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.

Other Benefits of Bisphosphonates

Bisphosphonates are multipurpose drugs. They are used for osteopenia and osteoporosis prevention as well as the management of breast cancer and other cancers that have spread to the bone. However, recent research has also suggested that bisphosphonates may be helpful in the prevention of certain cancers.

According to a new analysis published in December 2014 in Cancer, women who use bisphosphonates may have a lower risk for endometrial cancer.¹ In the analysis of 29,254 women, bisphosphonate users were half as likely to develop endometrial cancer. Other studies have also show that bisphosphonates may reduce the risk for certain cancers, but this was the first analysis to demonstrate a reduction in the risk for endometrial cancer with bisphosphonate use, according to the researchers. Further, several studies have suggested that bisphosphonates may help prevent other cancers, including lung, colon and breast cancers.

Additionally, another study presented in June 2014 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago indicated that women with metastatic breast cancer may be able to take zoledronic acid less often after the first year of monthly treatment.²

Specifically, results indicated that receiving zoledronic acid every 12 weeks after 1 year of monthly intravenous administration was as efficacious as continuing to receive monthly treatment, said study investigator Gabriel Hortobagyi, MD, professor of medical oncology at the University of Texas MD Anderson Medical Center in Houston.

Findings from this study could have an impact not just in the setting of metastatic breast cancer but for other solid tumors as well, such as multiple myeloma, where monthly intravenous bisphosphonates are used to prevent skeletal events and the loss of bone mass, according to Dr. Hortobagyi.

“Bisphosphonates stay in your blood for many, many years, and the reality is that bone has a very large capacity for storing bisphosphonates, and we don’t know what the limit is and how much it can accept. If you give lower doses or administer the drug less frequently, you would have fewer serious side effects. But that still has to be demonstrated. The studies are relatively small, and we don’t know if this applies to everybody,” Dr. Hortobagyi said in an interview with Endocrinology Advisor.

At present, there appears to be no “optimal” bisphosphonate treatment regimen because the studies are still being conducted. However, the current body of clinical evidence would suggest that structured holidays may be highly beneficial for a significant number of patients provided the patients are adequately monitored and reevaluated on a regular basis.

References

1. Alford SH et al. Cancer. 2014;121(3):441-447.
2. Hortobagyi GN et al. LBA9500. Presented at: 2014 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2014; Chicago.