[PHNUTR-L] Drug for Bones Is Newly Linked to Jaw Disease

[Kathrynne Holden, MS, RD]

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Drug for Bones Is Newly Linked to Jaw Disease
By GINA KOLATA
http://www.nytimes.com/2006/06/02/health/02jaw.html?_r=1&th&emc=th&oref=login

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."
-- 
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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