It seems paradoxical that a medicine designed to protect against bone fractures in fact might be the cause of broken legs. Adding to the confusion, the U.S. Food and Drug Administration released a statement in the same week as the medical conference that said there is no clear connection, based on available evidence, between the bisphosphonates — including Actonel, Boniva and Reclast in addition to Fosamax — and atypical femur fractures.
The unusual bone breaks — called atypical subtrochanteric femur fractures — were first documented in small clinical reports and through the FDA's MedWatch system, which monitors side effects of drugs after they've been approved. Such reports do not necessarily mean the drug is the cause of the problem, but multiple reports of the same side effect with the same drug can spur additional investigation. Other potential side effects of bisphosphonate drugs have been identified through the FDA's reporting system, including serious jaw deterioration and esophageal cancer.
Here's a closer look at what's known about the safety and effectiveness of bisphosphonates.
What is Osteoporosis?
Osteoporosis is a weakening of bones that results from bone loss occurring with age or because of disease. People with osteoporosis can suffer pain, lose inches from their height and are at high risk of fractures in their wrists, hips and vertebrae. Ten million Americans, men and women, have osteoporosis, and the disease causes about 1.5 million fractures every year, according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Doctors use bone density measurements to diagnose the condition, and recommend screening in women over age 65 and men over age 70. Earlier screening should be done in people with certain risk factors, such as those with a family history of osteoporosis or who have broken a bone after age 50; women who went through early menopause or recently stopped hormone therapy; and people taking medications such as prednisone, aromatase inhibitors or anti-seizure drugs.
How do Bisphosphonates Work?
Normal healthy bone is constantly being renewed through a cycle of dismantling and replacement of bone cells and minerals. Bisphosphonates get incorporated into newly formed bone in place of naturally occurring phosphate, along with calcium. They inhibit the breakdown of bone, thereby favoring the building-up side of the cycle.
The bisphosphonates are extremely effective at reducing the bone loss that occurs in osteoporosis. Clinical trials have shown that drugs such as Fosamax reduce the risk of fractures by 30% to 50% in people with osteoporosis, according to Dr. Daniel Solomon, a professor of medicine at Harvard Medical School, who studies the drugs.
How Might Bisphosphonates Make Bones Brittle?
Since the drugs interfere with normal bone turnover, it's not hard to imagine that bisphosphonate drugs may affect bone structure.
The atypical fractures in people taking Fosamax — the first of the drug class to be approved, in 1995 — now being noticed by orthopedic surgeons across the country are happening in the thigh bone below the hip rather than within the joint, which is the more normal pattern seen for bones with osteoporosis. And they're straight across the bone, unlike most osteoporotic breaks. They occur among people who have been taking the drug for five years or more.
The reports at the meeting of the American Academy of Orthopaedic Surgeons were detailed studies of bone structure in osteoporosis, in which bones of patients taking bisphosphonates were compared with those of patients receiving other osteoporosis treatments. In one of the reports, a research team led by Dr. Joseph Lane at New York's Hospital for Special Surgery did bone biopsies and found qualitative differences in bone that might explain the atypical fractures. A second study, by a group at New York Presbyterian Hospital, used sophisticated bone density scans and found that bisphosphonate drugs initially increased structural integrity of the femur but that the effect tapered off over four years of treatment.
What's the Risk for People Taking the Drugs?
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.
"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.