Atlantic City, NJDentists and oral surgeons are becoming increasingly worried about the rising number of patients they are seeing with osteonecrosis (ONJ).
ONJ is a painful, disfiguring, debilitating condition that essentially rots the jawbone, as a result of millions of Americans taking the relatively new class of osteoporosis medications.
The drugs belong to a class of medications known as bisphosphonates, and the most popular by far is Merck's Fosamax, which has been on the market for about a decade.
EM>Fosamax is Merck's second best selling drug, with revenue last year of $3.2 billion. According to the market research firm, Verispan, 4.2 million prescriptions were written for Fosamax in 2005.
Other drug makers market lesser known bisphosphonates, Procter & Gamble together with Sanofi-Aventis, markets Actonel, which gained FDA approval in 2000, and GlaxoSmithKline and Roche market Boniva which became available last year.
A small number of patients also receive intravenous versions of the bisphosphonates, Zometa and Aredia, as part of cancer treatment.
Critics say the drastic increase in the sale of these drugs over the past several years, to mostly women who are too young to even need them, is due to massive advertising campaigns aimed at consumers in their 40s and early 50s, with the intent that the newly recruited customers will take the drugs for life.
According to the market research firm, TNS Media Intelligence, in 2005 the drug makers combined spent more than $174 million advertising bisphosphonates, up from $54.8 million in 2003, before Boniva was added to the mix.
In treating osteoporosis, according to the August 3, 2006 Dallas Morning News:
"Bisphosphonates work by targeting the cells that constantly remodel internal bone structure. The engines of this turnover are cells called osteoclasts that clear away old bone, and cells called osteoblasts that form new bone in its place. Bisphosphonates slow the work of osteoclasts, but by doing so, also affect osteoblasts because the two work in tandem."
About 5 years ago, dental professionals first began suspecting a link between bisphosphonates and ONJ, and in 2004, the FDA acknowledged that it had received reports of the condition, mainly in cancer patients receiving the drugs intravenously and recommended that the professional product labeling for the drugs be revised to warn of the possibility of ONJ, but the changes to the labeling were not made until 2005.
Earlier this year, the American Association of Endodontists advised dental surgeons to consider patients on bisphosphonates to be at risk for ONJ.
Because many patients have now been on the drugs for several years, and because more and more prescriptions are being written for the drugs each year, experts say a high number of cases of patients with ONJ are expected to surface over the next few years.
And even though the warnings about the risk of ONJ are now being publicized, the problem for people who have been taking the drugs for years is that even if they quit, bisphosphonates remain in the bones indefinitely.
In addition to causing unbearable pain that often cannot be relieved with ordinary painkillers, ONJ can lead to the loosening of teeth and loss of dental implants, and a host of other problems such as difficulty eating, infections of the face and neck, halitosis, and headaches.
Experts are uncertain why the use of these drugs leads to ONJ. On June 15, 2006, Dr Brian Alpert, a maxillofacial surgeon at the University of Louisville School of Dentistry, told the Louisville Courier-Journal that the bisphosphonate may shut down the production of the osteoclasts, making it difficult for the bone to respond and recover if an infection sets in. In the mouth, where bacteria can actually reach the bone, he says, the drug makes it impossible to fight that bacteria.
A February 2006, study in the Journal of Obstetrics & Gynecology and Reproductive Biology, found that Fosamax caused significant DNA damage in white blood cells in 32 postmenopausal women over a 12-month period. White blood cells are key components of the body's immune system so critics say that even the possibility of such an effect is troubling.
Whatever the cause, experts warn that there is no cure and that the cases of ONJ are on the rise. Dr Alpert told the Courier-Journal that in 36 years of practice he has seen fewer than 5 cases but that he has now seen seven cases in the course of one year.
"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," Dr John Kalmar, an Ohio State University oral pathologist and author of a May 2006 review article in Annals of Internal Medicine, told the Philadelphia Inquirer on June 26, 2006.
Studies have also shown that over time, Fosamax may not accomplish its intended goal of preventing fractures, because experts are finding that the drug may indeed increase bone density but the bones of patients on Fosamax are more brittle and thus more likely to fracture.
In April 2006 the first Fosamax class action lawsuit against Merck was filed in Florida, claiming not only that the company knew about the ONJ risk but also that it refused to study the matter further and ignored requests by the FDA in 2004 to warn consumers about the condition.
According to the October 6, 2006 Chicago Tribune, some 15 class action lawsuits against Merck have been filed in the US. "This is a once-in-a-decade case," Pensacola, Florida, attorney Tim O'Brien, who specializes in pharma litigation and filed the first class action, told the Tribune.
"This is so rare," he says, "that you can actually trace back the injury to the cause of the injury."
"It's a signature injury," he told the Tribune.
In one of the latest public warnings, on October 11, 2006, the Pennsylvania Dental Association issued a press release to inform the public about ONJ and said that over "a thousand cases of ONJ had been reported in patients undergoing bisphosphonate treatment."
The press release referred to one of the largest reports on bisphosphonate-associated ONJ, in an article by Dr Salvatore Ruggiero, chief of the Division of Oral and Maxillofacial Surgery at the Long Island Jewish Medical Center.
"The patients represented in this series of case reports," the group wrote, "were preponderantly female and typically presented with bone pain, nonhealing extraction sockets or exposed bone."
"Most cases of osteonecrosis of the jaw associated with bisphosphonates have been diagnosed after dental procedures such as tooth extraction," the press release said, "however, the condition also can occur spontaneously," it warned.
"Because invasive dental procedures, such as gum surgery, extractions, or other surgery that affects the bone, can worsen bisphosphonate-associated oral conditions," the Dental Association advised, "anyone that has taken bisphosphonates should advise his or her dentist."
"It is especially vital that patients report any symptoms or oral changes to their physician or dentist," said Dr Sean Boynes, a PDA member and assistant professor at the University of Pittsburgh School of Dental Medicine.
"In addition," he added, "patients who have begun bisphosphonate therapy should have consistently scheduled dental hygiene appointments."
"The regularity of these evaluations is usually at the judgment of the treating physician or dentist," he wrote, "but could occur as often as every 3 months."
After being diagnosed with and researching ONJ, Dr Beverly Hurwitz, a Salt Lake City doctor who treats chronic pain, told the Salt Lake Tribune on June 26, 2006, that she sent out about 50 warning letters to dentists and oral surgeons in Utah. But as she only received a few replies, she says she is worried that dentists and the public are still uninformed about the condition.
"I know there are millions of women who are on these drugs who need a root canal or other work," Dr Hurwitz told the Tribune. "There are probably thousands of people who have this and haven't been diagnosed."
"People say this is a rare condition," she states, "but it's only rare because it hasn't been identified."
Dr Patrick Brain, an oral surgeon in Sandy, Utah, says more dentists and oral surgeons are becoming educated about the link between Fosamax and ONJ. "It's a big problem, and it's becoming more pervasive," he told the Tribune.
In the end, neither the warnings nor the lawsuits have slowed the sales of Fosamax. According to Merck's latest SEC filing, global sales for Fosamax were $771 million for the third quarter of 2006, representing a decrease of only 1% compared to third quarter 2005, and US sales for the quarter increased 7%. Overall, the company reported global sales for the first nine months of $2.3 billion, and Fosamax products remain the most prescribed drugs worldwide, Merck says, for the treatment of postmenopausal, male and glucocorticoid-induced osteoporosis.