Although the new studies describe possible ways that the drugs could cause atypical leg breaks, they cannot say how often this might happen or who is at risk. Solomon says the best evidence to date is a 2009 study published in the Journal of Bone and Mineral Research — the same paper, as it happens, on which the FDA based its announcement that not enough evidence exists to make a connection. Using medical records from nearly 12,000 patients in a Danish registry, it found similarly low rates of atypical fractures in patients taking bisphosphonates and patients not taking the drugs.
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Take bisphosphonates, break a leg?
Though two reports contend a connection exists between taking the drugs over a long period of time and getting these fractures, the FDA says such connection exists.
"We know these drugs reduce the risk of fracture," Solomon says — over a time span of three years, which was how long the clinical trials that proved the drugs' effectiveness ran. But, he adds, "we don't really know their risk-benefit ratio after five years."
To better address the question, scientists would need to conduct a large-scale study following tens of thousands of patients for at least five years — a very expensive and unlikely prospect.
Current estimates put the rate of atypical fractures at fewer than 1 in 10,000 patients who take bisphosphonates, according to the American Society for Bone and Mineral Research, a specialist group of scientists and doctors. (The group has assembled a task force to study the issue in detail and will present its findings in October.) "That's a very small number compared to the people on the drug who have benefited from its fracture protection," says Dr. John Adams, who directs UCLA's Orthopaedic Hospital Research Center, a number that is likely in the tens of millions.
But Lane says the types of fractures he's seen in patients are truly different from others. And though published studies are sparse, when he asked a conference room full of orthopedic surgeons how many had seen one of these atypical fractures, more than half the doctors raised their hands, he says. And this, he adds, is something new. "Twenty years ago, we never saw this kind of fracture. Maybe the drug forces you to get this kind of fracture instead of the more traditional … fractures." He thinks that interrupting drug treatment for a period of time — putting patients on what's called a "drug holiday" — might be the answer, noting that he and others at his hospital do just that.
How about those other scary-sounding side effects?
As with atypical fractures, other serious conditions have occurred in people taking bisphosphonates. Studies support an association between the drugs and osteonecrosis of the jaw, a bone-killing infection often triggered by dental work. The condition is rare — rates of osteonecrosis of the jaw have been estimated at between 1 in 10,000 and 1 in 100,000 — although Solomon, for one, thinks the rate may be significantly higher than that. In addition, the risks of these side effects can be minimized by taking some precautions, such as getting dental work done before starting on bisphosphonate therapy.
Closer investigation has not found any evidence for a connection between the bisphosphonates and atrial fibrillation (an abnormal heart rhythm that causes poor blood flow through the body), according to the FDA. The jury is still out on esophageal cancer, a condition so rare it may be impossible to establish a link to the drugs — only 23 cases of esophageal cancer in patients on Fosamax, the bisphosphonate that has been on the market longest, were reported in the U.S. over a decade.
In spite of the known or suspected risks, doctors say the benefits of bisphosphonate drugs — reducing fractures in people with osteoporosis — far outweigh the low risk of the potential adverse events. "Unequivocally, these are wonderful drugs," Lane says.
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