Features May 2013 Issue

The Why and When of a Bisphosphonate Drug Holiday

Experts stress importance of understanding the benefit-to-risk balancing act of bone-building drugs.

The popular bone-building drugs called bisphosphonates are known for their powerful impact on regaining bone density and reducing fractures. Yet, recent headlines have questioned the long-term efficacy and safety of bisphosphonates in women who take them, causing many to wonder if the drugs’ benefits are worth the risk.

Since the U.S. Food and Drug Administration (FDA) raised concerns in 2011 about the potential for serious side effects in women taking bisphosphonates, including alenodrate (Fosamax), risedronate (Actonel), zoledronic acid (Reclast) and ibandronate (Boniva), both physicians and their patients have been on alert. The possibility that taking the drugs long-term may actually weaken bones and increase the risk of atypical fractures of the thigh bone, esophageal cancer and osteonecrosis of the jaw (ONJ) have led many to stop the therapy and take an extended “drug holiday”—or, refuse the drug entirely as a potential initial treatment.

Now, almost two years later, the shadow of doubt cast on bisphosphonates continues to linger even among those women who could greatly benefit from the drugs. While there is evidence to support the relationship between long-term use of the medication and potential serious side effects, the reality is that the benefits almost always outweigh the risks for those at high risk of developing a fracture, according to Chad Deal, MD, Head of the Center for Osteoporosis and Metabolic Bone Disease at Cleveland Clinic.

“It’s a case-by-case decision on whether to use bisphosphonates, but patients should not make the decision on their own,” says Dr. Deal. “Many don’t want to start bisphosphonates because they think it will cause a fracture, but only their physician has the tools to help them make the best informed decision.”

Understanding the Risks
In 2012, 21 percent of patients taking bisphosphonates discontinued the medication without consulting their physician. Yet, in women or men whose bone density T-score is lower than -2.5 (osteoporosis is defined as a score of -2.5 or lower), or have already experienced a vertebral fracture, the drugs are key to reducing incidence of fractures and improving quality of life. Because bisphosphonates accumulate in the bone and provide some residual anti-fracture reduction when treatment is stopped, experts recommend a drug holiday after five to 10 years of therapy, according to a report in The Journal of Clinical Endocrinology & Metabolism (April 2010).

Additional support for taking a vacation from the medications was published in the Journal of Bone and Mineral Research (July 2012). Researchers from Kaiser Permanente calculated the incidence of atypical fractures of the femur according to the use and duration of bisphosphonates. A review of 1,835,116 patients, ages 45 years and older from January 1, 2007 until December 31, 2011 concluded that the incidence of atypical fractures of the femur increases with longer duration of bisphosphonate use, but the rate is much lower than the expected rate of hip fractures in elderly osteoporotic patients. Patients at risk for osteoporotic fractures should not be discouraged from initiating bisphosphonates due to strong evidence that these medicines can substantially reduce the incidence of typical hip fractures. Yet, the increased risk of atypical fractures should be taken into consideration when continuing bisphosphonates beyond five years, according to the study’s authors.

The Benefit-to-Risk Ratio
“This study showed that after eight years on bisphosphonate therapy, the risk for contralateral atypical fractures was about 120 per 100,000 patients each year,” explains Dr. Deal. “But, if your risk of suffering a primary fracture is greater than the possible risk of developing a subsequent atypical fracture, it would make sense to either begin or continue taking the medication. In most clinical trials the risk of having a typical hip fracture is more than 750 per 100,000 patients each year, and the risk of vertebral fractures is much greater.”

A key instrument used for making the decision to start bisphosphonate therapy is the Fracture Risk Assessment Tool (FRAX). Developed by the World Health Organization (WHO) task force in 2008, FRAX assesses an individual’s risk of fracture and offers general clinical guidance for treatment decisions. “FRAX gives us a good picture of a 10-year fracture risk,” says Dr. Deal. “Treatment is started in patients with a hip or spine T-score under -2.5 or if the 10-year fracture risk for major osteoporotic fracture is over 20 percent and hip fracture risk is over three percent. If, for instance, the 10-year fracture risk is below the recommended treatment thresholds, we need to consider treatment.”

When to Take a Holiday
Dr. Deal agrees that a drug holiday from bisphosphonates should be considered in all patients, but how long to treat before the holiday begins and how long of a holiday to take depends on the individual patient’s fracture risk, T-score and history of fracture. Some bisphosphonates continue to offer bone-health benefits long after they are stopped, including alendronate and zoledronic acid. Patients at lower fracture risk could be given a drug holiday after three years of therapy while those at high fracture risk might need to continue for 10 years. “We often follow those patients who are off therapy with markers of bone turnover. As long as the levels of these markers remain reduced, and the bone density does not fall and the patient doesn’t experience a fracture, the drug holiday could be continued,” says Dr. Deal.

Reaping the Benefits
The Fracture Intervention Trial Long-Term Extension (FLEX) randomized trial published in the Journal of the American Medical Association (December 2006) found that women who discontinued alendronate after five years demonstrated a moderate decline in bone mineral density (BMD) and a gradual increase in serum markers of bone turnover compared with women who continued taking alendronate for an additional five years. Clear fracture reduction benefit was shown for those with prior vertebral fracture or bone mineral density (BMD) T scores of −2.5 or lower, the study reports.

“There was no greater fracture risk in the hip and non-vertebral sites in those who discontinued alendronate, but there were more vertebral fractures in patients treated for only five years,” Dr. Deal explains. “A similar increase in vertebral fractures has been shown for patients who took zoledronic acid for three years versus those who remained on it for six years.”

A reasonable approach for patients with mild risk of fracture is to stop treatment after five years and remain off as long as bone mineral density is stable and no fractures occur.

Patients at higher risk of fractures should be treated for 10 years with bisphosphonates. “There is no question that in a certain subset of patients there is a benefit from longer-term therapy,” says Dr. Deal.