A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk

  • S. NayakEmail author
  • S. L. Greenspan
Original Article



We performed a systematic review on the effect of drug holidays (discontinuation) on bone mineral density (BMD) and fracture risk. Bisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3–5 years of initial treatment, while women who have low hip BMD may benefit from treatment continuation.


We performed a systematic review and meta-analysis on the effect of drug holidays (discontinuation) on BMD and fracture risk.


We searched PubMed, Embase, and Cochrane Library databases to locate controlled clinical trials and cohort studies evaluating the effect of drug holidays/discontinuation versus osteoporosis treatment continuation. We performed random-effects meta-analyses of hazard ratios of hip and any clinical osteoporotic fracture for individuals who discontinued bisphosphonates compared to persistent users.


Thirteen records reporting results from eight different studies met inclusion criteria. The FLEX study found a reduced clinical vertebral fracture risk with 10 years of alendronate therapy compared to 5 (RR 0.45, 95% CI 0.24–0.85), and the HORIZON extension studies found a reduced risk of morphometric vertebral fracture with 6 years of zoledronic acid therapy compared to 3 (OR = 0.51, 95% CI 0.26–0.95); subgroup analyses showed that women with low hip BMD T-scores after the initial treatment period benefitted from continued treatment in terms of reduced vertebral fracture risk. Meta-analysis of adjusted hazard ratios of hip and any clinical osteoporotic fracture for women who discontinued bisphosphonates revealed no significant differences in the risk of hip fracture (summary estimate of HR 1.09, 95% CI 0.87–1.37) or any clinical fracture (summary estimate of HR 1.13, 95% CI 0.75–1.70) compared to persistent users.


Bisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3 to 5 years of initial treatment, while women who have low hip BMD may benefit from treatment continuation.


Bisphosphonates Drug holiday Meta-analysis Osteoporosis Systematic review 


Compliance with ethical standards

Conflicts of interest


Supplementary material

198_2018_4791_MOESM1_ESM.docx (88 kb)
ESM 1 (DOCX 88 kb)


  1. 1.
    Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B (2014) The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 29:2520–2526CrossRefGoogle Scholar
  2. 2.
    U.S. Department of Health and Human Services. Bone health and osteoporosis: a report of the surgeon general. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General, 2004Google Scholar
  3. 3.
    Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement 2000;17(1):1–45Google Scholar
  4. 4.
    Lin JT, Lane JM (2004) Osteoporosis: a review. Clin Orthop Relat Res 425:126–134CrossRefGoogle Scholar
  5. 5.
    Nguyen ND, Ahlborg HG, Center JR, Eisman JA, Nguyen TV (2007) Residual lifetime risk of fractures in women and men. J Bone Miner Res 22:781–788CrossRefGoogle Scholar
  6. 6.
    Blume SW, Curtis JR (2011) Medical costs of osteoporosis in the elderly Medicare population. Osteoporos Int 22:1835–1844CrossRefGoogle Scholar
  7. 7.
    Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R, National Osteoporosis F (2014) Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 25:2359–2381CrossRefGoogle Scholar
  8. 8.
    Adler RA, El-Hajj Fuleihan G, Bauer DC et al (2016) Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 31:16–35CrossRefGoogle Scholar
  9. 9.
    Higgins JPT, Green S (editors). Cochrane handbook for systematic reviews of interventions Version 5.1.0 [updated March 2011]. Box 6.4.b: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximizing version; PubMed format. The Cochrane Collaboration, 2011. Available from Accessed Jan 2018
  10. 10.
    Higgins JP, Altman DG, Gotzsche PC et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928CrossRefGoogle Scholar
  11. 11.
    Wells GA SB, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed June 2018
  12. 12.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefGoogle Scholar
  13. 13.
    Adams AL, Adams JL, Raebel MA, Tang BT, Kuntz JL, Vijayadeva V, McGlynn EA, Gozansky WS (2018) Bisphosphonate drug holiday and fracture risk: a population-based cohort study. J Bone Miner Res 33:1252–1259CrossRefGoogle Scholar
  14. 14.
    Black D, Reid I, Boonen S et al (2012) 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 27:243–254CrossRefGoogle Scholar
  15. 15.
    Black D, Reid I, Cauley J et al (2015) The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 30:934–944CrossRefGoogle Scholar
  16. 16.
    Black D, Schwartz A, Ensrud K et al (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296:2927–2938CrossRefGoogle Scholar
  17. 17.
    Bone H, Hosking D, Devogelaer J, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA, Alendronate Phase III Osteoporosis Treatment Study Group (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199CrossRefGoogle Scholar
  18. 18.
    Cosman F, Cauley J, Eastell R, Boonen S, Palermo L, Reid I, Cummings S, Black D (2014) Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to discontinue treatment? J Clin Endocrinol Metab 99:4546–4554CrossRefGoogle Scholar
  19. 19.
    Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG (2008) Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday. Osteoporos Int 19:1613–1620CrossRefGoogle Scholar
  20. 20.
    Curtis JR, Chen R, Li Z, Arora T, Saag K, Wright NC, Daigle S, Kilgore M, Delzell E (2017) The impact of the duration of bisphosphonate drug holidays on hip fracture rates [abstract]. Arthritis Rheumatol 69(suppl 10)Google Scholar
  21. 21.
    Ensrud K, Barrett-Connor E, Schwartz A et al (2004) Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res 19:1259–1269CrossRefGoogle Scholar
  22. 22.
    Mignot MA, Taisne N, Legroux I, Cortet B, Paccou J (2017) Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk. Osteoporos Int 28:3431–3438CrossRefGoogle Scholar
  23. 23.
    Miller PD, Watts NB, Licata AA, Harris ST, Genant HK, Wasnich RD, Ross PD, Jackson RD, Hoseyni MS, Schoenfeld SL, Valent DJ, Chesnut CH 3rd (1997) Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment. Am J Med 103:468–476CrossRefGoogle Scholar
  24. 24.
    Schwartz A, Bauer D, Cummings S et al (2010) Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res 25:976–982CrossRefGoogle Scholar
  25. 25.
    Tonino R, Meunier P, Emkey R et al (2000) Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group. J Clin Endocrinol Metab 85:3109–3115PubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2019

Authors and Affiliations

  1. 1.Berkeley Madonna, Inc.BerkeleyUSA
  2. 2.University of Pittsburgh School of MedicinePittsburghUSA

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