Skip to main content

Advertisement

SpringerLink
Log in

Fracture risk following intermission of osteoporosis therapy

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Given the widespread practice of recommending drug holidays, we reviewed the impact of medication discontinuation of two common anti-osteoporosis therapies (bisphosphonates and denosumab). Trial evidence suggests the risk of new clinical fractures, and vertebral fracture increases when osteoporosis treatment with bisphosphonates or denosumab is stopped.

Introduction

The aim of this paper was to review the available literature to assess what evidence exists to inform clinical decision-making with regard to drug holidays following treatment with bisphosphonates (BiP) or denosumab.

Methods

Systematic review.

Results

Differing pharmacokinetics lead to varying outcomes on stopping therapy. Prospective and retrospective analyses report that the risk of new clinical fractures was 20–40% higher in subjects who stopped BiP treatment, and vertebral fracture risk was approximately doubled. Rapid bone loss has been well described following denosumab discontinuation with an incidence of multiple vertebral fractures around 5%. Studies have not identified risk factors for fracture after stopping treatment other than those that provide an indication for treatment (e.g. prior fracture and low BMD). Studies that considered long-term continuation did not identify increased fracture risk, and reported only very low rates of adverse skeletal events such as atypical femoral fracture.

Conclusions

The view that patients on long-term treatment with bisphosphonates or denosumab should always be offered a drug holiday is not supported by the existing evidence. Different pharmacokinetic properties for different therapies require different strategies to manage drug intermission. In contrast, long-term treatment with anti-resorptives is not associated with increased risk of fragility fractures and skeletal adverse events remain rare.

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

Similar content being viewed by others

References

  1. Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 17(12):1726–1733. https://doi.org/10.1007/s00198-006-0172-4

    Article  CAS  PubMed  Google Scholar 

  2. Lindsay R, Watts NB, Lange JL, Delmas PD, Silverman SL (2013) Effectiveness of risedronate and alendronate on nonvertebral fractures: an observational study through 2 years of therapy. Osteoporos Int 24(8):2345–2352. https://doi.org/10.1007/s00198-006-0274-z

    Article  CAS  PubMed  Google Scholar 

  3. Reyes C, Tebe C, Martinez-Laguna D, Ali MS, Soria-Castro A, Carbonell C, Prieto-Alhambra D (2017) One and two year persistence with different anti-osteoporosis medications: a retrospective cohort study. Osteoporos Int 28(10):2997–3004. https://doi.org/10.1007/s00198-017-4144-7

    Article  CAS  PubMed  Google Scholar 

  4. Roerholt C, Eiken P, Abrahamsen B (2009) Initiation of antiosteoporotic therapy in patients with recent fractures: a nationwide 606 analysis of prescription rates and persistence. Osteoporos Int 20(2):299–307. https://doi.org/10.1007/s00198-008-0651-x

    Article  CAS  PubMed  Google Scholar 

  5. Silverman SL, Adachi JD, Dennison E et al (2016) Bisphosphonate drug holidays: we reap what we sow. Osteoporos Int 27(3):849–852. https://doi.org/10.1007/s00198-015-3453-y

    Article  CAS  PubMed  Google Scholar 

  6. Whittaker M, Guo J, Kehoe T et al (2012) Bisphosphonates for osteoporosis – where do we go from here? N Engl J Med 366:2048–2051. https://doi.org/10.1056/NEJMp1202619

    Article  CAS  Google Scholar 

  7. Anagnostis P, Paschou SA, Mintziori G, Ceausu I, Depypere H, Lambrinoudaki I, Mueck A, Perez-Lopez FR, Rees M, Senturk LM, Simoncini T, Stevenson JC, Stute P, Tremollieres FA, Goulis DG (2017) Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement. Maturitas 101:23–30. https://doi.org/10.1016/j.maturitas.2017.04.008

    Article  CAS  PubMed  Google Scholar 

  8. Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST, Hodgson SF, Kleerekoper M, Luckey M, McClung M, Pollack R, Petak S (2010) American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis: executive summary of recommendations. Endocr Pract 16:1016–1019. https://doi.org/10.4158/EP.16.6.1016

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, American Society for Bone and Mineral Research et al (2010) A typical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 25:2267–2294. https://doi.org/10.1002/jbmr.253

    Article  PubMed  Google Scholar 

  10. Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ, Greenspan SL, McKinney R Jr, Pignolo RJ, Sellmeyer DE (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 31:16–35. https://doi.org/10.1002/jbmr.2708

    Article  CAS  PubMed  Google Scholar 

  11. Compston J, Cooper A, Cooper C, Gittoes N, Gregson C, Harvey N, Hope S, Kanis JA, McCloskey EV, Poole KES, Reid DM, Selby P, Thompson F, Thurston A, Vine N et al (2017) UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos 12(1):43. https://doi.org/10.1007/s11657-017-0324-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rabar S, Lau R, O’Flynn N, Li L, Barry P Guideline Development Group (2012) risk assessment of fragility fractures: summary of NICE guidance. BMJ 345:e3698. https://doi.org/10.1136/bmj.e3698

  13. Watts NB, Chines A, Olszynski WP, McKeever CD, McClung MR, Zhao 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 

  14. Bianchi G, Czerwinski E, Kenwright A, Burdeska A, Recker RR, Felsenberg D (2012) Long-term administration of quarterly IV ibandronate is effective and well tolerated in postmenopausal osteoporosis: 5-year data from the DIVA study long-term extension. Osteoporos Int 23(6):1769–1778. https://doi.org/10.1007/s00198-011-1793-9

    Article  CAS  PubMed  Google Scholar 

  15. Black DM, Boonen S, Cauley JA, Cummings SR, Lippuner K, Leung PC, Martinez RLM, Ruzycky ME, Eastell R (2012a) Erratum: 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(12):2612–2254. https://doi.org/10.1002/jbmr.1494

    Article  CAS  Google Scholar 

  16. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, Cummings SR, Hue TF, Lippuner K, Lakatos P, Leung PC, Man Z, Martinez RLM, Tan M, Ruzycky ME, Su G, Eastell R (2012b) 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. https://doi.org/10.1002/jbmr.1494

    Article  CAS  PubMed  Google Scholar 

  17. Black DM, Reid IR, Cauley JA, Cosman F, Leung PC, Lakatos P, Lippuner K, Cummings SR, Hue TF, Mukhopadhyay A, Tan M, Aftring RP, Eastell R (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. https://doi.org/10.1002/jbmr.2442

    Article  CAS  PubMed  Google Scholar 

  18. Bone HG, Bolognese MA, Yuenn CK, Kendler DL, Miller PD, Yang YC, Grazette L, Martin JS, Gallagher JC (2011) 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 96(4):972–980. https://doi.org/10.1210/jc.2010-1502

    Article  CAS  PubMed  Google Scholar 

  19. Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Mellstrom D, Radominski SC, Reginster JY, Resch H, Roman Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S (2013) The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 98(11):4483–4919. https://doi.org/10.1210/jc.2013-1597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Borah B, Dufresne T, Nurre J, Phipps R, Chmielewski P, Wagner L, Lundy M, Bouxsein M, Zebaze R, Seeman E (2010) Risedronate reduces intracortical porosity in women with osteoporosis. J Bone Miner Res 25(1):41–47. https://doi.org/10.1359/jbmr.090711

    Article  CAS  PubMed  Google Scholar 

  21. Brown JP, Reid IR, Wagman RB, Kendler D, Miller PD, Jensen JEB, Bolognese MA, Daizadeh N, Valter I, Zerbini CAF, Dempster DW (2014) Effects of up to 5 years of denosumab treatment on bone histology and histomorphometry: the FREEDOM study extension. J Bone Miner Res 29(9):2051–2056. https://doi.org/10.1002/jbmr.2236

    Article  CAS  PubMed  Google Scholar 

  22. Brown JP, Roux C, Torring O, Ho PR, Beck Jensen JE, Gilchrist N, Recknor C, Austin M, Wang A, Grauer A, Wagman RB (2013) Discontinuation of denosumab and associated fracture incidence: analysis from the fracture reduction evaluation of denosumab in osteoporosis every 6 months (FREEDOM) trial. J Bone Miner Res 28(4):746–752. https://doi.org/10.1002/jbmr.1808

    Article  CAS  PubMed  Google Scholar 

  23. 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. https://doi.org/10.1210/jc.2014-1971

    Article  CAS  PubMed  Google Scholar 

  24. Eastell R, Boonen S, Cosman F, Reid IR, Palermo L, Cummings SR, Black DM (2015) Relationship between pretreatment rate of bone loss and bone density response to once-yearly ZOL: HORIZON-PFT extension study. J Bone Miner Res 30(3):483–758. https://doi.org/10.1002/jbmr.2361

    Article  CAS  Google Scholar 

  25. Eastell R, Hannon RA, Wenderoth D, Rodriguez-Moreno J, Sawicki A (2011) Effect of stopping risedronate after long-term treatment on bone turnover. J Clin Endocrinol Metab 96(11):3367–3373. https://doi.org/10.1210/jc.2011-0412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ferrari S, Adachi JD, Lippuner K, Zapalowski C, Miller PD, Reginster JY, Torring O, Kendler DL, Daizadeh NS, Wang A, O’Malley CD, Wagman RB, Libanati C, Lewiecki EM (2015) Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years. Osteoporos Int 26(12):2763–2771. https://doi.org/10.1007/s00198-015-3179-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hassler N, Gamsjaeger S, Hofstetter B, Brozek W, Klaushofer K, Paschalis EP (2015) Effects of long-term alendronate treatment on postmenopausal osteoporosis bone material properties. Osteoporos Int 26(1):339–352. https://doi.org/10.1007/s00198-014-2929-5

    Article  CAS  PubMed  Google Scholar 

  28. Leder BZ, Tsai JN, Uihlein AV, Wallace PM, Lee H, Neer RM, Burnett-Bowie SAM (2015) Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-switch study): extension of a randomised controlled trial. Lancet 386(9999):1147–1155. https://doi.org/10.1016/S0140-6736(15)61120-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McClung MR, Lewiecki EM, Geller ML, Bolognese MA, Peacock M, Weinstein RL, Ding B, Rockabrand E, Wagman RB, Miller PD (2013) Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial. Osteoporos Int 24(1):227–235. https://doi.org/10.1007/s00198-012-2052-4

    Article  CAS  PubMed  Google Scholar 

  30. McNabb B, Vittinghoff E, Eastell R, Schwartz AV, Bauer DC, Ensrud K, Barrett-Connor E, Black DM (2014) A model of BMD changes after alendronate discontinuation to guide postalendronate BMD monitoring. J Clin Endocrinol Metab 99(11):4094–4100. https://doi.org/10.1210/jc.2014-1193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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. https://doi.org/10.1002/jbmr.1864

    Article  CAS  PubMed  Google Scholar 

  32. Miller PD, Recker RR, Reginster JY, Riis BJ, Czerwinski E, Masanauskaite D, Kenwright A, Lorenc R, Stakkestad JA, Lakatos P (2012) Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE long-term extension study. Osteoporos Int 23(6):1747–1756. https://doi.org/10.1007/s00198-011-1773-0

    Article  CAS  PubMed  Google Scholar 

  33. Miller PD, Wagman RB, Peacock M, Lewiecki EM, Bolognese MA, Weinstein RL, Ding B, San Martin J, McClung MR (2011) Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. J Clin EndocrinolMetab 96(2):394–402. https://doi.org/10.1210/jc.2010-1805

    Article  CAS  Google Scholar 

  34. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Man Z, Mellstrom D, Radominski SC, Reginster JY, Resch H, Ivorra JAR, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG (2012) Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 27(3):694–701. https://doi.org/10.1002/jbmr.1479

    Article  CAS  PubMed  Google Scholar 

  35. Papapoulos S, Lippuner K, Roux C, Lin CJF, Kendler DL, Lewiecki EM, Brandi ML, Czerwinski E, Franek E, Lakatos P, Mautalen C, Minisola S, Reginster JY, Jensen S, Daizadeh NS, Wang A, Gavin M, Libanati C, Wagman RB, Bone HG (2015) The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension study. Osteoporos Int 26(12):2773–2783. https://doi.org/10.1007/s00198-015-3234-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Recknor C, Czerwinski E, Bone HG, Bonnick SL, Binkley N, Palacios S, Moffett A, Siddhanti S, Ferreira I, Ghelani P, Wagman RB, Hall JW, Bolognese MA, Benhamou CL (2013) Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. Obstet Gynecol 121(6):1291–1299. https://doi.org/10.1097/AOG.0b013e318291718c

    Article  CAS  PubMed  Google Scholar 

  37. Roschger P, Lombardi A, Misof BM, Maier G, Fratzl-Zelman N, Fratzl P, Klaushofer K (2010) Mineralization density distribution of postmenopausal osteoporotic bone is restored to normal after long-term alendronate treatment: qBEI and sSAXS data fromthe fracture intervention trial long-term extension (FLEX). J Bone Miner Res 25(1):48–55. https://doi.org/10.1359/jbmr.090702

    Article  CAS  PubMed  Google Scholar 

  38. Ensrud KE, Barrett-Connor EL, Schwartz A, Santora AC, Bauer DC, Suryawanshi S, Feldstein A, Haskell WL, Hochberg MC, Torner JC, Lombardi A, Black DM, for the Fracture Intervention Trial Long-Term Extension Research Group (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. https://doi.org/10.1359/JBMR.040326

    Article  CAS  PubMed  Google Scholar 

  39. 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 (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. https://doi.org/10.1001/jama.296.24.2927

    Article  CAS  PubMed  Google Scholar 

  40. Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guañabens N, Obermayer-Pietsch B, Ralston SH, Eastell R, Zillikens MC (2017) Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 105:11–17. https://doi.org/10.1016/j.bone.2017.08.003

    Article  PubMed  Google Scholar 

  41. Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Torring O, Valter I, Wang AT, Brown JP (2017) Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 33(2):190–198. https://doi.org/10.1002/jbmr.3359

    Article  PubMed  Google Scholar 

  42. Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O (2017) Clinical features of 24 patients with rebound associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res 32(6):1291–1704. https://doi.org/10.1002/jbmr.3110

    Article  CAS  PubMed  Google Scholar 

  43. McClung MR, Wagman RB, Miller PD, Wang A, Lewiecki EM (2017) Observations following discontinuation of long-term denosumab therapy. Osteoporos Int 28(5):1723–1732. https://doi.org/10.1007/s00198-017-3919-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Popp AW, Varathan N, Buffat H, Senn C, Perrelet R, Lippuner K (2018) Bone mineral density changes after 1 year of denosumab discontinuation in postmenopausal women with long-term denosumab treatment for osteoporosis. Calcif Tissue Int 103(1):50–54. https://doi.org/10.1007/s00223-018-0394-4

    Article  CAS  PubMed  Google Scholar 

  45. Zanchetta MB, Boailchuk J, Massari F, Silveira F, Bogado C, Zanchetta JR (2018) Significant bone loss after stopping long-term denosumab treatment: a post FREEDOM study. Osteoporos Int 29(1):41–47. https://doi.org/10.1007/s00198-017-4242-6

    Article  CAS  PubMed  Google Scholar 

  46. Adachi JD, Bone HG, Daizadeh NS, Dakin P, Papapoulos S, Hadji P, Recknor C, Bolognese MA, wang A, Lin CJF, Wagman RB, Ferrari S (2017) Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM extension study. BMC Musculoskelet Disord 18:174. https://doi.org/10.1186/s12891-017-1520-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwiński E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S (2017) 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 5(7):513–523. https://doi.org/10.1016/S2213-8587(17)30138-9

    Article  CAS  PubMed  Google Scholar 

  48. Schwarz AV, Bauer DC, Cummings SR, Cauley JA, Ensrud KE, Palermo L, Wallace RB, Hochberg MC, Feldstein AC, Lombardi A, Black DM, FLEX Research Group (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. https://doi.org/10.1002/jbmr.11

    Article  CAS  Google Scholar 

  49. Bauer DC, Schwartz A, Palermo L, Cauley J, Hochberg M, Santora A, Cummings SR, Black DM (2014) Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: the FLEX study. JAMA Intern Med 174(7):1126–1134. https://doi.org/10.1001/jamainternmed.2014.1232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Törring O, Valter I, Wang AT, Brown JP (2018) Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 33(2):190–198. https://doi.org/10.1002/jbmr.3337

    Article  CAS  PubMed  Google Scholar 

  51. 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. https://doi.org/10.1007/s00198-018-4460-6

    Article  CAS  PubMed  Google Scholar 

  52. Adams AL, Adams JL, Raebel MA, Tang BT, Kuntz JL, Vi jayadeva 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. https://doi.org/10.1002/jbmr.3420

    Article  CAS  PubMed  Google Scholar 

  53. Curtis J, Chen R, Li Z, Arora T, Saag K, Wright N, Daigle S, Kilgore M, Delzell E (2018) The impact of bisphosphonate drug holidays on fracture rates. Abstract 1006 presented at the ASBMR meeting

  54. Strom O, Landfeldt E, Garellick G (2015) Residual effect after oral bisphosphonate treatment and healthy adhere effects – the Swedish Adherence Register Analysis (SARA). Osteoporos Int 26(1):315–325. https://doi.org/10.1007/s00198-014-2900-5

    Article  CAS  PubMed  Google Scholar 

  55. 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. https://doi.org/10.1007/s00198-015-3447-9

    Article  CAS  PubMed  Google Scholar 

  56. Mignot MA, Taisne N, Legroux I, Cortet B, Paccou J (2017) Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk. Osteporosis Int 28:3431–3438. https://doi.org/10.1007/s00198-017-4215-9

    Article  CAS  Google Scholar 

  57. 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 19:1613–1620. https://doi.org/10.1007/s00198-008-0604-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, Cauley J, Leung PC, Booen S, Santora A, de Papp A, Bauer DC et al (2010) Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 362(19):1761–1771. https://doi.org/10.1056/NEJMoa1001086

    Article  CAS  PubMed  Google Scholar 

  59. Schilcher J, Michaëlsson K, Aspenberg P (2011) Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 364(18):1728–1737. https://doi.org/10.1056/NEJMoa1010650

    Article  CAS  PubMed  Google Scholar 

  60. Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K (2015) Risk of femoral fracture during and after bisphosphonate therapy. Acta Orthop 86(1):100–107. https://doi.org/10.3109/17453674.2015.1004149

    Article  PubMed  PubMed Central  Google Scholar 

  61. Adams AL, Li BH, Ryan DS, Geiger EJ, Dell RM, Black DM. (2018) Do drug holidays reduce atypical femur fracture risk?: results from the Southern California Osteoporosis Cohort Study (SOCS). Abstract 1005 presented at the ASBMR meeting

  62. Dell RM, Adams AL, Greene DF, Funahashi TT, Silverman SL, Eisman EO, Zhou H, Burchetter RJ, Ott SM (2012) Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 27(12):2544–2550. https://doi.org/10.1002/jbmr.1719

    Article  PubMed  Google Scholar 

  63. Khow KS, Shibu P, Yu SC, Chehade MJ, Visvanathan R (2017) Epidemiology and postoperative outcomes of atypical femoral fractures in older adults: a systematic review. J Nutr Health Aging 21(1):83–91. https://doi.org/10.1007/s12603-015-0652-3

    Article  CAS  PubMed  Google Scholar 

  64. Kharazmi M, Hallberg P, Schilcher J, Aspenberg P, Michaëlsson K (2016) Mortality after hip fracture. J Bone Miner Res 31(3):491–497. https://doi.org/10.1002/jbmr.2767

    Article  CAS  PubMed  Google Scholar 

  65. Marx RE (2003) Pamidronate and zoledronate induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61(9):1115–1117. https://doi.org/10.1016/S0278-2391(03)00720-1

    Article  PubMed  Google Scholar 

  66. Lo JC, O’Ryan FS, Gordon NP, Yang J, Hui RL, Martin D, Hutchinson M, Lathon PV, Sanchez G, Silver P, Chandra M, McCloskey CA, Staffa JA, Willy M, Selby JV, Go AS (2010) Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68(2):243–253. https://doi.org/10.1016/j.joms.2009.03.050

    Article  PubMed  Google Scholar 

  67. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, Reid IR, Ruggiero SL, Taguchi A, Tetradis S, Watts NB, Brandi ML, Peters E, Guise T, Eastell R, Cheung AM, Morin SN, Masri B, Cooper C, Morgan SL, Obermayer-Pietsch B, Langdahl BL, Al Dabagh R, Davison KS, Kendler DL, Sándor GK, Josse RG, Bhandari M, El Rabbany M, Pierroz DD, Sulimani R, Saunders DP, Brown JP, Compston J et al (2015) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 30(1):3–23. https://doi.org/10.1002/jbmr.2405

    Article  PubMed  Google Scholar 

  68. Woo SB, Hellstein JW, Kalmar JR (2006) Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144(10):753–761. https://doi.org/10.7326/0003-4819-144-10-200605160-00009

    Article  CAS  PubMed  Google Scholar 

  69. Marx RE, Sawatari Y, Fortin M, Bromand V (2005) Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention and treatment. J Oral Maxillofac Surg 63(11):1567–1575. https://doi.org/10.1016/j.joms.2005.07.010

    Article  PubMed  Google Scholar 

  70. Masoodi N (2009) Oral bisphosphonates and the risk for osteonecrosis of the jaw. BJMP 2(2):11–15

    Google Scholar 

  71. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356(18):1809–1822. https://doi.org/10.1056/NEJMoa067312

    Article  CAS  PubMed  Google Scholar 

  72. Choi WS, Lee JI, Yoon HJ, Min CK, Lee SH (2017) Medication-related osteonecrosis of the jaw: a preliminary retrospective study of 130 patients with multiple myeloma. Maxillofac Plast Reconstr Surg 39(1):1. https://doi.org/10.1186/s40902-016-0099-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Eiken PA, Prieto-Alhambra D, Eastell R, Abrahamsen B (2017) Surgically treated osteonecrosis and osteomyelitis of the jaw and oral cavity in patients highly adherent to alendronate treatment: a nationwide user-only cohort study including over 60,000 alendronate users. Osteporosis Int 28(10):2921–2928. https://doi.org/10.1007/s00198-017-4132-y

    Article  CAS  Google Scholar 

  74. Abrahamsen B, Eiken P, Prieto-Alhambra D, Eastell R (2016) Risk of hip, subtrochanteric, and femoral shaft fractures among mid and long term users of alendronate: nationwide cohort and nested case-control study. BMJ 353:i3365. https://doi.org/10.1136/bmj.i3365

    Article  PubMed  PubMed Central  Google Scholar 

  75. Cairoli E, Eller-Vainicher C, Ulivieri FM, Zhukouskaya VV, Palmieri S, Morelli V, Beck-Peccoz P, Chiodini I (2014) Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis. Osteoporos Int 25(4):1401–1905. https://doi.org/10.1007/s00198-014-2619-3

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by an unrestricted grant from MSD. The sponsor did not have any role in preparation, review or approval of the manuscript. The initial systematic review was performed by Nadia Corp. We are grateful to the Committee of Scientific Advisors of the International Osteoporosis Foundation for their review and endorsement of this paper.

Author information

Authors and Affiliations

  1. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, SO16 6YD, UK

    E.M. Dennison & C. Cooper

  2. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

    C. Cooper

  3. Centre for Metabolic Bone Diseases, University of Sheffield Medical School, University of Sheffield, Sheffield, UK

    J.A. Kanis

  4. Mary McKillop Health Institute, Australian Catholic University, Melbourne, Australia

    J.A. Kanis

  5. World Health Organization Collaborating Center for Public Health Aspects of Musculoskeletal Health and Ageing, Department of Public Health, Epidemiology and Health Economics, University of Liège, Liège, Belgium

    O. Bruyère

  6. Cedars-Sinai/UCLA Medical Center and OMC Clinical Research Center, Beverly Hills, CA, USA

    S. Silverman

  7. Academic Unit of Bone Metabolism, Department of Oncology and Metabolism, The Mellanby Centre For Bone Research, University of Sheffield, Sheffield, UK

    E. McCloskey

  8. Department of Medicine, Holbaek Hospital, Holbaek, Denmark

    B. Abrahamsen

  9. OPEN, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

    B. Abrahamsen

  10. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

    D. Prieto-Alhambra

  11. GREMPAL Research Group, Idiap Jordi Gol and CIBERFes, Universitat Autonoma de Barcelona and Instituto de Salud Carlos III, Barcelona, Spain

    D. Prieto-Alhambra

  12. Division of Bone Disease, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland

    S. Ferrari

Authors
  1. E.M. Dennison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J.A. Kanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. O. Bruyère
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Silverman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. McCloskey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. Abrahamsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. Prieto-Alhambra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

On behalf of the IOF Epidemiology/Quality of Life Working Group

Corresponding author

Correspondence to C. Cooper.

Ethics declarations

Competing interests

JAK reports grants from Amgen, Eli Lilly and Radius Health; non-financial support from Medimaps and Asahi; and other support from AgNovos. JAK is the architect of FRAX but has no financial interest. CC reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB. OB reports research grants from Biophytis, IBSA, MEDA, Servier and SMB outside the submitted work. DPA reports grants from Amgen, Servier and UCB, and departmental fees for speaker or consultancy services from Amgen and UCB. BA declares research grants from Novartis and UCB, speaker fees from Amgen and consulting and speaker fees from UCB. SF reports consulting and/or speaker honoraria from Amgen, UCB, Lilly, Labatec, Agnovos and Pfizer. EM reports Consultant/Advisor/Speaker fees from ActiveSignal, AgNovos, Amgen, AstraZeneca, Consilient Healthcare, Fresenius Kabi, GSK, Hologic, Internis, Lilly, Medtronic, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, Synexus, Tethys, UCB, Warner Chilcott, research support from ActiveSignal, AgNovos, Amgen, AstraZeneca, Consilient Healthcare, Fresenius Kabi, GSK, Hologic, Internis, Lilly, Medtronic, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, Synexus, Tethys, UCB, Warner Chilcott, ARUK, I3 Innovus, MRC, IOF, Unilever. ED reports consulting and speaker fees from Pfizer and UCB.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dennison, E., Cooper, C., Kanis, J. et al. Fracture risk following intermission of osteoporosis therapy. Osteoporos Int 30, 1733–1743 (2019). https://doi.org/10.1007/s00198-019-05002-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-019-05002-w

Keywords

Search

Navigation