Skip to main content
SpringerLink
Log in

Discontinuation of bisphosphonates in seniors: a systematic review on health outcomes

  • Review
  • Published:
Archives of Osteoporosis Aims and scope Submit manuscript

Abstract

Purpose

Bisphosphonates are used to treat osteoporosis. Despite their benefits on bone mineral density (BMD) and fractures, they have shown adverse effects, sometimes severe, during chronic use. Taken for several years, they achieve long-term bone retention, making deprescribing feasible. This review aimed to synthesize evidence on the success and health outcomes of deprescribing of bisphosphonates in seniors, aged over 60 years.

Methods

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including articles in English, French, or German published before July 2020. Eligible studies included seniors having discontinued bisphosphonates and reported on health outcomes; some allowed meta-analyses on fracture risk.

Results

The review included 9 RCTs and 9 cohort studies of moderate quality. Bisphosphonates were discontinued after 2 to 7 years of use, and BMD or fractures were assessed during follow-up of 0.5 to 5 years. A significant reduction in BMD after discontinuation was observed in 9 of 10 studies. Results on fracture risk after discontinuation are mitigated: 6 RCT extensions showed no increase in the risk of any osteoporotic fractures after discontinuation. Meta-analyses including 4 RCTs showed an increased odds ratio of vertebral fractures of 2.04 (95% CI, 1.39–2.99) among discontinuers. Results from 2 large cohort studies showed no increased risks of any osteoporotic or vertebral fractures, while 2 studies found increased fracture risks.

Conclusion

Bisphosphonates have successfully been discontinued low overall fracture risk after at least 3 years of use, but a risk for decreased BMD and increased vertebral fractures remained.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Sözen T, Özışık L, Başaran NÇ (2017) An overview and management of osteoporosis. Eur J Rheumatol 4(1):46–56

    Article  PubMed  Google Scholar 

  2. Williams SA, Chastek B, Sundquist K, Barrera-Sierra S, Leader D Jr, Weiss RJ, Wang Y, Curtis JR (2020) Economic burden of osteoporotic fractures in US managed care enrollees. Am J Manag Care 26(5):e142–e149

    Article  PubMed  Google Scholar 

  3. 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(10):2359–2381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tu KN, Lie JD, Wan CKV, Cameron M, Austel AG, Nguyen JK, Van K, Hyun D (2018) Osteoporosis: a review of treatment options. P & T 43(2):92–104

    Google Scholar 

  5. Kennel KA, Drake MT (2009) Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clin Proc 84(7):632–637 (quiz 638)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, Whelan DB, Weiler PJ, Laupacis A (2011) Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. Jama 305(8):783–789

    Article  CAS  PubMed  Google Scholar 

  7. McGowan K, McGowan T, Ivanovski S (2018) Risk factors for medication-related osteonecrosis of the jaws: a systematic review. Oral Dis 24(4):527–536

    Article  CAS  PubMed  Google Scholar 

  8. American Geriatrics Society 2019 Updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc 67(4):674–694

  9. Adami G, Jaleel A, Curtis JR, Delzell E, Chen R, Yun H, Daigle S, Arora T, Danila MI, Wright NC et al (2020) Temporal trends and factors associated with bisphosphonate discontinuation and restart. J Bone Miner Res 35(3):478–487

    Article  CAS  PubMed  Google Scholar 

  10. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L 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(24):2927–2938

    Article  CAS  PubMed  Google Scholar 

  11. Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ 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(1):16–35

    Article  CAS  PubMed  Google Scholar 

  12. Villa JC, Gianakos A, Lane JM (2016) Bisphosphonate treatment in osteoporosis: optimal duration of therapy and the incorporation of a drug holiday. HSS J 12(1):66–73

    Article  PubMed  Google Scholar 

  13. Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D (2019) Pharmacological management of osteoporosis in postmenopausal women: an endocrine society* clinical practice guideline. J Clin Endocrinol Metab 104(5):1595–1622

    Article  PubMed  Google Scholar 

  14. Shoback D, Rosen CJ, Black DM, Cheung AM, Murad MH, Eastell R (2020) Pharmacological management of osteoporosis in postmenopausal women: an endocrine society guideline update. J Clin Endocrinol Metab 105(3):587–594

    Article  Google Scholar 

  15. Kanis JA, Odén A, Johansson H, McCloskey EV (2013) Chapter 68 - Fracture Risk Assessment: the development and application of FRAX®. In: Marcus R, Feldman D, Dempster DW, Luckey M, Cauley JA (eds) Osteoporosis, 4th edn. Academic Press, San Diego, pp 1611–1637

    Chapter  Google Scholar 

  16. Anagnostis P, Paschou SA, Mintziori G, Ceausu I, Depypere H, Lambrinoudaki I, Mueck A, Pérez-López FR, Rees M, Senturk LM et al (2017) Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement. Maturitas 101:23–30

    Article  CAS  PubMed  Google Scholar 

  17. Tremblay Z, Furrer D MM, Morais J, Breton MC, Laurin D, Morin M, Sirois C, Tourigny A, Vedel I, Farrell B, Carmichael PH, Giguère A, Kröger E (2021) Health impacts and characteristics of deprescribing interventions in older adults – protocol for an ongoing systematic review, meta-analysis and Delphi panel. JMIR Research Protocols. https://doi.org/10.21203/rs.3.rs-50167/v1

  18. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors) (2020) Cochrane handbook for systematic reviews of interventions version 6.1 (updated September 2020). Cochrane

  19. National Institute for Health and Care Excellence. Methods for the Development of NICE Public Health Guidance [Internet]. London: National Institute for Health and Care Excellence (NICE); 2012 Sep 26. Process and Methods Guides No. 4

  20. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA (2015) Prisma-P Group: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1

    Article  PubMed  PubMed Central  Google Scholar 

  21. Scottish Intercollegiate Guidelines Network (SIGN) (2014) SIGN 50: a guideline developer’s handbook. SIGN, Edinburgh

    Google Scholar 

  22. Viswanathan M, Berkman ND (2012) Development of the RTI item bank on risk of bias and precision of observational studies. J Clin Epidemiol 65(2):163–178

    Article  PubMed  Google Scholar 

  23. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S et al (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64(4):401–406

    Article  PubMed  Google Scholar 

  24. Balduzzi S, Rücker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 22(4):153–160

    Article  PubMed  Google Scholar 

  25. A language and environment for statistical computing. https://www.gbif.org/fr/tool/81287/r-a-language-and-environment-for-statistical-computing. Accessed 13 Sept 2021

  26. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  27. Hedges LV (1984) Research synthesis: the state of the art. Int J Aging Hum Dev 19(2):85–93

    Article  CAS  PubMed  Google Scholar 

  28. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558

    Article  PubMed  Google Scholar 

  29. Borenstein M, Hedges LV, Higgins JP, Rothstein HR (2009) Publication bias. In: Wiley J (ed) Introduction to Meta-Analysis

  30. Ensrud KE, Barrett-Connor EL, Schwartz A, Santora AC, Bauer DC, Suryawanshi S, Feldstein A, Haskell WL, Hochberg MC, Torner JC 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(8):1259–1269

    Article  CAS  PubMed  Google Scholar 

  31. Schwartz AV, Bauer DC, Cummings SR, Cauley JA, Ensrud KE, Palermo L, Wallace RB, Hochberg MC, Feldstein AC, Lombardi A 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(5):976–982

    Article  CAS  PubMed  Google Scholar 

  32. McNabb BL, Vittinghoff E, Schwartz AV, Eastell R, Bauer DC, Ensrud K, Rosenberg E, Santora A, Barrett-Connor E, Black DM (2013) BMD changes and predictors of increased bone loss in postmenopausal women after a 5-year course of alendronate. J Bone Miner Res 28(6):1319–1327

    Article  CAS  PubMed  Google Scholar 

  33. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, Cummings SR, Hue TF, Lippuner K, Lakatos P 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(2):243–254

    Article  CAS  PubMed  Google Scholar 

  34. Cosman F, Cauley JA, Eastell R, Boonen S, Palermo L, Reid IR, Cummings SR, Black DM (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(12):4546–4554

    Article  CAS  PubMed  Google Scholar 

  35. Black DM, Reid IR, Cauley JA, Cosman F, Leung PC, Lakatos P, Lippuner K, Cummings SR, Hue TF, Mukhopadhyay A 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(5):934–944

    Article  CAS  PubMed  Google Scholar 

  36. Tonino RP, Meunier PJ, Emkey R, Rodriguez-Portales JA, Menkes C-J, Wasnich RD, Bone HG, Santora AC, Wu M, Desai R et al (2000) Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women*. J Clin Endocrinol Metab 85(9):3109–3115

    CAS  PubMed  Google Scholar 

  37. Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC et al (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350(12):1189–1199

    Article  CAS  PubMed  Google Scholar 

  38. Watts NB, Chines A, Olszynski WP, McKeever CD, McClung MR, Zhou X, Grauer A (2008) Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int 19(3):365–372

    Article  CAS  PubMed  Google Scholar 

  39. Naylor KE, Bradburn M, Paggiosi MA, Gossiel F, Peel NFA, McCloskey EV, Walsh JS, Eastell R (2018) Effects of discontinuing oral bisphosphonate treatments for postmenopausal osteoporosis on bone turnover markers and bone density. Osteoporos Int 29(6):1407–1417

    Article  CAS  PubMed  Google Scholar 

  40. Stock JL, Bell NH, Chesnut CH 3rd, Ensrud KE, Genant HK, Harris ST, McClung MR, Singer FR, Yood RA, Pryor-Tillotson S et al (1997) Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am J Med 103(4):291–297

    Article  CAS  PubMed  Google Scholar 

  41. Xu LH, Adams-Huet B, Poindexter JR, Maalouf NM (2016) Determinants of change in bone mineral density and fracture risk during bisphosphonate holiday. Osteoporos Int 27(5):1701–1708

    Article  CAS  PubMed  Google Scholar 

  42. 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(12):3431–3438

    Article  CAS  PubMed  Google Scholar 

  43. 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(11):1613–1620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Curtis JR, Saag KG, Arora T, Wright NC, Yun H, Daigle S, Matthews R, Delzell E (2020) Duration of Bisphosphonate drug holidays and associated fracture risk. Med Care 58(5):419–426

    Article  PubMed  PubMed Central  Google Scholar 

  45. 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(7):1252–1259

    Article  CAS  PubMed  Google Scholar 

  46. Miller PD, Watts NB, Licata AA, Harris ST, Genant HK, Wasnich RD, Ross PD, Jackson RD, Hoseyni MS, Schoenfeld SL et al (1997) Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment. Am J Med 103(6):468–476

    Article  CAS  PubMed  Google Scholar 

  47. El Miedany Y (2020) FRAX: re-adjust or re-think. Arch Osteoporos 15(1):150

    Article  PubMed  PubMed Central  Google Scholar 

  48. Rolnick SJ, Pawloski PA, Hedblom BD, Asche SE, Bruzek RJ (2013) Patient characteristics associated with medication adherence. Clin Med Res 11(2):54–65

    Article  PubMed  PubMed Central  Google Scholar 

  49. Fink HA, MacDonald R, Forte ML, Rosebush CE, Ensrud KE, Schousboe JT, Nelson VA, Ullman K, Butler M, Olson CM et al (2019) Long-term drug therapy and drug discontinuations and holidays for osteoporosis fracture prevention: a systematic review. Ann Intern Med 171(1):37–50

    Article  PubMed  Google Scholar 

  50. Nayak S, Greenspan SL (2018) How can we improve osteoporosis care? a systematic review and meta-analysis of the efficacy of quality improvement strategies for osteoporosis. J Bone Miner Res 33(9):1585–1594

    Article  PubMed  Google Scholar 

  51. Chen F-P, Fu T-S, Lin Y-C, Fan C-M (2018) Risk factors and quality of life for the occurrence of hip fracture in postmenopausal women. Biomed J 41(3):202–208

    Article  PubMed  PubMed Central  Google Scholar 

  52. Albayrak I, Aydogmus M, Ozerbil OM, Levendoglu F (2016) The association between bone mineral density, quality of life, quality of sleep and fatigue. Acta Clin Belg 71(2):92–98

    Article  PubMed  Google Scholar 

  53. Aktaş Ö, Kaplan S, Sezer N (2018) An assessment of the relation between bone mineral density and clinic-demographic properties and life quality during postmenopausal period. J Back Musculoskelet Rehabil 31(5):803–810

    Article  PubMed  Google Scholar 

  54. Alexiou KI, Roushias A, Varitimidis SE, Malizos KN (2018) Quality of life and psychological consequences in elderly patients after a hip fracture: a review. Clin interv Aging 13:143–150

    Article  PubMed  PubMed Central  Google Scholar 

  55. Stanghelle B, Bentzen H, Giangregorio L, Pripp AH, Bergland A (2019) Associations between health-related quality of life, physical function and pain in older women with osteoporosis and vertebral fracture. BMC Geriatr 19(1):298

    Article  PubMed  PubMed Central  Google Scholar 

  56. Fatoye F, Smith P, Gebrye T, Yeowell G (2019) Real-world persistence and adherence with oral bisphosphonates for osteoporosis: a systematic review. BMJ open 9(4):e027049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gonnelli S, Caffarelli C, Letizia Mauro G, Di Munno O, Malavolta N, Migliaccio S, Nuti R (2019) Retrospective evaluation of persistence in osteoporosis therapy with oral bisphosphonates in Italy: the TOBI study. Aging Clin Exp Res 31(11):1541–1547

    Article  PubMed  Google Scholar 

  58. Iwamoto J, Okano H, Furuya T, Urano T, Hasegawa M, Hirabayashi H, Kumakubo T, Makita K (2016) Patient preference for monthly bisphosphonate versus weekly bisphosphonate in a cluster-randomized, open-label, crossover trial: Minodroate Alendronate/Risedronate Trial in Osteoporosis (MARTO). J Bone Miner Metab 34(2):201–208

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was funded by grants from the Canadian Institutes of Health Research (2016–18) and from the Réseau Québécois de recherche sur le vieillissement-FRQS (2015–16). It received support from the Centre d’excellence sur le vieillissement de Québec/CIUSSS de la Capitale Nationale.

Author information

Authors and Affiliations

  1. Faculté de médecine, Université Laval, Quebec City, Quebec, Canada

    Marianne Lamarre, André Tourigny & Anik Giguère

  2. Centre d’excellence sur le vieillissement de Québec, CIUSSS Capitale Nationale, Quebec City, Quebec, Canada

    Martine Marcotte, Danielle Laurin, Daniela Furrer, André Tourigny, Anik Giguère, Pierre-Hugues Carmichael, Rosa Martines & Edeltraut Kröger

  3. Faculté de pharmacie, Université Laval, Quebec City, Quebec, Canada

    Danielle Laurin & Edeltraut Kröger

  4. Institut sur le vieillissement et la participation sociale des aînés de l, Université Laval, Quebec City, Quebec, Canada

    Danielle Laurin & André Tourigny

  5. Centre de recherche du CHU de Québec, Université Laval, Quebec City, Quebec, Canada

    Danielle Laurin, André Tourigny, Anik Giguère & Edeltraut Kröger

  6. VITAM Centre de recherche sur la santé durable, Quebec City, Quebec, Canada

    Danielle Laurin, André Tourigny, Anik Giguère, Pierre-Hugues Carmichael & Edeltraut Kröger

  7. Faculty of Medicine, McGill University, Montreal, Quebec, Canada

    Isabelle Vedel, José Morais & Edeltraut Kröger

Authors
  1. Marianne Lamarre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martine Marcotte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Danielle Laurin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniela Furrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabelle Vedel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. André Tourigny
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anik Giguère
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pierre-Hugues Carmichael
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rosa Martines
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. José Morais
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Edeltraut Kröger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edeltraut Kröger.

Ethics declarations

Conflicts of interest

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Appendices

Appendix 1 Predictors of adverse health outcomes

Table 4

Appendix 2

Table 5

Appendix 3

Table

Table 6 Excluded studies
Full size table

6

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lamarre, M., Marcotte, M., Laurin, D. et al. Discontinuation of bisphosphonates in seniors: a systematic review on health outcomes. Arch Osteoporos 16, 133 (2021). https://doi.org/10.1007/s11657-021-01000-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11657-021-01000-w

Keywords

Search

Navigation