Effects of Continuing or Stopping Alendronate After 5 Years of Treatment. The Fracture Intervention Trial Long-term Extension (FLEX): A Randomized Trial

Abstract

Pharmacokinetic studies have shown that bisphosphonates remain in the bone matrix for many years and are gradually released as bone is resorbed. The terminal half-life of one of these drugs, alendronate, exceeds 10 years, raising the possibility that some of its skeletal effects may continue for years after treatment ceases. In the Fracture Intervention Trial, a randomized, double-blind, placebo-controlled trial conducted at 10 clinical centers in the US, 1,099 postmenopausal women who had taken alendronate for an average of 5 years were randomly assigned to take alendronate in a dose of 5 or 10 mg daily or placebo for 5 years longer. All participants had low bone mineral density (BMD) at the femoral neck at the outset. Follow-up for clinical fractures averaged 4.2 years. Adding 5 years of alendronate therapy in a daily dose of 5 or 10 mg maintained total hip BMD compared with placebo. The mean total hip BMD declined 1% in women taking the medication and 3.4% in placebo recipients. Similar changes were found for the femoral neck and trochanter when analyzed separately. Lumbar spine BMD increased by 5.3% in the alendronate group and 1.5% in placebo patients. Comparable differences were found for total-body and forearm BMD. At each site, the gain in BMD after 10 years on alendronate was significantly greater than when treatment was limited to 5 years. Markers of bone turnover remained close to baseline during continued alendronate therapy but increased gradually in women taking placebo. Despite a lack of significant differences between treatment groups for all clinical fractures or nonvertebral fractures, the risk of clinical vertebral fracture was significantly lower for women who continued on alendronate (2.4% versus 5.3% in placebo recipients). The relative risk was 0.45, with a 95% confidence interval of 0.24-0.85. Loss of height did not differ significantly. No histomorphometric differences were found when 18 iliac crest biopsies were examined. Women in the two groups had similar numbers of serious adverse effects, and there were no significant group differences in rates of withdrawal because of adverse events or in mortality rates. Continuing alendronate therapy for as long as 10 years maintains bone mass, reduces bone remodeling, and does not increase the risk of fracture. Maintaining active treatment may be especially beneficial for women who are at high risk of clinical vertebral fracture as evidenced by a history of fracture or very low BMD.