What to make of the new warning on bisphosphonates

Officials acknowledge a connection between the most popular bone drugs and rare thigh fractures.

In October 2010, the FDA issued a warning that long-term use of bisphosphonates — the class of drugs most widely prescribed for preventing and treating osteoporosis — may increase the risk of unusual fractures of the thigh. Reports of these fractures began to emerge in 2007. The bone breaks involved occur just below the hip joint (subtrochanteric) and in the long part of the thighbone (diaphyseal). They generally happen with little or no trauma and, in some cases, have occurred in both femurs. About half the time, patients notice pain or weakness in the affected thigh for weeks to months before the break. These fractures are atypical and rare, accounting for less than 1% of all osteoporotic hip and thigh fractures. So far, there is no way of telling in advance who is most vulnerable.

In September 2010, after extensive interviews and literature reviews, a task force of the American Society of Bone and Mineral Research (ASBMR) concluded that atypical thigh fractures could be a result of long-term bisphosphonate use. In a study published in the Journal of Bone and Mineral Research (/jbmr), the task force reviewed 310 cases and found that 94% of the patients involved had been taking bisphosphonates, usually for five years or more. The ASBMR recommended labeling changes to make bisphosphonate takers aware of the situation; the FDA was moved to act by this report and by evidence from its ongoing surveillance program.

In addition to expanded warning labels, bisphosphonate manufacturers will be required to provide descriptions of the risk to patients at the time they have their prescriptions filled. The FDA also recommends that bisphosphonate takers report any thigh pain to their clinicians and encourages clinicians to re-evaluate the need for these drugs in people who've been taking them for more than five years. Patients and clinicians are urged to report any adverse events to the agency's MedWatch program (see "Selected resources").

The medications included in the FDA's safety warnings are alendronate (Fosamax and Fosamax Plus D), risedronate (Actonel and Actonel with Calcium), delayed-release risedronate (Atelvia), ibandronate (Boniva), and zoledronic acid (Reclast). Bisphosphonates used for Paget's disease or high blood calcium due to cancer aren't affected by the FDA order.

Putting things in perspective

The main concern about osteoporosis is fractures, and bisphosphonates reduce the risk of fractures by as much as 50%. Moreover, since bisphosphonates were first approved in 1995, millions of women have taken them safely. But the emergence of bisphosphonate-linked thigh fractures is a reminder that we may not discover all of a drug's side effects until it's been on the market for several years. Clinical trials generally turn up the most common drug side effects; less common ones often don't show up until the drug has been used more widely and for a longer time.

Atypical thigh fractures aren't the only uncommon but serious problems associated with bisphosphonate use. In 2008, the FDA issued an alert about severe bone, joint, and muscle pain in bisphosphonate takers. (This side effect was included in the original prescribing information, but additional reports prompted the agency to beef up clinician awareness of it.) A very small percentage of bisphosphonate users — mostly cancer patients taking high doses intravenously — have developed osteonecrosis (bone death) of the jawbone. The rare instances of this complication among individuals taking lower, oral doses have been in people undergoing invasive dental procedures.

The mechanism behind bisphosphonates' involvement in atypical thigh fractures isn't clear, but scientists have some ideas about it. Bones continually undergo remodeling, a process that involves bone formation and bone breakdown (resorption). Bisphosphonates work by slowing resorption. The result is greater bone density and reduced fracture risk. But in some people, prolonged suppression of resorption may impair new bone formation and hinder the bone's normal ability to repair microscopic cracks produced by ordinary wear and tear. Also, while resorption is suppressed, mineralization continues, potentially resulting in more brittle, less resilient bone. In addition, scientists think that some people may naturally be poor bone remodelers, and in these individuals, bisphosphonate therapy may heighten fracture risk. As yet, however, no studies have demonstrated a specific mechanism linking bisphosphonates with these fractures.

What should you do?

If you're taking a bisphosphonate and experience thigh pain or a seemingly inexplicable fracture, stop taking the medication, and discuss alternatives with your clinician. Bisphosphonates aren't the only game in town (see "FDA-approved medications for treating osteoporosis"). For example, denosumab (Prolia), like alendronate, risedronate, and zoledronic acid, reduces the risk of spine, hip, and other nonspine fractures. (Most other medications used to treat osteoporosis chiefly reduce the risk of spine fractures.) Clinical trials found no serious side effects from denosumab after three years, but the drug has been on the market only since June 2010, and its risks won't be fully understood until it's been used more widely for a longer time. Denosumab works by a different mechanism than bisphosphonates.

If you've been taking a bisphosphonate for a while and are concerned about the long-term risks, talk to your clinician about taking a "drug holiday." Bisphosphonates build up in bone during treatment and exit gradually when you stop, so it's reasonable to take a break. There's little scientific evidence on how long you should take a bisphosphonate or how long a drug holiday should last. But in the April 2010 Journal of Clinical Endocrinology & Metabolism, clinicians at the Cincinnati Bone Health and Osteoporosis Center suggest that you judge by your individual fracture risk. (A tool for determining fracture risk is described below, in "Who should be treated?") They recommend 10 years of bisphosphonate therapy for people at high risk of fracture, followed by a one- to two-year drug holiday before resuming therapy. A woman at lower risk might be treated for five years before taking a break or even stopping altogether. If you take a drug holiday, have your bone mineral density (BMD) tested after a year or two. If it has declined significantly, you may need to resume treatment.

Who should be treated?

Until recently, the criteria for determining who should receive bone-strengthening drugs was based mainly on a measurement of BMD called a T-score. A woman with a T-score of –2.5 was diagnosed with osteoporosis, and drug treatment was recommended. It was less clear what to do for women with osteopenia (low BMD that doesn't qualify as full-blown osteoporosis), although some clinicians prescribed medications for these women as well. The problem is that BMD is not a perfect indicator of who's likely to break a bone. Women with the same T-scores don't necessarily have the same fracture risk, and up to half of all postmenopausal women who suffer fractures do not meet the criteria for osteoporosis at all.

In 2008, the FRAX tool (see "Selected resources") was introduced to improve risk assessment. It calculates the risk of a hip or other major fracture in the next 10 years and incorporates several risk factors besides BMD, including gender, height and weight, nontraumatic fracture after age 50, parental history of hip fracture, current smoking, use of corticosteroids, alcohol use, rheumatoid arthritis, and osteoporosis due to conditions such as premature menopause, malabsorption disorders, and type 1 diabetes. But even FRAX doesn't cover all the bases; for example, it doesn't take into account your risk of falling or the effects of some diseases and medications associated with low bone density (such as the widely prescribed proton-pump inhibitors and serotonin reuptake inhibitors). So it's no substitute for talking to your clinician about your particular situation.

The National Osteoporosis Foundation and the North American Menopause Society recommend considering drug therapy for postmenopausal women who have a T-score of –2.5 or below or have already had a hip or spine fracture. They suggest that women with osteopenia (a T-score of –1.0 to –2.5) consider drug treatment if they have a FRAX-estimated risk of 3% or more for hip fracture or 20% or more for other major fracture in the next 10 years.

Whether you have osteoporosis or osteopenia or don't — and whether you take medications for it or don't — lifestyle measures that help protect bone are important: every day, get 1,200 milligrams of calcium, mostly through foods, and 800 to 1,000 international units (IU) of vitamin D; don't smoke; don't drink excessive alcohol; and get regular weight-bearing exercise, such as brisk walking, calisthenics, or aerobics. Keep in mind that falls are one of the biggest risks for broken bones, especially hip fractures, which can be particularly devastating. There are many ways to prevent falls, including exercises and home safety precautions. To learn about them, go to the Web site of the Fall Prevention Center of Excellence, www.stopfalls.org.