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For several years medications prescribed to combat osteoporosis have been linked to a widely publicized condition in which jawbone tissue dies. Dr. Thomas B. Dodson explains: “Bisphosphonate-related osteonecrosis of the jaw’ is a mouthful.” His expertise is oral and maxillofacial surgery at Massachusetts General Hospital. He’s an expert on, let’s just call it BRONJ.

The problem has been linked to drugs called bisphosphonates, ranked 10th in U.S. sales among all drug categories, according to IMS Health, which analyzes pharmaceutical and health care markets. The majority of cases come after someone has been treated for cancer with potent, intravenous forms of the drugs. About 1 in 10 cancer patients treated with IV bisphosphonate develops the jaw problem.

But a handful of cases have shown up in women taking much smaller doses of the drugs for treatment of osteoporosis.

Bisphosphonates marketed as Actonel, Aredia, Boniva, Didronel, Fosamax, Reclast, Skelid, Zometa and others are meant to increase bone density in the short run by reducing the bone-loss part of the bone life cycle. But some scientists think the drugs may eventually hurt the jaw’s ability to heal after, say, a tooth extraction.

The estimates on the number of people who might experience the jaw problem range from 1 in 2,000 to as many as 1 in 300 people who take the drugs for osteoporosis. In the U.S., 55 million prescriptions for bisphosphonates are written annually, according to a 2007 report in the journal Osteoporosis International.

Most commonly, people with problems will see or feel some exposed bone in the mouth, as the dead bone works its way through gum or tissue, but without pain. In those cases, people are simply told to use an antibacterial mouthwash. If there’s pain or discomfort, and the area of exposed bone is small, a dentist will try to smooth down the exposed area.

In rare cases, the area of dead bone is large. “Then people run the risk of breaking the jaw, because the area is so large,” Dodson says.

So why would a medicine that circulates through the body result in a pharmaceutical punch to the jaw? It could be, Dodson says, that bone in the jaw metabolizes at a speedier rate than in other parts of the body, resulting in more of the drug being deposited there. Because there is more bacteria in the mouth area, that could add to inflammation and worsen the problem.

Or it could be, he says, that the mechanism of the drug is at work. Bisphosphonates inhibit cells that dissolve bone. “But dissolving bone is part of a healthy life cycle,” he says.

The natural balance between dissolving bone and making new bone is disrupted, and bone-producing cells now dominate. But when they die off, there are fewer cells to clean them out, so they remain, a dead mass.

New information has been released linking both Avandia and Fosamax, to adverse events. One study found that long-term use of Avandia increases risk for bone fractures. Additionally, a second study illustrates that Fosamax, which is used to prevent fractures in women with osteoporosis, may be associated with a higher risk of atrial fibrillation, a type of abnormal heart rhythm. Both studies were published in the April 28, 2008 issue of the Archives of Internal Medicine.

An estimated 3.5 million or more U.S. patients take Avandia, experts say. But in 2007, Avandia and four other drugs from the same class were given a “black box” warning, cautioning users of increased heart problems.

The recent study, led by Dr. Christian Meier of University Hospital Basel, Switzerland, looked at links between thiazolidinediones and fracture. It was designed to ascertain whether only women were affected and where fractures were most likely to occur. The research involved 1,020 men and women aged 30 to 89 who had sustained a fracture while taking Avandia, Actos, insulin or another anti-diabetic drug.

Compared to controls, individuals taking Avandia or Actos had more than double the risk of fractures, with the risk with Actos being slightly higher than with Avandia. Drug-associated fractures were particularly common at the wrist and hip. Both men and women were at risk, and the odds for fracture tended to rise with dose of drug taken.

The odds of sustaining a fracture were heightened in patients taking Avandia or Actos for 12 to 18 months and highest in those who were on the medication for two or more years.

Other anti-diabetic drugs did not show the same effect, but thiazolidinediones have a different mechanism of action (working at the cellular level) than other drugs for type 2 diabetes.

The findings echo some previous research that found an increased risk of fractures in women.

For now, the decision to use these particular diabetes drugs should be made on a case-by-case basis, experts said. Women who are postmenopausal and therefore at risk for fractures may want to be more careful, or take other measures to protect their bone health, they said.

“I think the benefit is more than the risk at this point. The benefit is huge in terms of glycemic control,” said Dr. Spyros G.E. Mezitis, endocrinology consultant and clinical investigator at Lenox Hill Hospital in New York City.

“It remains to be seen if the way we practice medicine is going to change. These are important analyses, but we need further evidence,” Mezitis added.

Nancy Pekarek, a spokeswoman for GlaxoSmithKline, the manufacturer of Avandia, noted, “We do have fractures on our label and, in fact, when we saw data from the ADOPT (a previous, long-term trial), we issued a ‘dear doctor’ letter.”

“The fractures have been observed, and we have made physicians aware of that so they can be watching for their patients and choose which drug is appropriate,” Pekarek said. Unlike this trial, the fractures seen in ADOPT were more likely to be in the upper arm, hand or foot as opposed to hip and spine.

The Fosamax study, led by Dr. Susan Heckbert of the University of Washington and Group Health, Seattle, looked at 719 women with confirmed atrial fibrillation in a “real world” setting, versus 966 controls (without atrial fibrillation).

The study found that 6.5% of women who had used Fosamax had atrial fibrillation compared to 4.1% of controls. Based on these findings, the researchers estimated that 3% of new cases of atrial fibrillation in this group of women might be attributable to the use of Fosamax.

Again, the authors cautioned, risks and benefits should be carefully weighed when prescribing the drug.

Other studies have also reported atrial fibrillation as a side effect of bisphosphonates, the class of drugs that includes Fosamax.

Ronald Rogers, a spokesman for Fosamax manufacturer Merck & Co. Inc., called the Fosamax fibrillation association an “old issue.” He also pointed to an article published earlier this year in the British Medical Journal that found no such association.

Rogers also pointed out that the current study is an observational one and therefore subject to limitations not seen in a previous randomized trial. That trial saw an increase in the incidence of “serious” atrial fibrillation among Fosamax patients, he said, but it did not reach a statistically significant difference.