus among experts, leaving some clinicians and women uncertain about what is best in individual cases. The F.D.A. recommends women continue taking the drugs as prescribed pending the safety review.

“The risk-to-benefit ratio strongly favors biphosphonate therapy,” said Dr. Elizabeth J. Shane, a Columbia University professor and bone specialist who was co-chairwoman of task forces on the femur and jaw issues for the American Society for Bone and Mineral Research. “And while we are upset and worried and do not want to do anything that would cause anybody harm, we don’t want to go back to 1990 and just have nothing for osteoporosis.”

Dr. Shane said the F.D.A. responded well to a society report last year by adding the label warning on atypical femur breaks. But she said other groups had not adopted the society’s recommendations to develop a specific diagnostic code and national registry to track them.

“We need to figure out who is at risk to have these strange fractures,” Dr. Shane said in an interview. Merck and other companies finance her research projects at Columbia.

Dr. Susan M. Ott, an associate medical professor and bone specialist at the University of Washington, who takes no research funds from industry, summarized the current science in a 12-page review article published by the Cleveland Clinic Journal of Medicine on Thursday.

“In my opinion, after five years in most cases it ought to be stopped,” Dr. Ott said in an interview. She prescribes the drugs for shorter periods, but said evidence shows growing risks and no proven benefits after five years.

“The longest anybody could have taken this drug is 15 years now,” Dr. Ott said. “It’s an ongoing experiment, and there are a few million women in the country who are participating in it. I keep wanting to say, ‘You’re all guinea pigs after five years because that’s when the studies stopped.’ ”

Dr. Paul D. Blumenthal, an F.D.A. adviser who cannot attend the meeting because of a schedule conflict, said he thought the panels might recommend a “drug holiday” for some women. But he termed it “kind of a weak escape” without the benefit of better science.

Dr. Blumenthal, who is a Stanford University professor and bone specialist, said he did not think there was convincing evidence of harm related to duration of treatment.

As the F.D.A. is issuing its report next Wednesday, lawyers will be selecting a jury for a bellwether Fosamax trial at the United States District Court in Manhattan. Linda Secrest, a Florida woman who used Fosamax from 1998 to 2005, is suing Merck for product liability. She has osteonecrosis of the jaw.

Merck is facing about 1,115 lawsuits over jaw damage and 535 over unusual femur fractures and other bone injuries, the company said last month in a quarterly report. Merck has won three of the first cases to go to court on the jaw damage and lost one, in which the jury awarded $8 million. Merck is appealing. Mr. Rogers said the company was defending all the cases vigorously.

Timothy O’Brien, a lawyer from Pensacola, Fla., who represents Ms. Secrest and the woman who was awarded $8 million, said the F.D.A. panels’ safety review was long overdue. “I’m very glad they’re finally doing a safety review after 16 years,” he said.

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