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Evidence summaries

Effects of Continuing or Stopping Alendronate after 5 Years of Treatment

For many women, discontinuation of alendronate after 5 years for up to 5 more years appears not to increase fracture risk, but women at high risk of clinical vertebral fractures (such as those with vertebral fractures or very low BMD) may benefit by continuing beyond 5 years. Level of evidence: "B"

A randomized trial 1 with 1099 subjects compared the effects of discontinuing alendronate treatment after 5 years vs. continuing for 10 years among elderly women (mean age 73 years). Compared with continuing alendronate (5 mg/d or 10 mg/d), switching to placebo for 5 years resulted in declines in bone mineral density, BMD at the total hip (-2.4%, 95% CI -2.9% to -1.8%) and spine (-3.7%, 95% CI -4.5% to -3.0%), but mean levels remained at or above pre-treatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate 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 to 1.32) was not significantly different between those continuing and discontinuing 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 to 0.85) but no significant reduction in morphometric vertebral fractures (RR 0.86, 95% CI 0.60 to1.22). No significant between-group differences were seen in serious adverse experiences. A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities.

A systematic review and consensus of expert opinion 2 concluded that discontinuation of bisphosphonates should be considered after treatment of more than 5 years with alendronate, risedronate or zoledronic acid. No robust recommendations was made for ibandronate and denosumab due to limited evidence. For those who have not experienced fractures before or during therapy and the fracture risk is low, a "drug holiday" can be recommended.

Comment: The level of evidence is downgraded by imprecise results (the trial had limited power to detect modest differences in fracture rates reflected in the wide CIs for fracture outcomes).

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References

  • Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR, 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 Dec 27;296(24):2927-38. [PubMed]
  • Anagnostis P, Paschou SA, Mintziori G et al. Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement. Maturitas 2017;(101):23-30. [PubMed]

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