(06/02/06)The New York Times
By GINA KOLATA
Published: June 2, 2006
In the last 10 years, millions of patients have taken a class of drugs that can prevent agonizing broken and deteriorating bones. The drugs once seemed perfectly safe and have transformed life for patients with cancer or osteoporosis.
But recently there have been reports of a serious side effect: death of areas of bone in the jaw. Everyone agrees that the condition, osteonecrosis of the jaw, is an uncommon complication, but that its true incidence is not known. It is estimated that among the 500,000 American cancer patients who take the drugs because their disease is affecting their bones, 1 to 10 percent may develop the problem.
As for the millions of osteoporosis patients, who take lower doses, the condition seems less common. But no one knows how much less. Some oral surgeons have as many as a couple of dozen cases, but their clinics have become centers to which patients elsewhere are referred. Among people with osteoporosis, only 15 cases of the new ailment have been reported in the medical literature.
So for now, doctors and dentists are perplexed. Firm data are scarce to nonexistent, studies that may provide answers are only about to begin, and medical organizations and drug companies are scrambling to provide guidance, often based only on hunches. Some dentists are refusing to treat patients taking the drugs, fearful that the dental work will induce a case of osteonecrosis, and lawyers are lining up to sue the drugs’ makers, saying they failed to give patients adequate warning.
Doctors say worried patients hearing about the ailment are starting to besiege them. The patients want to know whether they should stop taking the drugs, called bisphosphonates. They want to know whether they should shun invasive dental procedures, like tooth extractions and implants, which appear to set off the condition. They want to know whether osteonecrosis of the jaw can be treated and, if so, how likely it is that a person will recover.
Some patients who have not developed osteonecrosis have decided to stop taking the drugs until more is known “I’m giving myself a little holiday,” said Judy Langley, 63, of Anacortes, Wash., who because of osteoporosis has been taking a bisphosphonate for seven years.
Doctors also say the level of alarm among patients, as well as some physicians and dentists, is itself alarming. “The whole thing has spun out of control,” said Dr. Ethel Siris, director of the Toni Stabile Osteoporosis Center at Columbia University.
The Food and Drug Administration is aware of the issue, said Laura Alvey, a spokeswoman, and has required that all bisphosphonate labels disclose the link to osteonecrosis of the jaw. The problem is that patients cannot easily abandon the drugs. Cancer patients, mostly those with multiple myeloma and breast cancer whose disease has spread to their bones, generally take one of two bisphosphonates, Zometa or the older Aredia, intravenously. The drugs, doctors say, largely prevent excruciating bone pain and fragile bones that break like kindling.
Osteoporosis patients, on the other hand, usually take bisphosphonates as pills, in much lower doses. Those drugs Fosamax, Actonel and Boniva reduce the risk of fractures of the spine or hip, injuries that can create a steady downward spiral in patients’ condition.
Even if patients stop taking the drugs, they are not free of them. Bisphosphonates remain in bone for years, and no one knows how long the osteonecrosis risk remains. Some doctors and dentists suggest stopping the drugs for a few months before and after an invasive dental procedure. Others say six months to a year may be better.
As for what happened to patients who developed the condition, oral surgeons say some got better but many did not. It now appears that the best treatment is with antibiotic rinses; cutting away the dead bone just made things worse.
So little is known, said Dr. Bruce L. Pihlstrom, acting director of the division of clinical research at the National Institute of Dental and Craniofacial Research that the most fundamental questions lack answers. The institute is starting studies, but for now “we have to be careful that we’re not too alarmist about this,” Dr. Pihlstrom said. “We just don’t have the information we need.”
The story of bisphosphonates (pronounced bis-FOS-fo-nates) began in 2003 with a letter in The Journal of Oral Maxillofacial Surgery calling osteonecrosis of the jaw “a growing epidemic.” Its author, Dr. Robert E. Marx, chief of oral and maxillofacial surgery at the University of Miami, reported on 36 patients who had received intravenous bisphosphonates. All had “painful bone exposure,” as is typical with the condition, and “were unresponsive to surgical or medical treatments,” Dr. Marx wrote. “The common denominator,” he said in a telephone interview, “was that they all had cancer. Then we started looking at their treatment. The one common thread was bisphosphonates.”
But not everyone was convinced. “My first reaction was that maybe there is an association but this wasn’t enough,” said Dr. Regina Landesberg, an oral and maxillofacial surgeon at Columbia University. “I wanted to see more data.”
Meanwhile, another oral and maxillofacial surgeon, Dr. Salvatore Ruggiero of Long Island Jewish Hospital, was gathering his own data. At first he saw patients with breast cancer or multiple myeloma who arrived with exposed bone in their mouths. “It looks like a piece of ivory with little tiny holes in it,” Dr. Ruggiero said. “The one drug they were all on was bisphosphonates.” He tried scraping away the dead bone and letting it heal, but that only made things worse. “We were creating a larger bone wound that didn’t heal,” Dr. Ruggiero said. He called local cancer specialists, but “they said they did not have any experience with this kind of complication.” He contacted Novartis, which makes Zometa and Aredia, the intravenous drugs. “They had no record of the problem,” Dr. Ruggiero said.
Dr. John A. Hohneker, vice president for oncology medical affairs and services at Novartis, said the company got its first patient report in December 2002. “We did a literature search looking for osteonecrosis of the jaw,” Dr. Hohneker said. “There are a lot of unknowns there. There really isn’t even a consistent definition of what osteonecrosis of the jaw is, and the true incidence is unknown.”
But as case reports began to trickle in, Novartis put a warning of the condition on the drugs’ labels, even before the F.D.A. required it, and appointed an advisory board, which included Dr. Ruggiero. In the meantime, Dr. Ruggiero and others had noticed something new: osteoporosis patients taking bisphosphonate pills who had developed osteonecrosis of the jaw. In 2004, he published a report on 63 patients 56 with cancer, the rest with osteoporosis.
Still, the number of reported cases remains tiny. A recent article in The Annals of Internal Medicine reviews the published papers. They include reports of osteonecrosis in 388 cancer patients; 3 patients with Paget’s disease, a degenerative bone disorder treated with oral bisphosphonates; and 15 with osteoporosis.
The authors of that article, led by Dr. Sook-Bin Woo of the School of Dental Medicine at Harvard, estimated the risk for cancer patients taking intravenous drugs at 6 to 10 percent. The risk for osteoporosis patients, taking the lower doses, is unknown, they said. But Dr. Catherine H. Van Poznak, a breast cancer specialist at the University of Michigan, said it was very hard to get good estimates of risk from the sort of data, mostly case reports, that have been published so far. “The case definition in one report can be different from the case definition in another,” Dr. Van Poznak said. And not every case has been published or reported. “We’ve seen about 20 patients at Columbia,” Dr. Landesberg says. “But it’s so impossible to get a handle on what the incidence is. You just don’t know.” Lawyers, though, are advertising for plaintiffs and beginning to file suits. Novartis says it does not comment on litigation. Merck, which makes Fosamax, a bisphosphonate for osteoporosis, says 15 suits have been filed against it, while Roche, which makes Boniva, used for osteoporosis, reports none. Two suits have been filed against Procter & Gamble, which makes Actonel, for osteoporosis, and Didronel, for Paget’s disease. All the companies say osteonecrosis never emerged in their clinical trials, involving tens of thousands of patients.
As professional medical and dental societies formulate guidelines, scientists say that what they really need are some good studies, which are only about to begin, as to what advice is helpful. Drug holidays, for example. Should cancer patients stop taking bisphosphonates for a year or so and then start again? Should osteoporosis patients stop periodically? “The pharmaceutical industry has every desire that a patient who starts on a bisphosphonate would take it for life,” said Dr. Robert Gagel of the M. D. Anderson Cancer Center in Houston. “The bone community, of which I am a member, has always been a bit suspicious of that viewpoint.”
Some patients say they are left unsure of the medical advice they have already been given. Joan McDevitt, 53, of Franklin, Me., took steroids for an eye problem, a treatment that may increase the risk of osteonecrosis. Then, with low bone density, she began taking an oral bisphosphonate. A year and a half later, this February, she had an infected tooth extracted. The hole would not heal, and pieces of bone from her jaw kept splintering and coming out. Her oral surgeon, Ms. McDevitt said, “cut into the jaw he cut and filed the bone down.” It did not help. “I had horrible sores back there,” she said, “ungodly painful sores. I was in agony. I had never had anything like that in my life.”
Ms. McDevitt is now no better. “I still can’t eat on that side of my mouth,” she said. “The skin is really thin, and it’s still sore.” Her oral surgeon never mentioned osteonecrosis, but her doctor’s partner figured it out. She stopped taking the bisphosphonate. “Hopefully it will heal,” Ms. McDevitt said. “It’s pretty scary.”