Absolute Risk for Femur Fracture Low With Bisphosphonates

May 04, 2011

May 4, 2011 — Almost 78% of all Swedish women aged 55 years and older who sustained an atypical femur fracture in 2008 had taken bisphosphonates, but the absolute risk for such breaks is small enough to justify prescribing the drugs, according to a study published in the May 5 issue of the New England Journal of Medicine (NEJM).

For patients taking bisphosphonates, the age-adjusted relative risk for an atypical femur fracture — a clean, horizontal break spreading from the lateral side and occurring with minimal or no trauma — was 47.3%, the study reported. The crude incidence of the fractures was 0.09 per 10,000 patient-years among women who had never taken the drug compared with 5.5 among those who had ever taken it.

An undisplaced femoral fatigue fracture associated with bisphosphonate treatment. National Institutes of Health

These results "should be reassuring for bisphosphonate users," write lead author Jörg Schilcher, MD, from the Department of Experimental and Clinical Medicine, Faculty of Health Science, Linköping University, Linköping, Sweden, and colleagues. "With a correct indication, the benefits of fracture prevention...will greatly outweigh the risk of atypical femoral fracture."

Experts interviewed by Medscape Medical News call the study definitive because researchers not only studied a massive number of participants — all 1.5 million women in Sweden who were aged 55 years or older in 2008 — but also reviewed the x-rays of nearly all those who had particular kinds of femur fractures.

"It's the largest and most comprehensive study of this issue that I've seen," said Sundeep Khosla, MD, president of the American Society for Bone and Mineral Research (ASBMR) and a professor of medicine and physiology at the Mayo Clinic in Rochester, Minnesota.

The study's conclusions echo those in other recent studies on the worrisome fractures and the bone-building drugs for osteoporosis. An article published in February in the Journal of the American Medical Association, for example, reported that long-term use of bisphosphonates boosted the risk for these fractures, but those authors noted that the absolute risk for fracture is low and is outweighed by the benefits of the therapy.

In October 2010, the US Food and Drug Administration (FDA) revised the labels of bisphosphonates to warn about the possible increased risk for subtrochanteric femur fractures, which occur just below the hip joint, and diaphyseal or "shaft" femur fractures, occurring in the long part of the bone. Agency officials at the time said that patients taking bisphosphonates for osteoporosis should continue to do so because the drugs prevent far more fractures than they may trigger.

The label revision applies only to bisphosphonates with FDA approval for osteoporosis, such as alendronate (Fosamax, Merck) and risedronate sodium (Actonel, Proctor & Gamble Pharmaceuticals). Bisphosphonates for the treatment of Paget's disease and high blood calcium levels caused by cancer are not affected.

A report by an ASBMR task force had recommended such a label change a month before the FDA decision.

Study Supports Efficacy of Drug Holidays

Dr. Schilcher and coauthors combed the National Swedish Patient Register and found 12,777 women aged 55 years and older who broke their femur in 2008. Of these, 1271 had subtrochanteric or diaphyseal fractures. The researchers were able to track down x-rays for 1234 women. A review of these x-rays revealed that 59 women in this group had atypical femur fractures.

Elizabeth Shane, MD, cochair of last year's ASBMR task force, told Medscape Medical News that other studies on bisphosphonates have classified some fractures as atypical without relying on x-ray review for confirmation. "That is a particular strength of the [NEJM] study," said Dr. Shane, a professor of medicine at Columbia University in New York City.

Of the subset of 59 women with atypical femur fractures, 46, or almost 78%, had used bisphosphonates. This figure compares with 83,311 Swedish women in all who had taken the medication, based on the Swedish Prescribed Drug Register.

The authors found that the elevated risk for atypical femur fractures with bisphosphonates was independent of coexisting conditions and concurrent use of other drugs, such as proton-pump inhibitors, that are known to affect bone metabolism. This risk diminishes by 70% per year after patients stop taking bisphosphonates, a finding that has encouraging implications for their long-term use, said Dr. Shane.

Because it is not clear how long patients with osteoporosis can be safely treated with bisphosphonates, the ASBMR recommends that clinicians consider discontinuing them after 5 years. At that point, many physicians give their patients a "drug holiday" for 1 or 2 years and then resume the therapy. Dr. Shane said that the rapid decline in fracture risk after drug withdrawal helps justify a holiday.

"Now there seems to be evidence that giving patients intermittent drug holidays is appropriate to do," she said. Dr. Khosla agreed, saying the decrease in fracture risk provides "reassurance that a [drug holiday] is good clinical practice."

Senior author Per Aspenberg, MD, PhD, reports receiving consulting fees from Eli Lilly and Amgen and grant support to his institution, Linköping University, from Eli Lilly and Amgen, as well as holding stock in AddBIO, a company trying to commercialize a method for bisphosphonate coating of implants to be inserted in bone, and holding a patent for this method. Dr. Aspenberg is a cofounder of the company. No other authors have reported any relevant financial relationships.

Dr. Khosla has reported no relevant financial relationships. Dr. Shane reports receiving research grants from Merck, Eli Lilly, and Novartis.

N Engl J Med. 2011;364:1728-1737. Abstract


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