The task force also recommends that women who are not at high risk of fracture after three to five years of bisphosphonate treatment be considered for a two- to three-year drug holiday.
Marcy B. Bolster, MD, associate professor of medicine, Harvard Medical School, in the Division of Rheumatology, Allergy and Immunology at Massachusetts General Hospital, Boston, says the recommendations “will help ensure that drug holidays are considered in all patients treated with bisphosphonates and that there are more specific reasons, or risk factors, to inform the decision to continue oral therapy for longer than five years and IV bisphosphonate therapy for longer than three years.
“It is clear from the recommendations that decisions for duration of therapy should be individualized and should include informed decision making shared between the healthcare provider and the patient,” she says.
Efficacy Data
Evidence supporting bisphosphonate therapy beyond five years is from two randomized, double-blind discontinuation trials: the FLEX study with oral alendronate and the HORIZON extension study with IV zoledronic acid. A five-year follow-up of patients in the FLEX study showed that those who continued oral alendronate therapy after four to five years of therapy had significantly less bone loss at all skeletal sites and fewer clinical vertebral fractures than those who had switched to placebo. In the HORIZON study extension, postmenopausal women who had already received three annual IV infusions of zoledronic acid and then continued therapy for another three years had fewer morphometric spine fractures than those who switched to placebo therapy.
Treatment efficacy—larger increases in bone mineral density and lower rates of fracture—is dependent on patient adherence to therapy, the task force said. Less than 50% of patients who start oral therapy continue for more than one year due to cost, co-morbidities, side effects, concern about side effects, inconvenience, use of multiple medicines and poor understanding of the benefits. About 30% of patients who receive an initial IV infusion return for the second infusion a year later.
Assessing Risk & Benefit
The report includes a discussion of the potential risks of bisphosphonate therapies. One of the potential harms of prolonged bisphosphonate therapy has been the risk for atypical femoral fractures. For the first three to five years of bisphosphonate therapy, the risk–benefit ratio clearly favors treatment for those at significant risk of osteoporotic fracture, with an estimate of averting 162 fractures of the spine, hip or forearm per one atypical femoral fracture caused, Drs. Adler and El-Hajj Fuleihan say. “In the five- to 10-year period, there is sustained vertebral fracture risk reduction for those who remain at higher fracture risk, but a similar estimate for the risk–benefit ratio is difficult to define due to insufficient data. It is probably lower due to the evidence that atypical femoral fractures increase with duration of bisphosphonate use,” they say. Even so, atypical femoral fractures are uncommon and occur in less than 0.2% of patients on eight to 10 years of bisphosphonate therapy.
