Management of Drug Holidays

Abstract

Bisphosphonates are effective to reduce the risk of osteoporotic fractures, according to prospective randomized trials. However, concerns have been raised recently about safety of long-term administration of these treatments. Based on the potential persistence of effects of these drugs after their discontinuation, it has been suggested that a drug holiday, i.e., a temporary discontinuation of the treatment, could be advisable. There are no evidence-based data to support the management of such drug holidays. Following discontinuation, there is a decrease in BMD and an increase in bone resorption. Patients with a T score higher than −2.5 at the femoral neck after the appropriate duration of treatment may not suffer from a drug holiday. Follow-up of bone markers and BMD is necessary to decide when to resume treatment.

Keywords

Drug holiday Osteoporosis Fracture Bisphosphonate Atypical femoral fracture Bone mineral density Biomarkers of bone remodeling Discontinuation of treatment 

References1

  1. 1.
    Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364:1728–37.PubMedCrossRefGoogle Scholar
  2. 2.
    Watts NB, Chines A, Olszynski P, McKeever CD, Mc Clung MR, Zhou X, et al. Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int. 2008;19:365–72.PubMedCrossRefGoogle Scholar
  3. 3.
    *Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, 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;296:2927–38. *Large study assessing bone effects of discontinuation of alendronate.PubMedCrossRefGoogle Scholar
  4. 4.
    *Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-pivotal fracture trial (PFT). J Bone Miner Res. 2012;27:240–2. *Large study assessing bone effects of discontinuation of zoledronate.CrossRefGoogle Scholar
  5. 5.
    Greenspan SL, Emkey RD, Bone III HG, Weiss SR, Bell NH, Downs RW, et al. Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137:875–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SAA, Brzyski R, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299:1036–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Neele SJ, Evertz R, De Valk-De Roo G, Roos JC, Netelenbos JC. Effect of 1 year of discontinuation of raloxifene or estrogen therapy on bone mineral density after 5 years of treatment in healthy post menopausal women. Bone. 2002;30:599–603.PubMedCrossRefGoogle Scholar
  8. 8.
    Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972–80.PubMedCrossRefGoogle Scholar
  9. 9.
    Brown JP, Roux C, Törring O, Ho RR, Beck-Jensen JE, Gilchrist N, et al. Discontinuation of denosumab and associated fracture incidence: analysis from the FREEDOM trial. J Bone Miner Res. 2013;28:746–52.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    **Schwartz AV, Bauer DC, Cummings SR, Cauley JA, Ensrud KE, Palermo L, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010;25:976–82. **This study supports the concept of using femoral neck T score at the time of discontinuation of a treatment as a tool to assess fracture risk.PubMedCrossRefGoogle Scholar
  11. 11.
    Cosman F, Caulin F, Eastell R, Boos N, Palermo L, Reid KR et al. Who is at highest risk for new vertebral fractures after 3 years of annual zoledronic acid and who should remain on treatment? (internet). J Bone Miner Res. 2011;26 suppl 1:Abstract 1248 (cited 12 Feb 2012).Google Scholar
  12. 12.
    Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG. Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday. Osteoporos Int. 2008;19:1613–20.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for osteoporosis. Where do we go from here? N Engl J Med. 2012;366:2048–51.PubMedCrossRefGoogle Scholar
  14. 14.
    Seeman E. To stop or not to stop, that is the question. Osteoporos Int. 2009;20:187–95.PubMedCrossRefGoogle Scholar
  15. 15.
    Diab DL, Watts NB. Bisphosphonate drug holiday: who, when and how long. Ther Adv Musculoskelet Dis. 2013;5(3):107–11.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, Hanley DA, Kendler DL, Yuen KY, Lewiecki EM. Bisphosphonate therapy for osteoporosis, benefits, risk, and drug holiday. Am J Med 2013;126:13–20Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Service de RhumatologieHôpital CochinParisFrance
  2. 2.INSERM U1153Paris-Descartes UniversityParisFrance

Personalised recommendations