FIT versus FLEX: Weighing the benefits of extending bisphosphonate therapy beyond 5 years

A randomized, double-blind, placebo-controlled trial published in the Journal of the American Medical Association (JAMA) found that women who discontinued alendronate after 5 years demonstrated a moderate decline in bone mineral density (BMD) and a gradual increase in serum markers of bone turnover compared with women who continued taking alendronate for an additional 5 years, but mean levels among patients who discontinued therapy remained at or above baseline levels measured 10 years earlier. In addition, no greater fracture risk other than for clinically detected vertebral fractures was seen in the discontinuation group compared with patients who continued alendronate for 10 years.

The Fracture Intervention Trial Long-Term Extension (FLEX) is a continuation of the Fracture Intervention Trial (FIT), a randomized, blinded, placebo-controlled trial that evaluated the daily use of alendronate (either 5 or 10 mg/d) on BMD and the risk of fractures. In FIT, 6,459 postmenopausal women aged 55 to 81 years were randomized to receive alendronate (n=3,236) or placebo (n=3,223); mean follow-up was 3.8 years. FIT demonstrated that for women with low BMD (T score ≤–2.5) but no vertebral fractures, 4 years of alendronate therapy increased BMD and decreased the risk of first vertebral deformity. Further, among those women with low BMD and existing vertebral fractures, alendronate significantly reduced the incidence of vertebral fractures.

In the FLEX trial, all study participants who had received alendronate in the FIT trial, were not lost to follow-up, and had received and responded to alendronate for ≥3 years were re-randomized to receive either alendronate 5 mg/d (n=329), alendronate 10 mg/d (n=333), or placebo (n=437) for an additional 5 years. Study end points included BMD, serum markers of bone turnover, and fracture rates. FIT participants who did not meet the above criteria and/or had extremely low BMD (T score ≤3.5), were taking other bone-active medications, or had any contraindications to bisphosphonate use were excluded from the FLEX trial.

The authors noted the increased benefits of bone mass maintenance and reduced bone remodeling with the use of alendronate for 10 years versus 5 years; however, they also pointed out that there was no demonstrated increase in fracture risk for many women who discontinued alendronate after ≤5 years. They stated: "The findings in the FLEX trial do suggest that women with vertebral fractures or very low BMD are considered high risk for clinical vertebral fractures and may benefit by continued alendronate use beyond 5 years."

In a similar, smaller, long-term study of alendronate, the BMD differences between continuous alendronate use for 10 years versus 5 years followed by 5 years of placebo use were 4% for the spine and approximately 3% to 4% for the hip. Unlike the FLEX trial, this study did not report fracture rates.

Authors of the FLEX trial noted several limitations of their work, including the fact that the trial may have been underpowered to detect significant differences in fracture rates among the study groups and that the average participant in the trial at baseline was a 73-year-old postmenopausal woman, so results might not be applicable to younger women, men, or the very elderly.

In response to the research, Cathleen S. Colón-Emeric, MD, MHSc, from the Duke University Medical Center, Durham, NC, remarked in a related editorial: "Findings from FIT and similar trials established that starting bisphosphonate therapy in post-menopausal women with osteoporosis or a low-trauma fracture substantially reduces their risk of vertebral fractures, pain, and disability. Now, armed with FLEX data, physicians may be able to begin telling women when they have had enough of a good thing." Dr Colón-Emeric said a long-term, randomized, controlled trial designed to evaluate fracture instead of BMD changes, although likely too expensive, would be optimal."The FLEX trial therefore provides the best data likely to be available on this question," she said.

SOURCES Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: The Fracture Intervention Trial Long-Term Extension (FLEX): A randomized trial. JAMA. 2006;296:2927–2938.

Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348:1535–1541.

Bone HG, Hosking D, Devogelaer JP, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199.

Colón-Emeric CS. Ten vs five years of bisphosphonate treatment for postmenopausal osteoporosis: Enough of a good thing [editorial]. JAMA. 2006;296:2968-2969.