Skip to main content

Advertisement

SpringerLink
Log in

De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis

  • Review
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Bone-modifying agents (BMAs) such as bisphosphonates and denosumab are usually administered every 4 weeks (standard) in patients with bone metastases from breast cancer to prevent skeletal-related events (SREs). Recent randomized controlled trials suggest every 12-week (de-escalated) dosing interval may be non-inferior. The objective of this systematic review and meta-analysis was to compare the efficacy and harms of standard with de-escalated administration of BMA’s in patients with bone metastases from breast cancer.

Methods

We searched Medline, PubMed, and the Cochrane Register of Controlled Trials from 1947 to March 14, 2018 and conference abstracts from (2014–March 14, 2018) for randomized clinical trials comparing every 4-week and every 12-week dosing interval of bone-modifying agents. Using PRISMA guidelines, meta-analyses were performed using random-effects models, with findings reported as risk ratios with 95% confidence intervals (CI).

Results

From a total of 1311 citations, we identified 8 full-text articles and 1 abstract comprising data from 5 completed randomized clinical trials (n = 1807). Zoledronate administration every 12 weeks compared to every 4 weeks produced a summary risk ratio of 1.05 (95% CI 0.88–1.25) for patients with ≥ 1 on-study SRE indicating similar efficacy. These results did not differ whether patients had received prior intravenous bisphosphonate. De-escalation was associated with a non-statistically significant lower risk of increased creatinine (summary risk ratio 0.41 [95% CI 0.15–1.16]). Currently, there are insufficient data for pamidronate and denosumab de-escalation.

Conclusions

These data are supportive of de-escalation of zoledronate from onset for patients with bone metastases from breast cancer.

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
Fig. 5

Similar content being viewed by others

References

  1. Coleman RE (1997) Skeletal complications of malignancy. Cancer-Am Cancer Soc 80(8 Suppl):1588–1594

    CAS  Google Scholar 

  2. Coleman RE, Rubens RD (1987) The clinical course of bone metastases from breast cancer. Br J Cancer 55(1):61–66

    Article  CAS  Google Scholar 

  3. Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA (2009) Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 115(2):423–428

    Article  Google Scholar 

  4. Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27(3):165–176

    Article  CAS  Google Scholar 

  5. Richards MA, Braysher S, Gregory WM, Rubens RD (1993) Advanced breast cancer: use of resources and cost implications. Br J Cancer 67(4):856–860

    Article  CAS  Google Scholar 

  6. Body JJ, Chevalier P, Gunther O, Hechmati G, Lamotte M (2013) The economic burden associated with skeletal-related events in patients with bone metastases secondary to solid tumors in Belgium. J Med Econ 16(4):539–546

    Article  Google Scholar 

  7. Clemons M, Gelmon KA, Pritchard KI, Paterson AHG (2012) Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: the state of the art. Curr Oncol 19(5):259–268

    Article  CAS  Google Scholar 

  8. Holen I, Coleman RE (2010) Bisphosphonates as treatment of bone metastases. Curr Pharm Des 16(11):1262–1271

    Article  CAS  Google Scholar 

  9. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, Apffelstaedt J, Hussein M, Coleman RE, Reitsma DJ et al (2001) Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 7(5):377–387

    CAS  PubMed  Google Scholar 

  10. Van Poznak C, Somerfield MR, Barlow WE, Biermann JS, Bosserman LD, Clemons MJ, Dhesy-Thind SK, Dillmon MS, Eisen A, Frank ES et al (2017) Role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update. J Clin Oncol 35:3978

    Article  CAS  Google Scholar 

  11. Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS, Bosserman LD, Geoghegan C, Hillner BE, Theriault RL et al (2011) American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 29(9):1221–1227

    Article  Google Scholar 

  12. Network NCC: Breast Cancer Version 1.2018 (April 23, 2018) (2018)

  13. Hutton B, Addison C, Mazzarello S, Joy AA, Bouganim N, Fergusson D, Clemons M (2013) De-escalated administration of bone-targeted agents in patients with breast and prostate cancer—a survey of Canadian oncologists. J Bone Oncol 2(2):77–83

    Article  Google Scholar 

  14. Van Poznak CH, Von Roenn JH, Temin S (2011) American society of clinical oncology clinical practice guideline update: recommendations on the role of bone-modifying agents in metastatic breast cancer. J Oncol Pract 7(2):117–121

    Article  Google Scholar 

  15. Verma S, Kerr-Cresswell D, Dranitsaris G, Charbonneau F, Trudeau M, Yogendran G, Cesta AM, Clemons M (2004) Bisphosphonate use for the management of breast cancer patients with bone metastases: a survey of Canadian Medical Oncologists. Support Care Cancer 12(12):852–858

    Article  Google Scholar 

  16. Amadori D, Aglietta M, Alessi B, Gianni L, Ibrahim T, Farina G, Gaion F, Bertoldo F, Santini D, Rondena R et al (2013) Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol 14(7):663–670

    Article  CAS  Google Scholar 

  17. Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, Qin R, Go RS, Grubbs SS, O’Connor T et al (2017) Effect of longer-interval versus standard dosing of zoledronic acid on skeletal events in patients with bone metastases A randomized clinical trial. Jama-J Am Med Assoc 317(1):48–58

    Article  CAS  Google Scholar 

  18. Hortobagyi GN, Van Poznak C, Harker WG, Gradishar WJ, Chew H, Dakhil SR, Haley BB, Sauter N, Mohanlal R, Zheng M et al (2017) Continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone: the OPTIMIZE-2 randomized clinical trial. Jama Oncol 3:906

    Article  Google Scholar 

  19. Fernandes R, Siegel P, Komarova S, Hilton J, Addison C, Ibrahim MFK, Werier J, Dennis K, Singh G, Amir E et al (2016) Future directions for bone metastasis research—highlights from the 2015 bone and the Oncologist new updates conference (BONUS). J Bone Oncol 5(2):57–62

    Article  Google Scholar 

  20. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA (2015) Grp P-P: preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. Br Med J 2015:349

    Google Scholar 

  21. Higgins JPT, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JAC et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Br Med J 343:d5928

    Article  Google Scholar 

  22. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schunemann HJ, Grp GW (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br Med J 336(7650):924–926

    Article  Google Scholar 

  23. Schünemann H BJ, Guyatt G, Oxman A (eds) (2013) GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group, 2013

  24. McMaster University dbEP, Inc. (2015) GRADEpro GDT: GRADEpro guideline development tool [Software]

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

    Article  Google Scholar 

  26. The Nordic Cochrane Centre TCC (2014) Copenhagen: review manager (RevMan) [Computer program]. Version 5.3

  27. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Bmj 339:b2535

    Article  Google Scholar 

  28. Addison CL, Pond GR, Zhao HJ, Mazzarello S, Vandermeer L, Goldstein R, Amir E, Clemons M (2014) Effects of de-escalated bisphosphonate therapy on bone turnover biomarkers in breast cancer patients with bone metastases. Springerplus 3:577

    Article  Google Scholar 

  29. Amir E, Freedman O, Carlsson L, Dranitsaris G, Tomlinson G, Laupacis A, Tannock IF, Clemons M (2013) Randomized feasibility study of de-escalated (every 12 week) versus standard (every 3 to 4 week) intravenous pamidronate in women with low-risk bone metastases from breast cancer. Am J Clin Oncol-Cancer 36(5):436–442

    Article  CAS  Google Scholar 

  30. Coleman RE, Wright J, Houston S, Agrawal R, Purohit OPK, Hayward L, Simmonds P, Waterhouse A, Marshall H, Investigators B (2012) Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer. J Clin Oncol 30(15):511

    Google Scholar 

  31. Kuchuk I, Beaumont JL, Clemons M, Amir E, Addison CL, Cella D (2013) Effects of de-escalated bisphosphonate therapy on the functional assessment of cancer therapy-bone pain, brief pain inventory and bone biomarkers. J Bone Oncol 2(4):154–157

    Article  Google Scholar 

  32. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R, Berardi R, Gascon P, Tonkin KS et al (2007) Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 25(28):4431–4437

    Article  CAS  Google Scholar 

  33. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R, Berardi R, Gascon P, Tonkin KS et al (2008) Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 14(20):6690–6696

    Article  CAS  Google Scholar 

  34. Templeton AJ, Stalder L, Bernhard J, Brauchli P, Gillessen S, Hayoz S, KlIngblel D, Matter-Walstra K, Thurlimann BJK, Von Moos R (2014) Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks: a noninferiority phase III trial (SA 96/12, REDUSE). J Clin Oncol 32(15):20

    Google Scholar 

  35. Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S (2009) Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27(10):1564–1571

    Article  CAS  Google Scholar 

  36. National Cancer Institute PROCSG (2006) Common Terminology Criteria for Adverse Events (CTCAE) v3.0

  37. Smith MR, Coleman RE, Klotz L, Pittman K, Milecki P, Ng S, Chi KN, Balakumaran A, Wei R, Wang H et al (2015) Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events. Ann Oncol 26(2):368–374

    Article  CAS  Google Scholar 

  38. Ibrahim MFK, Clemons MJ, Hutton B, Hilton JF, Vandermeer L, Mazzarello S, Shorr R (2015) Should de-escalation of bone-targeted agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis. J Clin Oncol 26:2205

    CAS  Google Scholar 

  39. Cao L, Yang YJ, Diao JD, Zhang XH, Liu YL, Wang BY, Li ZW, Liu SX (2017) Systematic review and meta-analysis comparing zoledronic acid administered at 12-week and 4-week intervals in patients with bone metastasis. Oncotarget 8(52):90308–90314

    PubMed  PubMed Central  Google Scholar 

  40. Yanae M, Fujimoto S, Tane K, Tanioka M, Fujiwara K, Tsubaki M, Yamazoe Y, Morishima Y, Chiba Y, Takao S et al (2017) Increased risk of SSEs in bone-only metastatic breast cancer patients treated with zoledronic acid. J Bone Oncol 8:18–22

    Article  Google Scholar 

  41. Shapiro CL, Moriarty JP, Dusetzina S, Himelstein AL, Foster JC, Grubbs SS, Novotny PJ, Borah BJ (2017) Cost-effectiveness analysis of monthly zoledronic acid, zoledronic acid every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases: CALGB 70604 (alliance). J Clin Oncol 35:3949

    Article  CAS  Google Scholar 

  42. Clemons M (2016) A pragmatic randomised, multicentre trial comparing 4-weekly versus 12-weekly administration of bone-targeted agents in patients with bone metastases from either castration-resistant prostate cancer or breast cancer—the REaCT-BTA Study. Clinicaltrialsgov NCT02721433

Download references

Funding

This project received no outside funding and was supported with internal research funds.

Author information

Authors and Affiliations

  1. Division of Medical Oncology, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Box 912, Ottawa, ON, K1H 8L6, Canada

    Arif Ali Awan, John Hilton & Mark Clemons

  2. Department of Medicine and School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada

    Brian Hutton, Dean Fergusson & Mark Clemons

  3. Cancer Research Group, Ottawa Hospital Research Institute, Ottawa, Canada

    Sasha Mazzarello, Lisa Vandermeer, Brianne Bota, Carol Stober, Marta Sienkiewicz & Mark Clemons

  4. Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA

    Catherine Van Poznak

  5. The Ottawa Hospital, Ottawa, Canada

    Risa Shorr

Authors
  1. Arif Ali Awan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian Hutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John Hilton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sasha Mazzarello
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Catherine Van Poznak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lisa Vandermeer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Brianne Bota
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carol Stober
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marta Sienkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dean Fergusson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Risa Shorr
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mark Clemons
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark Clemons.

Ethics declarations

Conflict of interest

Dr. Awan reports participating in the Novartis Canada Advisory Board on the use of Ribociclib. Dr. Hutton reports personal fees from Cornerstone Research, outside the submitted work. Dr. van Poznak reports personal fees from UpToDate and institutional research funds from Bayer, outside the submitted work. The remaining authors declare that they have no conflicts of interest (Hilton, Mazzarello, Vandermeer, Bota, Stober, Sienkiewicz, Fergusson, Shorr, and Clemons).

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

Not applicable as this is a systematic review.

Additional information

Publisher's Note

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

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Awan, A.A., Hutton, B., Hilton, J. et al. De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 176, 507–517 (2019). https://doi.org/10.1007/s10549-019-05265-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-019-05265-1

Keywords

Search

Navigation