Bisphosphonate Treatment: How Long Is Long Enough?
By Diane L. Schneider, MD, MSc
The answer to this question is far from certain. Let me state at the beginning, there are no definitive answers. The evidence is thin in this area. In this “data-free” zone, expert opinion has driven the changes for managing patients on long-term bisphosphonate therapy with stopping their medicine for a year or two then resuming it, known as a drug holiday, or switching to another medicine, which is called sequential therapy.
A higher authority may soon dictate what we do. Long-term treatment with bisphosphonates is under evaluation by the FDA. The release of an updated assessment by the FDA is expected soon.
In the fall of 2010, the FDA first addressed this issue in response to the report on atypical subtrochanteric and diaphyseal femoral fractures by a task force of the American Society for Bone and Mineral Research. The FDA required new safety information to be included in the labeling that was effective January 2011. In addition to including information on atypical femur fractures, all bisphosphonates labeling for the indication of osteoporosis states,“The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.”
What should you do with patients on bisphosphonates therapy, especially those on it for five or more years? Unfortunately, in this era of evidence-based medicine, clinical trial evidence is lacking. The pivotal fracture trials were of three- or four-year duration. The continuation of some of the trials beyond the initial registration period used bone mineral density (BMD) as the primary outcome because statistical power was inadequate for an evaluation of fractures. The longest experience in clinical trials has been using alendronate for 10 years.
The current recommendation, which suggests consideration of stopping bisphosphonates after five years for a drug holiday, is primarily based on the Fracture Intervention Trial Long-Term Extension (FLEX) study. The FLEX results provide some guidance, but it is not cut and dry. To review, the original participants in the Fracture Intervention Trial (FIT) who were taking the active study drug (alendronate) were recruited to continue in a five-year extension of the study. A total of 1,100 women were randomly reassigned into three groups: placebo and 5 or 10 mg of alendronate. The purpose of the study was to see whether continued treatment is required once patients have already increased their bone density and decreased the risk of a fracture.
Those women taking 5 or 10 mg daily, by the end of the study, had used alendronate for a total of 10 years. The study was designed to look primarily at BMD changes; because of the smaller group size, fractures were collected as adverse events. Those who switched to the placebo (the same as stopping for a drug holiday) lost all or almost all of what they had gained in bone density over the first five years. The two groups of subjects who continued to receive alendronate doses showed stable BMD at the hip sites. Lumbar spine BMD was maintained with a small increase in the placebo group, and those on alendronate gained more than 5%. At the spine, the average difference between groups was almost 4% at the end of FLEX.
Bone turnover markers showed that those continuing alendronate maintained stable lower levels of bone turnover. Those who were no longer taking alendronate showed a gradual rise in markers over five years. Their marker levels ended up close to the baseline measured 10 years earlier. This correlated with a slow decline in bone density after stopping alendronate.
The bone density and bone marker changes showed some residual effect for at least five years after subjects had ended a five-year course of therapy. In addition, no difference in the number of fractures was seen between the group that had stopped taking alendronate and the groups that had continued to take it.
Implications for Prescribing
Even though the FLEX study was not powered to look at fractures, investigators conducted a post hoc analysis that evaluated BMD along with fractures. They concluded that a patient’s BMD at five years and whether or not spine fractures were present were what mattered.
If BMD at the femoral neck is above -2.0 and there is no radiologic evidence of spine fractures, consider stopping alendronate. If BMD levels at the femoral neck of -2.5 or higher have not been achieved after five years, an additional five years of therapy may be beneficial. The gray zone is for women in the -2.0 to -2.5 range. Women who have had a spine fracture or are at high risk should continue therapy after five years.
The level of bone resorption and subsequent bone loss with stopping therapy depends on the individual bisphosphonate. The characteristics of the medicine determine the rate of return of bone resorption as measured by bone turnover markers. Based on the FLEX study and others where alendronate has been stopped, bone turnover gradually increases by about five years; risedronate has a shorter time frame of two to three years. Data are absent for ibandronate and zoledronic acid, but similar effects would be expected based on strength of binding to the bone: Ibandronate would be comparable to risedronate and zoledronic acid to alendronate. An analysis of one dose of zoledronic acid showed a fracture-reduction benefit for about three years. The sustained effect of bisphosphonates may occur from recycling with its release from bone at new sites of remodeling. The bisphosphonate may bind again to bone surfaces.
It is estimated that for alendronate, about 75 mg of medicine is retained in the skeleton with 10 years of alendronate at a dose of 10 mg per day or 70 mg per week. With stopping treatment, the release of alendronate from remodeling is estimated to be approximately the same as taking a daily dose of 2.5 mg. This results in a gradual trend up rather than rapid increase in bone turnover.
In general, if BMD has increased above the osteoporosis threshold and other significant risk factors for fracture are not present, a holiday of two to three years for alendronate and zoledronic acid and a shorter holiday of one to two years for risedronate or ibandronate may be a consideration. If a patient is still in the osteoporotic range and at high risk of fracture, options include remaining on the same medicine or using another medicine, not a bisphosphonate, for one to two years before continuing with the bisphosphonate.
If you stop, another important question follows: When do you restart? Here’s where bone markers may be helpful in addition to bone density. Checking a bone turnover marker may provide an idea about when the effect of the bisphosphonate is waning. However, this is another data-free zone. At this point, there is no evidence that fracture risk remains reduced when bone markers are reduced and bone density is stable when a patient is off medicines.
The scant data available to direct decisions in the area of how long to treat with bisphosphonates and drug holidays have given rise to a cacophony of advice. Your job as the advising doctor is to weigh the risks and benefits in formulating a prudent plan of action for the individual patient.
— Diane L. Schneider, MD, MSc, a geriatrician and epidemiologist, is a former associate professor of medicine at the University of California, San Diego, author of The Complete Book of Bone Health, and cofounder of 4BoneHealth.