MENOPAUSE

Some can take a holiday from bisphosphonate therapy

Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. 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.

There is evidence that bone metabolism continues to be affected for some time when alendronate is stopped after 2 to 5 years of treatment, as Black and colleagues found in the Fracture Intervention Trial Long-Term Extension (FLEX) and others have demonstrated.¹⁰ This raises the possibility that patients can take a “drug holiday” after several years of treatment. (This study was also reported in the March issue of OBG Management in “Examining the Evidence,” with a commentary by Steven R. Goldstein, MD.)

The FLEX trial attempted to determine whether it is better to continue or stop alendronate after several years’ exposure. One thousand ninety-nine women who had taken alendronate for 3 to 6 years in the FIT trials were randomly assigned to 5 or 10 mg of alendronate daily or placebo. All subjects received 500 mg of calcium and small vitamin D supplements and were followed for an additional 5 years.

The 2 alendronate groups were pooled for the analyses. Patients who switched to placebo for 5 years had declines in BMD at the total hip (2.4%) and spine (3.7%), compared with those who continued alendronate. However, values at the end of 5 years without therapy remained at or above pretreatment levels. Indices of bone turnover increased modestly when therapy was discontinued, but again the rates of bone turnover remained substantially lower than pretreatment values.

Fractures were collected as an exploratory endpoint. Compared with women who stopped treatment, women who continued alendronate reduced their risk of developing a clinical vertebral fracture by 55% (from 5.3% in the placebo group to 2.4% in the alendronate group). No difference was observed in the incidence of nonvertebral fractures between the 2 groups.

Who should take a holiday, and who can stay put?

Unfortunately, this study does not clearly answer the question. Patients at high risk for spine fracture, including those with a previous fracture, appeared to fare better if they continued treatment. Patients at lower risk did equally well whether they stopped or continued alendronate. This suggests that it would be appropriate to stop treatment in women who are not at high risk, including women who do not have osteoporosis by BMD criteria and have not experienced a fragility fracture since menopause.

The reason for stopping therapy in patients at low risk is because there was no added benefit observed with continued treatment, not because of concerns about risk.

When should the holiday end?

If treatment is stopped, the clinical question of whether and when to restart treatment becomes a challenge. The changes in bone density after treatment is stopped are too small to discern in individual patients. In theory, monitoring one or more bone-turnover markers is a more sensitive way to determine when the effects of bisphosphonates on skeletal remodeling are dissipating, but this approach is backed by very little clinical experience.

Another unresolved issue is whether the response after stopping treatment is the same in patients taking risedronate, ibandronate, or lower doses of alendronate.