Effects of continuing or stopping alendronate after 5 years of treatment - The Fracture Intervention Trial long-term extension (FLEX): A randomized trial

Context The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. Objective To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. Design and Setting Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial ( FIT). Participants One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. Intervention Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). Main Outcome Measures The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. Results Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (- 2.4%; 95% confidence interval [CI], - 2.9% to - 1.8%; P <. 001) and spine (- 3.7%; 95% CI, - 4.5% to - 3.0%; P <. 001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% ( P <. 001) for C-telopeptide of type 1 collagen, 59.5% ( P <. 001) for serum N = propeptide of type 1 collagen, and 28.1% ( P <. 001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover ( double labeling) seen in all specimens. Conclusions Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years.