Are drugs for bones a threat to jaws?Rare side effect linked to treatments.
By Marie McCullough
Inquirer Staff Writer
Posted on Mon, Jun. 26, 2006
Across the country, dentists have begun asking patients a pointed question before deciding on treatment:
Do you take a bone-building medication such as Fosamax?
These widely used drugs, called bisphosphonates, have recently been linked to a rare side effect that causes parts of the jawbone to deteriorate and die.
The bulk of the 3,000 published cases of jaw osteonecrosis - meaning "dead bone" - have occurred after dental procedures, mostly in cancer patients on intravenous bisphosphonates. But the problem has also developed out of the blue in otherwise healthy people taking bisphosphonate pills to boost bone density.
"If you're going to be on this drug, make sure you really need it," said Alan Meltzer, a Voorhees periodontist.
Since 2003, when the first 36 cases were described in a medical journal, the Food and Drug Administration has required all bisphosphonate labels to include a precaution, hundreds of lawsuits have been filed against drug makers, and expert dental groups have issued advice for managing the tens of millions of people now on the drugs.
Still, there are no good treatments for what specialists have begun calling "bisphossy jaw." Nor is it clear that quitting the drugs reduces the risk, because bisphosphonates can persist for years in the bone. The incidence, variation and progression of the jaw disease are also unclear.
"What we have seen and heard from health-care givers is that more and more people are showing up with milder forms, so the true incidence rate now is anybody's guess," said John R. Kalmar, an Ohio State University oral pathologist and author of a May review article in Annals of Internal Medicine. "We're telling people to be cautious."
The advent of bisphosphonates about a decade ago was a boon for people whose bones were riddled by cancer treatment, osteoporosis, or a disorder called Paget's disease. Since 1995, 191 million prescriptions have been filled for oral Fosamax, Actonel, and Boniva, plus millions more for intravenous Zometa, Aredia and generic Pamidronate.
However, the benefits and risks of the drugs differ for these patient groups, experts say.
For people with advanced cancer, bisphosphonates can reduce the painful, crippling damage to bones that can be a side effect of cancer treatment. But studies suggest that 3 percent to 10 percent of such patients will develop osteonecrosis of the jaw, both because intravenous bisphosphonates are so potent and because cancer treatment itself is a risk factor for bone death.
Novartis, maker of Zometa and Aredia, says it has so far received reports of 2,500 cases of jawbone damage.
"The seriousness... ranges from being asymptomatic to requiring sections of the jaw to be removed," Novartis said in a May 2005 informational letter to dentists.
For healthy people seeking to boost bone density, the risk of jawbone death appears to be remote; the estimate from Fosamax maker Merck & Co. is less than one out of 100,000 patients per year.
On the other hand, many postmenopausal women taking the pills may not really need them. Low bone density does not automatically progress to osteoporosis, and even when it does, a debilitating fracture is not inevitable.
Crystal Baxter, a former University of Pittsburgh professor of prosthodontics who now practices in Arizona, said she is very leery of doing elective dental implants in patients who have taken oral bisphosphonates. "The scary thing," she said, "is that these drugs are being marketed to practically every aging woman in the world."
It has become clear - through trial and terrible error - that trying to fix bisphossy jaw with invasive dental procedures only makes it worse.
Ruth Ann Dutton, 66, of Atco, for example, went to her regular dentist after a shard of bone spontaneously broke through her gum. Although she had taken Aredia and Zometa for advanced breast cancer, the splintering of her jaw was not triggered by a dental procedure.
"He did a root canal, but it never got better," she recalled.
A year ago, she was referred to Meltzer, who prescribed antibiotics and antiseptic rinses.
"Right now, it's doing pretty decent," she said. "The hole is mostly closed up."
Barry Levin, an Elkins Park periodontist, said one of his elderly patients has not been as fortunate. She quit Fosamax after tooth extractions led to a diagnosis of osteonecrosis, but bone grafted to her damaged jaw has not healed properly.
"It's been a nightmare," Levin said.
Bisphosphonates build bone by tamping down the normal turnover of bone cells. Kalmar and other experts speculate that osteonecrosis develops when the drugs are too effective at suppressing bone regeneration.
Why hasn't the problem shown up after, say, hip replacement surgery? Experts say the jaws are particularly vulnerable because cells turn over faster there than in other bones. Jaws are also constantly exposed to minor trauma from chewing, and to bacteria from the mouth.
"Unlike the hip, the mouth is not sterile," said Long Island Medical Center oral surgeon Salvatore Ruggiero, whose 2004 article on bisphossy jaw was among the first.
A similar phenomenon, dubbed "phossy jaw," was recognized in the mid-1800s among match factory workers who chronically inhaled the phosphorus on match tips.
"The onset of the disease was generally quite slow, an average of five years... The lower jaw was more commonly affected than the upper jaw, exactly as seen in the bisphosphonate-associate osteonecrosis," Heiner K. Berthold, a drug expert with the German Medical Association, wrote this month in Annals of Internal Medicine. "Many patients committed suicide because of pain and disfigurement."
Novartis - which received the first report of jaw osteonecrosis in December 2002 - says it has made public the cases it knows about. It also enlisted M.D. Anderson Cancer Center in Texas to review patient records and try to gauge the incidence among the 2.8 million patients treated worldwide with Aredia or Zometa. It has sent letters and brochures to inform physicians and patients and formed an expert advisory committee on which Ruggiero sits.
But makers of oral bisphosphonates - Merck, Roche (Boniva) and Procter & Gamble (Actonel) - have done little to alert patients other than updating their labels as required by the FDA. Merck has also put information on its Web site.
These firms stress that in research studies involving tens of thousands of patients, no cases of jaw osteonecrosis were reported.
More recently, "we have received rare reports," said Merck spokesman Chris Loder.
Not so quiet are dozens of law firms now seeking injured clients through advertising online and on television and radio.
Advice for Patients
Although osteonecrosis of the jaw is not well understood, the American Dental Association and other expert groups have issued recommendations.
Before starting bisphosphonates, have a comprehensive dental exam and treat any tooth or gum problems.
While on bisphosphonates, make sure to brush and floss daily, and get regular dental care. If you need an invasive dental procedure, discuss the risks with your doctor. Seek the most conservative possible treatment. Avoid elective procedures that would require bone to heal.
If dental surgery is necessary, consider taking antibiotics and use daily oral rinses.
If osteonecrosis develops, special imaging studies, such as computed tomography scans, may help with diagnosis and treatment. Consider discontinuing bisphosphonate therapy until the jaw heals. If dead bone must be removed, it should be done with as little trauma to adjacent tissues as possible.
Contact staff writer Marie McCullough at 215-854-2720 or firstname.lastname@example.org