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The Fracture Intervention Trial Long-term Extension (FLEX): A Randomized Trial

Dennis M. Black, PhD; Ann V. Schwartz, PhD; Kristine E. Ensrud, MD, MPH; Jane A. Cauley, DrPH; Silvina Levis, MD; Sara A. Quandt, PhD; Suzanne Satterfield, MD; Robert B. Wallace, MD; Douglas C. Bauer, MD, MPH; Lisa Palermo, MA; Lois E. Wehren, MD; Antonio Lombardi, MD; Arthur C. Santora, MD; Steven R. Cummings, MD; for the FLEX Research Group

JAMA. 2006;296:2927-2938.

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.

Trial Registration  clinicaltrials.gov Identifier: NCT 00398931

Author Affiliations: San Francisco Coordinating Center (Drs Black, Schwartz, Bauer, and Cummings and Ms Palermo), Departments of Epidemiology and Biostatistics (Drs Black and Schwartz and Ms Palermo) and Medicine (Dr Bauer), University of California, San Francisco, and California Pacific Medical Center Research Institute (Dr Cummings), San Francisco; Department of Medicine, VA Medical Center, Minneapolis, Minn (Dr Ensrud); Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pa (Dr Cauley); Department of Medicine, University of Miami, Miami, Fla (Dr Levis); School of Medicine, Wake Forest University, Winston-Salem, NC (Dr Quandt); Department of Preventive Medicine, University of Tennessee, Memphis (Dr Satterfield); College of Medicine, University of Iowa, Iowa City (Dr Wallace); and Merck Research Laboratories, Rahway, NJ (Drs Wehren, Lombardi, and Santora).

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