Evelyn Pringle August 16, 2006
Merck's second-best selling drug, Fosamax, has been linked to jaw bone death, a condition that can involve severe pain, infection, loose teeth, exposed bone, loss of function and disfigurement, according to the American Association of Oral and Maxillofacial Surgeons. And yet sales of the drug remain steady with no decrease whatsoever.
Aside from causing unbearable pain that can not be relieved by ordinary painkillers, osteonecrosis of the jaw (ONJ), can also lead to infections of the face and neck, headaches, bad breath, and difficulty eating. In severe cases, patients may have difficulty breathing or require a feeding tube to avoid malnutrition, according to the July 27, 2006, Sidney Morning Herald.
The debate over the cause of the rise in cases of ONJ picked up speed in 2003, when Dr Robert Marx, chief of oral and maxillofacial surgery at the University of Miami, wrote a paper in the Journal of Oral Maxillofacial Surgery and referred to osteonecrosis of the jaw as "a growing epidemic."
Dr Marx cited 36 patients who had received intravenous bisphosphonates, the class of drugs to which Fosamax belongs, and experienced "painful bone exposure," and "were unresponsive to surgical or medical treatments."
Other bisphosphonates include Actonel, Boniva, Bonefos, Didronel, Aredia, Skelid and Zometa.
Since 2003, more than 3,000 published cases of ONJ have been reported, according to the July 24, 2006, Goldsboro News-Argus. While most of the cases involve cancer patients on the intravenous versions of the drug, a few years ago, ONJ began turning up in otherwise healthy women taking Fosamax to increase bone density.
Most documented cases have been in people who have had a tooth extraction, a root canal, oral surgery or some other type of mouth trauma. At present there is no effective treatment or cure for ONJ.
According to John Matthews, vice-president of the Australian Dental Association, "Normally you would treat a condition like this by performing surgery to remove the dead bone."
But the problem is that the drug deposits in the entire skeleton and surgical intervention, which may bring temporary relief, simply exposes more bone to infection and death.
And stopping Fosamax before dental work, experts say, will not lower the risk of ONJ because the drug remains in the bones for up to 10 years.
Experts say that despite the FDA warning sent to prescribing physicians in 2004, its been an uphill battle getting medical professionals to recognize the seriousness of the problem. While most dentists and oncologists are aware of the danger, doctors who commonly write the prescriptions for Fosamax seem to be far less informed because there has been virtually no decrease in the number of prescriptions written for the drug.
Until recently Fosamax was prescribed to older women with osteoporosis, a known risk factor in bone fracture. But in recent years, Merck has aggressively promoted the drug for use by much young women still in their 40s and 50s, who have minimal risk factors. And due to an intentional marketing strategy by Merck, these younger women are being advised to stay on Fosamax for the rest of their lives.
Experts warn that the risk of ONJ in younger women is actually higher than with elderly women because they are more likely to have all their teeth and the potential need for future extractions, implants, or dental surgery is higher.
Although Fosamax may improve bone density, as far as fracture prevention, experts say its benefits are modest and that in fact, if taken for more than ten years, the drug can actually make bones more brittle and more likely to fracture.
Fosamax entered the US market in 1995, and within 10 years, it became Merck's second best selling drug, with world-wide sales of $3.2 billion in 2005, and over 22 million prescriptions written in the US alone, according to the drug research firm IMS Health.
It was the first oral bisphosphonate to gain FDA approved and is the biggest seller in its class. Merck's SEC filing for the second quarter of 2006, reports Fosamax sales of $821 million.
Because Fosamax is relatively new, experts say, the long term risk of ONJ is unknown. In addition, unreported cases of may be considerable, according to Diane Wysowski of the FDA's Office of Drug Safety, because doctors may attribute the pain caused by the condition to osteoporosis.
Dr Gregory Lutcavage, an oral and facial reconstructive surgeon, told Argus-News, there are three bisphosphonate drugs under scrutiny: Fosamax, Aredia, and Zometa.
In the early 1990s, he said, the intravenous version of the drug, Aredia and Zometa, were primarily used in treating bone cancer to prevent bone and spinal fractures. He says both drugs were excellent because they prolonged and improved the cancer patient's quality of life.
But Fosamax, taken orally, and for far less serious conditions, has become a different matter since dentists began noticing patients on Fosamax whose dental extractions would not heal properly.
This is not the first time problems have surfaced with this type of drugs, Dr Lutcavage advises. As far back as 1846, he says, there were reports of patients having jaw problems as the result of the cumulative effect of the drugs.
With oral versions of these medications being prescribed more frequently, Dr Lutcavage told Argus-News, this is just the tip of the iceberg. As time goes on, he anticipates more cases in younger patients.
"What scares me the most are the ones that are not cancer patients," he says. "Some of these patients are going to be in their mid-40s and on."
Complicating the issue further is the fact that the effects are not readily seen; they're cumulative, he warns. "(Patients) may be on these drugs for a long period of time; it may not show," he said.
The average time for the IV medications is 12.7 months, he says, but Fosamax is a little over three years.
For people on these drugs, Dr Lutcavage cautions against doing anything to remove teeth because of the adverse effects that could result. "We're looking at a loss of jaw," he said.
And while reconstruction is an option by installing a titanium plate instead of bone replacement, he told Argus-News, he fears the plates and screws will loosen up over time.
The treatment available is merely symptomatic. "We just try to get them comfortable again," he said. "It's going to get to the point where people will have to live with exposed bone because we don't have the treatment."
Dr Susan Ott, an osteoporosis expert at the University of Washington, told the LA Times on April 6, 2006, that the issue is especially worrisome because the number of women taking bisphosphonates is likely to increase because women are now reluctant to take estrogen for menopause. "These drugs are still relatively new and problems sometimes take years to show up," she said.
"We're not quite sure what we're dealing with over the long haul," she told the Times. "Side effects like this should make ordinary, healthy women think twice."
The Times set off a fire storm among internet bloggers when it published a letter from Dr David P Eisenman, Assistant professor at the David Geffen School of Medicine at UCLA, in response to the article that said in part: "Congratulations for unduly frightening hundreds of little old ladies."
A woman name Elizabeth responded with: "Now, if that isn't the most chauvinistic, demeaning, and condescending comment I've ever read, I don't know what is."
"There are plenty of women taking Fosamax and other bisphosphonates," she wrote, "who are not little old ladies."
"And so what if some of them are little and they are old?" she added. "Does that mean they can't reason," she wrote, "that they can't ask questions about the medications they put in their bodies?"
"I am sickened by the attitudes of male doctors toward these "little old ladies" and indeed "ladies" in general," Elizabeth continued.
"If you wonder why the people are getting fed up with doctors this is a perfect example," she told the doctor, "Your flippant attitude about something as serious as jaw necrosis is horrifying."
In any event, experts are not so sure that the number of women with ONJ is minute. "We've uncovered about 1,000 patients in the past six to nine months alone, so the magnitude of the problem is just starting to be recognized," Kenneth Hargreaves, chair of the endodontics department at the University of Texas Health Science Center, told the LA Times on April 3, 2006.
According to Dr Salvatore Ruggiero, "Even though the chances of getting this are small, considering there are 23 million women taking this drug, we could be talking about a significant number of people," he said in the Times article.
"Risks increase the longer you're on the drugs," he advises, "and it can take years for the complication to manifest itself."
And, since it is known that at least 90% of drug side effects are never reported to the FDA, experts warn that the actual number of people stricken with ONJ is definitely much higher.
In April 2006, the American Association of Endodontists released a position statement saying: "Until further information is available, it would appear prudent to consider all patients taking bisphosphonates to be at some risk."
So how does Merck get doctors to keep right on prescribing Fosamax? Well for starters, on July 28, 2006, the New York Times, reported that on a recent Tuesday, "Steaming containers of Chinese food were destined for the 20 or so doctors and employees of Nassau Queens Pulmonary Associates."
And the newspaper said Merck picked up the $258 tab.
Dr John Scott, assistant professor of family medicine at the University of Medicine and Dentistry of New Jersey - Robert Wood Johnson Medical School, has been examining the interaction between medical practices and pharmaceutical sales representatives.
“We found that some offices get breakfast and lunch every day,” Dr Scott told the Times.
He calls lunch the “currency” that buys access to doctors’ offices for sales representatives and notes that some doctors, hard pressed to meet payrolls, say the lunches provide an added benefit to their employees.
According to Dr Scott, most doctors claim they were not influenced by food deliveries and other small gifts, but he told the Times, “They do influence prescribing.”
As it turns out, when broken down per employee, the $258 lunch only cost Merck $10.75 per person, which is reportedly within industry guidelines that allow for the purchase of modest meals.
But the $258 lunch could easily return thousands of dollars, the Times points out, in prescriptions for Fosamax and Singulair, "the two drugs discussed during lunch with two Merck representatives."
Dr Scott cited several studies that found the lunches and other small gifts and free drug samples do lead doctors to prescribe the more expensive brand names when cheaper generic versions of the same drugs are available and effective.
These concerns have resulted in an effort to ban the free meals. The hospital at the University of Pennsylvania began barring industry-paid lunches, effective July 1, 2007, its medical director, Dr Patrick Brennan told the New York Times.
“It curries favor and it creates influence, and it introduces influences into decision-making processes that we think ought not to be there,” he said.
The University of Michigan Health System barred drug company sponsored lunches last year, and according to the Times, officials estimate the lunches had been worth $2.5 million annually.
According to Merck there were no signs of the ONJ in clinical trials sponsored by the company. However, a deeper look at Merck's studies reveals the company often maintains total control over what studies are published.
For instance, for a 2002 paper touting the benefits of Fosamax for the treatment of osteoporosis, the paper's lead author, Susan Greenspan, was a professor at Harvard Medical School at the time, and Merck (1) paid for the recruitment and participation of 327 study subjects; (2) collected the data from 25 separate study sites; (3) coordinated the early phases of the study; and (4) provided expertise in study conduct. Merck also retained full control and ownership of the research.
Moreover, these days universities have all kinds of conflicts of interest stemming from financial ties to the industry. For example, according to an April 12, 2006, article in The Phoenix, overall, Harvard Medical School now receives nearly a quarter of its research funding from nonfederal sources, including to $2.1 million from Merck, and a recent Harvard SEC filing shows a holdings of $16 million worth of Merck stock.
In any event, according to Dr Eric Colman, of the FDA's Division of Endocrine and Metabolic Drugs, serious adverse reactions that may not have been apparent in pre-marketing studies emerge in half of all approved prescription drugs. "People need to realize there are unknown side effects with every drug, and these medications are no exception," he told the LA Times.
For Dr Lucavage, the whole situation involving ONJ has been very frustrating, especially watching patients suffer, he says, while drug companies delayed going public about the risks. "One drug company did not come out with the update to their circular until about three or four months ago," he told Argus-News. "We were seeing this three years ago."
"I said to my partners several years ago," he says, "this is a class action suit waiting to happen."
Apparently, the doctor is psychic because on July 11, 2006, the LA Times reported: "As Merck & Co. defends itself against a deluge of litigation involving its pain reliever Vioxx, the pharmaceutical giant also is fielding the first of what could be another wave of lawsuits involving Fosamax, its second-biggest seller."