Has Osteoporosis Been Overtreated?

(This article appeared previously on Medshadow.org.)

Since the mid-90s, when Fosamax (alendronate) was first approved, bisphosphonates have been commonly used to effectively treat osteoporosis in millions of patients. The class of drugs that work to rebuild and strengthen bone tissue, bisphosphonates are taken either orally or as injections. But they are not without side effects. And recently, some of the potential long-term effects of these medications, while rare, have come under scrutiny.

Conversations about what those effects might or might not be and who should be taking the drugs have been taking place in the media and medical community alike.

One issue is that no one really knows yet what the optimum length of time patients should be taking these drugs. A Food and Drug Administration (FDA) review of studies, discussed in The New England Journal of Medicine, caused a stir when it questioned whether continued use of bisphosphonates truly helps patients or might put them at increased risk for atypical fractures or other side effects.

The study suggests that taking bisphosphonates beyond five years doesn't necessarily continue to improve bone density or strength for all patients. One recommendation is that patients who were initially at low risk for osteoporosis-related fractures may benefit from discontinuing the medication after three to five years, while those patients at a greater risk from the outset may benefit from continuing.

"Bone is a slow-changing tissue and its metabolism is a gradual process," says Dr. Kurt Kennel, assistant professor of medicine in the Division of Endocrinology, Metabolism and Nutrition at the Mayo Clinic, who was not involved in the FDA review.

"A big concern I have is the unknown. Will bone strength remain stronger, like we think it does in the first years of therapy, or will it paradoxically not be as strong or healthy in the long run because we've manipulated it with these rather long-lasting medications?" he asked.

Kennel points to the fact that there hasn't been enough time to study the long-term residual effects of bisphosphonates; they simply haven't been around for that long.

"In other therapies we are confident in saying the effects of the medicine are gone once we stop giving them," he says. "So if we have reservations in terms of long-term safety, we can always counter that concern with the medicine being out of the body. Whereas with bone, the exact opposite is true. It has every reason to still be in the body and every reason it has some impact decades down the road."

Here's a rundown of the short-term side effects of bisphosphonates:

Oral Bisphosphonates (Fosamax, Boniva and Actimel; all available in generic form)

The biggest complaint is upper gastrointestinal discomfort such as nausea, abdominal pain and heartburn. Patients are encouraged to take the medication with a full glass of water and remain upright for 30 minutes to an hour after consumption.

Intravenous Bisphosphonates (Reclast, or zoledronic acid)

It's not uncommon for patients to experience flu-like symptoms 24 to 72 hours after receiving the infusion; typically, symptoms lessen with the second and subsequent doses. This "acute phase response," says Kennel, could occur in as few as one in three patients, but more likely it's 50 percent of them. Often, the symptoms are so minor that people don't report them to their doctors.

Here's a rundown of the long-term side effects of bisphosphonates:

Atypical Femur Fracture

This side effect, while statistically rare, has emerged as one of the primary concerns of bisphosphonate use. A typical osteoporosis fracture often happens in the hip or the neck of the femur (the long bone in the thigh). But some osteoporosis patients taking bisphosphonates end up with breaks in the middle of their femur.

The reason is unclear. Kennel suggests, however, that since the medicine doesn't discriminate in terms of its target in the skeleton, the same dose that is strengthening the weakened bones might be too much for other locations. Those might include the middle of the femur, which needs some flexibility for normal walking function.

It's a paradox: The drug makes the bone stronger, but may also leave it less resilient and more prone to a stress fracture or a break.

"If you treat 1,000 women with osteoporosis with a bisphosphonate for three years, you'll prevent about 100 fractures. And perhaps out of those 1,000 patients, one of them might have a atypical femur fracture," says  Dr. Michael Lewiecki, director of the New Mexico Clinical Research & Osteoporosis Center, and clinical assistant professor of medicine, University of New Mexico School of Medicine. (Several of his studies were part of the FDA review.) Most of the atypical femur fractures occur in patients who have taken bisphosphonates for seven years or more, says Lewiecki.

In some cases, researchers might consider a drug holiday as an option.

"After being treated for three to five years, if your fracture risk is no longer very high, you could consider stopping taking the drug, and there would presumably be enough of the medication built up in your bones that it would continue to be effective and reduce the risk of fractures for at least a year or two afterwards," Lewiecki says.

As the level of medication goes down, he explains, you'll presumably lower your risk of an atypical fracture. That said, a bisphosphonate holiday doesn't equal bisphosphonate retirement; when bone density decreases again and fracture risk increases, medication will be needed.

Osteonecrosis of the Jaw (ONJ)

ONJ is defined as exposed bone in the jaw that persists at least eight weeks after identification. The occurrence of ONJ among oral bisphosphonate users is quite low — one in 100,000 patients — according to a report published by the National Institutes of Health, with the incidence slightly higher among IV patients.

More often than not, ONJ doesn't happen spontaneously but is associated with trauma to the jaw, typically a tooth extraction, says Kennel. A patient being considered for bisphosphonate therapy who also requires dental treatment probably shouldn't do both simultaneously. "It just doesn't make sense to be taking the medicine and having teeth pulled when the teeth could be pulled first and start the medicine later," he says.

Atrial Fibrillation

There is some suggestion that IV bisphosphonate use in particular might contribute to increased risk of developing atrial fibrillation, a common type of heart rate problem. There tends to be an overlap in the demographic of patients who have a high risk for osteoporosis and for atrial fibrillation, says Kennel. As such, "those at high risk for atrial fibrillation might have greater reason to consider this potential adverse effect," he says.

Esophageal Cancer

Amid some concerns, an evaluation by the National Institutes of Health examined several studies and refutes direct correlation between bisphosphonate treatment and esophageal cancer.

Normal, healthy bones are constantly breaking down and building themselves back up. Cells called osteoclasts are responsible for the breaking down; osteoblasts are in charge of replacing lost cells. In fact, "all of us probably replace our skeleton about once every 10 years through this process of bone remodeling," says Lewiecki.

In post-menopausal women, and about 20 percent of men over 70, that system can become unbalanced and more bone is removed than can be replaced, decreasing bone density. "The first three to five years after the onset of menopause, there's an accelerated rate of bone loss," says Lewiecki.

With bisphosphonate treatment, the medicine is absorbed by the bone and behaves almost in a time-release fashion, slowing down the rate of bone loss, helping to increase bone density, improve the integrity of the bones and ultimately prevent osteoporosis-related fractures.

Experts seem to agree that for the average person, a multi-pronged approach to a consistent, fairly rigorous exercise regimen might help slow down some of the effects of osteoporosis.

The National Osteoporosis Foundation recommends both weight-bearing and muscle-strengthening exercises for better bone health. Exercises that improve balance are also important to prevent falls.

"The message we try to give people," says Kennel, "is [that exercise] attenuates the changes, it doesn't necessarily stop them. But like a lot of other things, maybe I would have the problem at 90 anyway, but by being a healthy person, I won't have it when I'm 70."

As for diet, adequate intake of calcium and vitamin D are essential for skeletal health. Dairy products, dark green leafy vegetables and some types of fish are all high in calcium, though there is some debate about the best options.

Many doctors recommend a vitamin D supplement, since concerns about sun exposure (our bodies make vitamin D as a result of sun hitting our unprotected skin) prevent many people from absorbing enough through the skin.

When the FDA approved bisphosphonates in the 1990s, it was not just to treat but also to prevent osteoporosis in women who showed no signs of symptoms. There was little consideration then about duration of treatment or what the long-term effects might be.

"We've passed through that phase and now the thinking is, we want to identify those people who are high risk for fracture and treat them. And that's a situation where we feel the benefits far outweigh the risks," says Lewiecki.

And what about those who were treated back then? If they're now showing symptoms of disease, did that course of medicine impact what happens today? The answers aren't clear, suggests Kennel.

"You've already used the medicine, so would it be safe to use again?" he asks. "Right now it's a question of: Did it really do any good, and did it complicate what we might do when they're in their 70s or 80s, when they might have an acute need for some sort of help or treatment?" he adds.

"The general concept with bisphosphonates is the same with all medications," says Lewiecki. "We want to use the lowest possible dose for the shortest period of time… and if we can achieve our goals for treatment with a lower dose or by giving for a lesser period of time, then we'd always like to do that."