Bisphosphonate ‘Drug Holidays’: Are They Beneficial?

Although a “drug holiday” from bisphosphonate therapy is not justified in certain patients, such as those who remain at high risk for spine fracture, it may be reasonable for patients who are not at high risk, according to some experts.

Studies have shown that bisphosphonates accumulate in bone, leading to a reservoir that continues to be released for months or years after treatment is stopped.

“A bisphosphonate holiday is never required, but it can be considered in patients who, after 3 to 5 years of therapy, are at modest risk for fracture,” said Michael McClung, director of the Oregon Osteoporosis Center in Portland. “In my opinion, most patients are candidates for a holiday after 10 years of therapy except those patients who have had recent hip or spine fracture.”

How Long Should a Drug Holiday Last?

The duration of a holiday after risedronate therapy should be 1 year, whereas duration of 2 to 3 years is appropriate for patients who have been treated with alendronate or zoledronic acid, according to Dr. McClung.

“At the end of those intervals, the patient should be reassessed and treatment restarted if the patient meets criteria for osteoporosis therapy,” he said.

It is important to note, however, that these recommendations are not evidence-based. Rather, they are based on the limited clinical information and knowledge of bisphosphonate pharmacology, according to Dr. McClung.

He also said that there does not appear to be a greater effect on fracture risk with bisphosphonate therapy of more than 3 years compared with shorter-term therapy (1 to 3 years). It is unknown whether the duration of therapeutic response after stopping treatment might be longer if there has been a longer duration of prior treatment.

“It is crucial if a drug holiday is taken that the patient is not forgotten, and they are started back on treatment,” Dr. McClung said in an interview with Endocrinology Advisor. “They can’t be forgotten; they need to be reassessed and bone mineral density is part of that risk of fracture.”

The only duration-dependent risk of long-term bisphosphonate therapy is atypical femoral fracture. The risk for that complication is reported to decrease rapidly, by 70% per year, when treatment is stopped, according to Dr. McClung. The rationale for a bisphosphonate holiday is to allow this decrease in risk for atypical femoral fracture to occur without incurring increased risk for fragility fracture while off therapy.

Official Opinion

Bart L. Clarke, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and a spokesman for the American Society for Bone and Mineral Research (ASBMR), said the ASBMR currently does not have an official policy on bisphosphonate drug holidays. However, the society has a task force that is just completing its work, and a manuscript summarizing guidance on this topic will be issued shortly.

“Generally, I would give a holiday after 5 years of oral bisphosphonate therapy or after 3 years of intravenous zoledronic acid therapy in most patients, per the FDA recommendation. The only patients to whom I wouldn’t give a drug holiday are those who have had a fracture while on treatment or those whose femoral neck T-scores are below –2.5 at the end of their 3 to 5 years of treatment,” Dr. Clarke told Endocrinology Advisor.

“Alendronate is thought to stay in the skeleton as long as 10 years after the last dose is taken and slowly washes out of the skeleton over that interval. All bisphosphonates are similar, with varying duration of this interval,” he said.