Bisphosphonate Holiday: Pros, Cons


SAN FRANCISCO — How long to continue bisphosphonate therapy after the first few years is an open question, with some validity to each of the possible answers, according to Dr. Steven T. Harris.

“This is a hot-button issue. It comes up all the time,” he said at a meeting on diabetes and endocrinology sponsored by the University of California, San Francisco. There are limited data to guide clinicians on how long to extend bisphosphonate therapy, and whether it's risky for patients to interrupt treatment with a drug holiday.

“From my perspective, there is no clinical mandate that says after x number of safe years of therapy, you have to stop,” said Dr. Harris of the university. For some patients who have been on daily bisphosphonates for years and who are tired of coordinating their lives around taking the drug on an empty stomach with plain water, a drug holiday lasting a few years probably is acceptable, the data suggest.

Concerns about continuing bisphosphonates for decades revolve around the misconception that the drug “must be building bad bone or brittle bone or crummy bone—abnormal bone. That's absolutely not true,” said Dr. Harris, who has been a consultant for and received event funding from companies that make bisphosphonates. Bone biopsies done after 5 years of risedronate therapy or 10 years of alendronate therapy have shown histologically normal bone. More importantly, fracture rates remained lower than with placebo therapy after 7 years of risedronate therapy or 10 years of alendronate therapy, studies have shown. If bisphosphonates built abnormal bone, “you'd expect to see the fracture rates go up with extended therapy,” Dr. Harris explained.

For high-risk patients (however one defines that), it's reasonable to continue bisphosphonate therapy, he said. For example, for a 72-year-old patient with a T score of −3.4 who broke her wrist 3 years ago and has three compression fractures, “are you really going to stop her bisphosphonate after 5 years? I think not.”

On the issue of interrupting bisphosphonate therapy with a drug holiday, the key data come from the FLEX (Fracture Intervention Trial Long-Term Extension) study of 1,099 postmenopausal women who had taken alendronate for 3–6 years and were randomized to 5 more years of therapy (5 or 10 mg daily) or placebo (JAMA 2006;296:2927–38).

Those who continued alendronate had a significantly lower risk of having a clinical vertebral spine fracture, defined as a painful fracture causing someone to seek medical attention (relative risk, 0.45 compared with placebo). There were no significant differences between the groups in rates of morphometric spine fracture or nonspine fracture.

The gains in femoral neck and total hip densities that were seen in all patients during the first 3 years of bisphosphonate therapy remained stable in those who continued with the drug; however, the densities drifted down in those who were on placebo, so that there was a small but statistically significant difference between the groups 5 years after randomization.

Moreover, the difference between the groups in the number of clinical vertebral fractures amounted to an absolute relative risk reduction of 2.9%—from 5.3% in the placebo group to 2.4% in the alendronate group—for a relative risk reduction of 55%.

An unpublished subgroup analysis of the FLEX study data by other investigators showed that stopping or continuing alendronate made no difference in the risk for nonvertebral fractures in osteopenic patients (defined as those with a T score between −1 and −2.5) but that it did affect osteoporotic patients (those with a T score of −2.5 or lower at randomization). Osteoporotic patients were half as likely to develop nonvertebral fractures (absolute risk reduction, 13%) if they remained on the bisphosphonate, he said.

“If you have a low-risk patient who's been on therapy for years, I do think you can get away with stopping for awhile,” Dr. Harris said. Just don't expect the benefits to persist forever, he added, “though it's an issue that is admittedly a bit unsettled.”

'There is no clinical mandate that says after x number of safe years of therapy, you have to stop.' DR. HARRIS

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