Yes. But the amount of bone loss is clinically small (2% to 3%) in women who stop taking alendronate after 5 years of therapy. At 10 years after initiation of alendronate (5 years after discontinuation), bone mineral density remained well above baseline value.
This large, multicenter trial will help us better define clinical management with the bisphosphonates—although this study looked specifically at alendronate. An earlier and smaller study of 226 subjects by Greenspan and colleagues demonstrated that bone mineral density (BMD) maintains itself for 15 months after discontinuation of alendronate.1 This trial by Black and colleagues—the FLEX trial—is a 5-year extension of the Fracture Intervention Trial (FIT).2 It randomized 1,099 women who had taken alendronate for 5 years in FIT to alendronate 5 mg daily (n=329), 10 mg daily (n=333), or placebo (n=437) for 5 additional years. Women were excluded from FLEX if their T-score was less than -3.5 or their BMD was lower than at entry into FIT.
In the FLEX trial, women who switched to placebo after 5 years of alendronate lost a statistically significant but clinically small amount of BMD—approximately 2% to 3%—compared with those who continued taking alendronate for a full 10 years. In all groups, however, BMD levels remained well above baseline at the time of entry into FIT.
Similarities in fracture rates, too
Despite the small difference in BMD measurements between groups, there was no increase in overall clinical fractures or radiographically detected vertebral fractures among women in the placebo group. However, there was a statistically significant 2.9% increase in absolute risk for clinically detected vertebral fractures. One reason for these somewhat surprising findings may be that the trial was powered to detect BMD changes rather than fractures. Nevertheless, it appears that, for some women, 5 years of bisphosphonate therapy may be enough to realize fracture-reduction benefits.
The magnitude of the absolute reduction in clinical vertebral fractures was greatest in women with T-scores worse than -2.5 at the beginning of FLEX, as well as in those with a baseline vertebral fracture at entry. The authors conclude that women at high risk of vertebral fracture because of previous vertebral fractures may be considered for continued therapy. Obviously, a long-term study powered for fractures rather than BMD measurement would be ideal, if extraordinarily expensive.
Who can take a ‘drug holiday’?
Women who have a good response to 5 years of bisphosphonate therapy (ie, a 3–5% increase in hip BMD, 8–10% increase in spine BMD, and a T-score better than -3.5) do not appear to be at increased risk of vertebral fracture after a “drug holiday” of up to 5 years. Such an approach would clearly improve the cost-effectiveness of bisphosphonate therapy. However, it would also necessitate careful BMD monitoring because the BMD values listed above are mean findings. Close monitoring would identify women who might be rapidly losing BMD and who need to resume bisphosphonate therapy or an alternative. Therefore, the treatment center should be reliable, with use of the same dual-energy x-ray absorptiometry (DXA) machine whenever possible.
Today, almost all patients are treated with once-weekly dosing. Although this regimen appears to be equivalent to daily dosing,3 it could confound the findings of FLEX.
Bottom line: Consider stopping alendronate in selected patients
Findings from FIT and similar trials established that the initiation of bisphosphonate therapy in postmenopausal women with osteoporosis or a previous nontraumatic fracture substantially reduces their risk of vertebral and nonvertebral fractures.4 These new data from the FLEX trial will allow us to discontinue bisphosphonate therapy in some women after 5 years without exposing them to additional risk.5