Bone-building drugs linked to bone-rotting side effectJun 13, 2006 | Star Ledger Michael Erlichman walked into his dental office last week and encountered a patient with an unusual but growing problem.
An elderly woman was complaining about soreness caused by her dentures, but there was nothing Erlichman could do to relieve her pain. That's because she suffers from a rare jawbone disease that is increasingly being linked to a group of drugs for osteoporosis and cancer. And he noted she'd been taking one of those drugs for several years.
"There's more concern about this all the time now," said Erlichman, an oral surgeon in Little Falls. "The drugs are known to truly help people, but they can also cause the jawbone to become inert to the point where you can't drill a cavity or perform an implant.
"You can't do anything with these patients. And I worry about others developing the problem."
Each year, millions of Americans seeking to ward off brittle bones take pills that belong to a class of medicines called bisphosphonates. By far, the most popular pill is Merck's osteoporosis drug, Fosamax, which has been available for a decade. A much smaller number of patients receive an intravenous version of the medication as part of their chemotherapy.
To date, the incidence of drug-induced jawbone disease remains rare. Researchers report fewer than 400 cases of the disease, known as osteonecrosis, a painful and debilitating condition that essentially rots the jawbone. And the vast majority of these cases 94 percent are associated with a pair of intravenous medicines sold by Novartis, according to an article last month in the Annals of Internal Medicine.
Nonetheless, oral surgeons and dentists are increasingly worried the number of cases will multiply, and warnings have been posted on Web sites run by their professional groups. The problem, they say, is that bisphosphonates remain in the bones for years. Given that more prescriptions are written each year for the pills, which include Actonel and Boniva, experts suggest the rate at which osteonecrosis will be diagnosed is likely to increase.
"The concentration in the bones begins to build up by the third year. So it's not surprising that we're starting to see more cases among people who take the pills," said Robert Marx, who chairs the oral and maxillofacial surgery department at the University of Miami medical school, and who first sounded the alarm about the problem three years ago.
Although Fosamax has been prescribed since 1995, usage grew dramatically about five years ago, which Marx said would explain why cases linked to that pill are only now being diagnosed. Actonel has been available since 2000, and Boniva was launched last year. Marx said he doesn't expect to see as many cases associated with those pills right now.
Marx believes Merck researchers didn't anticipate the extent to which bisphosphonates can effect the jaw compared with other bones. In his view, the Fosamax clinical trials should have looked for the problem. If they had, Marx said, "they could've predicted this might have occurred."
A Merck spokesman responded that Fosamax is linked to a very small number of cases compared with the millions of people who have taken the pill. In 1997, for instance, 1.5 million new prescriptions were written for Fosamax; that figure jumped to 4.5 million by 2002, but slid to 4.2 million last year, according to Verispan, a market-research firm.
The idea that greater use will result in an increased risk of osteonecrosis "isn't substantiated by the current data," Merck spokesman Chris Loder wrote in an e-mail. "To suggest so would be misleading and incorrect." But at the request of regulators, Merck last year changed Fosamax labeling to mention osteonecrosis has been reported among patients taking bisphosphonates.
Two studies about to be published are expected to substantiate that view, according to the lead author, Marjorie Jeffcoat of the University of Pennsylvania dental school. One study traced 320 Fosamax patients for two years and the other tracked 80 Fosamax and Actonel patients for five years.
"The data didn't show a cause and effect," said Jeffcoat. However, she noted the data didn't provide a definitive answer about whether a bisphosphonate pill could cause osteonecrosis if taken for a lengthy period of time.
The Merck spokesman added that no cases of osteonecrosis were found among 17,000 patients in its clinical trials, although he acknowledged the company has received side-effect reports. However, he argued these reports "do not necessarily indicate causality," declined to provide the number of side-effect reports received.
An FDA spokeswoman, Laura Alvey, said she could not immediately provide the number of side-effect reports the agency has received involving bisphosphonates and osteonecrosis.
Paula Koenigs, a spokeswoman for Procter & Gamble, which markets Actonel with Sanofi-Aventis, said there is no scientific study that concludes bisphosphonates cause osteonecrosis, and the jawbone disease wasn't seen in clinical trials.
Maureen Byrne, a spokeswoman for Roche, which jointly markets Boniva with Glaxo, said osteonecrosis wasn't seen in trials.
Nonetheless, the growing concerns about osteonecrosis are prompting lawsuits against the drugmakers. So far, Merck faces at least 15 lawsuits over Fosamax, while two have been filed against Procter & Gamble and Sanofi-Aventis.
One Florida lawyer, who is in the process of filing additional lawsuits against Merck, argued the company has failed to properly warn patients. He maintained that despite a 2004 report by the FDA's Office of Drug Safety, Merck hasn't added meaningful language in the Fosamax label to specifically indicate the risk of osteonecrosis.
"They never come out and say it's a risk factor," said Tim O'Brien, who noted that Novartis is so far the only company to have sent letters to doctors about the risk. "You have to read between the lines (of the product labeling) and read the medical literature to understand what they actually are saying. It's very misleading."
He added the FDA has cited Merck for being too aggressive in promoting Fosamax. The agency sent four letters between 1997 and 2001 for making unbalanced or misleading claims in promotional brochures or consumer advertising.
Lawsuits alleging damaging side effects caused by prescription drugs are increasingly common. The Vioxx scandal has generated more than 11,500 lawsuits against Merck. By comparison, the number of Fosamax lawsuits is minuscule, but the specter of more bad publicity doesn't thrill Wall Street.
"This is definitely a headache that the big drugmakers, especially Merck, don't need," said David Moskowitz, an industry analyst at Friedman Billings Ramsey, who noted Fosamax generated $3.2 billion in sales last year. "Merck has few growth drivers, and they can't afford for Fosamax to sustain too much damage."
One solution might crimp Fosamax sales. Hillel Ephros, who chairs the dentistry department at St. Joseph's Regional Medical Center in Paterson, wants doctors to consider alternatives before writing prescriptions for the pills.
"Everyone needs to know that osteonecrosis can't be fixed," said Ephros, who has seen seven cases of the disease. "The problem makes me feel shackled and frustrated. We have to defer and postpone procedures for patients on oral bisphosphonates, and the day may come when I will decline altogether. Maybe that can be prevented."
The drugmakers are advertising their pills widely. Last year, they spent $174.3 million, up from $54.8 million in 2003, according to TNS Media Intelligence, a market-research firm. That's because Boniva was launched last year with a big promotional effort, prompting Procter & Gamble and Sanofi-Aventis to spend more on Actonel.
One doctor suggests ads should explicitly and prominently mention the possibility the pills can cause osteonecrosis. Salvatore Ruggiero, chief of oral and maxillofacial surgery at Long Island Jewish Medical Center in New Hyde Park, N.Y., believes the risk of developing osteonecrosis is "very small," but few know it exists.
"The problem has taken a long time to manifest itself, and so I think it'd be unfair to say these drug companies expected this to happen. That'd be a real stretch. The lawyers are creating a perception that it's a big problem," he said. "But we need to realize that there is this side effect. And it needs to be better known."
For Mary Kyle, the debate is taking place too late.
A retired elementary school teacher who lives in Mount Laurel, Kyle said she was prescribed Fosamax four years ago to prevent osteoporosis, but recently was diagnosed with osteonecrosis after complaining of jaw pain. Last week, she filed a lawsuit against Merck.
"I was told I'll have this problem for the rest of my life," said Kyle, 58. "My oral surgeon couldn't give me much hope there's anything he can do. Now, I want to educate others. There are a lot of people on this drug and this problem may happen to them, but they may not know the drug is causing the problem."