Two studies presented at the 2010 conference of American Academy of Orthopaedic Surgeons (AAOS) are highlighting health concerns with long-term use of bisphosphonate medications, which are used to treat the bone loss caused by osteoporosis.

The studies suggest that when the medications are taken for longer than four years, the drugs, which are designed to strengthen bones, may actually make them weaker, leading to an increased risk of fractures in the femur, the long bone of the thigh.

In response to the studies, the Food and Drug Administration (FDA) has stated that it is conducting an ongoing review of the safety of this class of medications, which includes the popular drugs alendronate sodium (Fosamax), ibandronate sodium (Boniva), risedronate sodium (Actonel) and zolendronic acid (Reclast), to see if the increased risk of femur fractures outweighs the proven benefits.

And people like Jennifer P. Schneider, MD, PhD, a doctor of internal medicine in Tuscon, Ariz., say they feel validated by the results of the new studies.  

In 2001, Dr. Schneider was riding the subway while visiting New York City when one wrong step changed her life.

“The train jolted. I stepped hard on that leg and it buckled. The femur broke, and I fell,” she says.

At the age of 57, Dr. Schneider was hospitalized for weeks, needed two surgeries and had to use a walker for a year-and-a-half.

It was years before she learned the bizarre fracture caused in a low-impact situation could have been related to the long-term affects of the prescription medication alendronate sodium (Fosamax) that she had been taking for about seven years to treat osteoporosis.

“I had pain in my thigh for several months before that, and back then, nobody even suspected it was connected to Fosamax, and the doctor didn’t think anything was wrong with my leg. But I was walking around with an undiagnosed stress fracture of the femur,” she says.

On March 1, 2010, the FDA approved a change to the patient labeling for Fosamax that informs people taking the drug about the risk of low-energy femoral fractures.

Merck, the company that makes Fosamax, says it updated the labeling to reflect the experiences reported by patients, not to “reflect a conclusion that post-marketing event is caused by the product,” says Ron Rogers, a company spokesman.

“Just because a post-marketing event has been reported doesn't mean there's a causal relationship. In fact at this point, no causal relationship has been established between bisphosphonates and low femural fractures,” Rogers says.

He continues, “In clinical studies, which are the gold standard for assessing the benefits and risks of medications, Fosamax has not been associated with an increased fracture risk at any skeletal site. “

New research sheds light on rise in rare fracture

Bisphosphonates are a type of drug designed to prevent and treat osteoporosis by building bone and stopping calcium loss.

Many previous studies have shown that short-term use of these medications is very successful early on at stopping the outflow or destruction of bone and preventing fractures of the hip and spine.

But with long-term use of these medications, doctors have been seeing a growing number of patients suffering from a rare type of thigh fracture as a result of little or low trauma. Such trauma can happen from stepping off a curb too hard, for example, or from a relatively minor fall.

Two new studies presented at the 2010 AAOS conference in March are trying to understand why.

“For the first time we’re having some explanation for what up until now has only been a hypothesis,” Dr. Schneider says.

Melvin Rosenwasser, MD, a surgeon who is the director of the orthopaedic hand and trauma service at New York-Presbyterian Hospital, is the lead author of one of those studies. He found that long-term bisphosphonate treatment changes the structure of bone and leads to fractures in some patients.

“It’s a drug that works. But at some point a burden has been assumed by use of it that may be leading some patients to have a complication of the treatment,” he says. “We may be homing in on a group of patients who’ve been on the drug for a long time and may be vulnerable to the fractures.”

Dr. Rosenwasser and his colleagues identified 112 postmenopausal women with primary osteoporosis. Sixty-two had been taking bisphosphonates for at least four years, while 50 in a control group took only calcium and vitamin D supplements. Doctors used a series of X-ray scans to evaluate the structure of women’s femurs over time, looking at measures of strength and structural integrity.

They discovered that the longer the treatment, the more structural integrity declined. It went from 3.8 percent above pretreatment baseline to 1.3 percent after at least four years on the medication. There were also declines in the control group, which was expected since those patients were only taking supplements.

Dr. Rosenwasser says his team’s conclusion is that bone properties change after long-term bisphosphonate use in a way that makes them more likely to fracture.

“We think something is happening over time that may be changing the character of the bone,” Dr. Rosenwasser says.

“I don’t want to be too alarmist. It’s not 100 percent of patients at seven years are breaking their femurs. But some are,” Dr. Rosenwasser explains. “They are all losing something, but not at the same rate or speed or level. It’s not homogenous. They are individuals. That’s why some people’s would break and someone else who’s weak but not critically weak won’t break.”

Rosenwasser says he and his colleagues have not yet identified the point someone is likely to fracture. He says that will require further study.

“There is some magic number that we don’t have yet. Is five years OK, but six years bad? I don’t know. I just know as they go farther and farther into a treatment plan we see this effect more and at some point with some patients, the bone breaks,” Dr. Rosenwasser says.

For the second study, Joe Lane, MD, an orthopaedic trauma surgeon at the Hospital for Special Surgery in New York City, studied patients who had already fractured or broken their legs.

He took bone biopsies of the fractured femur of 21 postmenopausal women who had been using bisphosphonates for an average of eight-and-a-half years. After analyzing the data, he found that mineral properties were reduced in the biopsied tissue by about 30 percent, which researchers believe contributes to the risk of these kinds of fractures. Essentially, the medication they say is changing the ability of the bone to remake, remodel and strengthen itself over time.

“What they found was that even though the study had limitations of small numbers and people were on the drugs for several different years that varied, they did find some specific changes they felt could account for the fractures,” Dr. Schneider says.

“It’s extremely validating,” she says.

Bone drugs may have other, important benefits

Complicating the picture for patients, other news in March 2010 has found that bisphosphonate drugs may reduce the risk breast cancer in patients who take them for more than two years.

In a study published in the British Journal of Cancer, researchers followed nearly 6,000 women between the ages of 20 and 69 in Wisconsin, half of whom had been diagnosed with invasive breast cancer.

They discovered that women who had taken bisphosphonates for more than two years saw a nearly 40 percent reduction in their risk for breast cancer.

“Definitely for women who use these drugs we observed about a one-third reduction in the risk of breast cancer,” says Polly Newcomb, PhD, the lead author and head of the Cancer Prevention Program at the Fred Hutchinson Cancer Research Center in Seattle.

Researchers don’t know exactly how these drugs are helping to prevent breast cancer, but previous research has shown that in addition to their effects on bone, bisphosphonates appear to speed the death of cancer cells.

The researchers note that women who were obese did not appear to get this benefit from the drugs, and they think that may be due to elevated estrogen levels in obese women, which increase cancer risk.

Weighing benefits and risks

So what are patients on bisphosphonates to do?

“These drugs are associated with some benefits and some risks, so certainly, you would never take these drugs to reduce your risk of breast cancer,” Dr. Newcomb says. “If other studies support this, then this might be a good side effect, but these drugs also have serious side effects, too.”

Dr. Rosenwasser agrees.

“My only recommendation is to discuss this with their doctor if they’ve been on it chronically. Not to stop it right away,” especially if you’re just getting started on the treatment, Dr. Rosenwasser says. 

“If you are diagnosed today and your doctor says to go on it, you should because this study doesn’t say anything bad happens to patients initiated on the drug. In fact, it’s the reverse. It helps. Short-term patients had good parameters.”