[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307)

  • Original Article
  • Published:
Supportive Care in Cancer Aims and scope Submit manuscript

Abstract

Purpose

Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.

Methods

SWOG 0307 randomized women with stage I–III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.

Results

Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.

Conclusion

ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.

Clinical trial number

NCT00127205

Registration date

July 2005

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Does not apply

References

  1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2015) Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 386(10001):1353–1361

    Google Scholar 

  2. Dhesy-Thind S, Fletcher GG, Blanchette PS, Clemons MJ, Dillmon MS, Frank ES, Gandhi S, Gupta R, Mates M, Moy B, Vandenberg T, van Poznak CH (2017) Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. Clin Oncol 35(18):2062–2081

    Google Scholar 

  3. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, Zackrisson S (2019) Senkus E; ESMO Guidelines Committee. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 30(8):1194–1220

    CAS  PubMed  Google Scholar 

  4. Hadji P, Coleman RE, Wilson C, Powles TJ, Clézardin P, Aapro M, Costa L, Body JJ, Markopoulos C, Santini D, Diel I, Di Leo A, Cameron D, Dodwell D, Smith I, Gnant M, Gray R, Harbeck N, Thurlimann B, Untch M, Cortes J, Martin M, Albert US, Conte PF, Ejlertsen B, Bergh J, Kaufmann M, Holen I (2016) Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol 27(3):379–390

    CAS  PubMed  Google Scholar 

  5. Guise T (2010) Examining the metastatic niche: targeting the microenvironment. Semin Oncol 37(Suppl 2):S2–S14

    CAS  PubMed  Google Scholar 

  6. Roelofs AJ, Thompson K, Gordon S, Rogers MJ (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12(20 Pt 2):6222 s–6230 s

    CAS  Google Scholar 

  7. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CKM, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AHJ (2007) Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A 104(24):10022–10027

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Fromigue O, Lagneaux L, Body JJ (2000) Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res 15(11):2211–2221

    CAS  PubMed  Google Scholar 

  9. Clezardin P (2011) Bisphosphonates antitumor activity: an unrevealed side of a multifaceted drug class. Bone. 48(1):71–79

    CAS  PubMed  Google Scholar 

  10. Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61(9):1115–1117

    PubMed  Google Scholar 

  11. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F, American Association of Oral and Maxillofacial Surgeons (2014) American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg 72(10):1938–1956

    PubMed  Google Scholar 

  12. Miksad RA, Lai KC, Dodson TB, Woo SB, Treister NS, Akinyemi O, Bihrle M, Maytal G, August M, Gazelle GS, Swan JS (2011) Quality of life implications of bisphosphonate-associated osteonecrosis of the jaw. Oncologist. 16(1):121–132

    PubMed  PubMed Central  Google Scholar 

  13. Melea PI, Melakopoulos I, Kastritis E et al (2014) Conservative treatment of bisphosphonate-related osteonecrosis of the jaw in multiple myeloma patients. Int J Dent 2014:427273

    PubMed  PubMed Central  Google Scholar 

  14. O’Ryan FS, Lo JC (2012) Bisphosphonate-related osteonecrosis of the jaw in patients with oral bisphosphonate exposure: clinical course and outcomes. J Oral Maxillofac Surg 70(8):1844–1853

    PubMed  Google Scholar 

  15. Lee LW, Hsiao SH, Chen LK (2014) Clinical treatment outcomes for 40 patients with bisphosphonates-related osteonecrosis of the jaws. J Formos Med Assoc 113(3):166–172

    PubMed  Google Scholar 

  16. Assaf AT, Smeets R, Riecke B, Weise E, Gröbe A, Blessmann M, Steiner T, Wikner J, Friedrich RE, Heiland M, Hoelzle F, Gerhards F (2013) Incidence of bisphosphonate-related osteonecrosis of the jaw in consideration of primary diseases and concomitant therapies. Anticancer Res 33(9):3917–3924

    CAS  PubMed  Google Scholar 

  17. Aghaloo T, Hazboun R, Tetradis S (2015) Pathophysiology of osteonecrosis of the jaws. Oral Maxillofac Surg Clin North Am 27(4):489–496

    PubMed  PubMed Central  Google Scholar 

  18. Pichardo SE, van Merkesteyn JP (2013) Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin? Oral Surg Oral Med Oral Pathol Oral Radiol 116(3):287–292

    PubMed  Google Scholar 

  19. Kim JW, Landayan ME, Lee JY et al (2016) Role of microcracks in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw. Clin Oral Investig 20(8):2251–2258

    PubMed  Google Scholar 

  20. Estilo CL, Van Poznak CH, Wiliams T et al (2008) Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. Oncologist. 13(8):911–920

    PubMed  Google Scholar 

  21. Ngamphaiboon N, Frustino JL, Kossoff EB, Sullivan MA, O’Connor TL (2011) 1. Osteonecrosis of the jaw: dental outcomes in metastatic breast cancer patients treated with bisphosphonates with/without bevacizumab. Clin Breast Cancer 11(4):252–257

    CAS  PubMed  Google Scholar 

  22. Sedghizadeh PP, Yooseph S, Fadrosh DW, Zeigler-Allen L, Thiagarajan M, Salek H, Farahnik F, Williamson SJ (2012) Metagenomic investigation of microbes and viruses in patients with jaw osteonecrosis associated with bisphosphonate therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 114(6):764–770

    PubMed  PubMed Central  Google Scholar 

  23. Kalyan S, Wang J, Quabius ES, Huck J, Wiltfang J, Baines JF, Kabelitz D (2015) Systemic immunity shapes the oral microbiome and susceptibility to bisphosphonate-associated osteonecrosis of the jaw. J Transl Med 13:212

    PubMed  PubMed Central  Google Scholar 

  24. Mawardi H, Giro G, Kajiya M, Ohta K, Almazrooa S, Alshwaimi E, Woo SB, Nishimura I, Kawai T (2011) A role of oral bacteria in bisphosphonate-induced osteonecrosis of the jaw. J Dent Res 90(11):1339–1345

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim JH, Ko YJ, Kim JY, Oh Y, Hwang J, Han S, Kim S, Lee JH, Han DH (2015) Genetic investigation of bisphosphonate-related osteonecrosis of jaw (BRONJ) via whole exome sequencing and bioinformatics. PLoS One 10(2):e0118084

    PubMed  PubMed Central  Google Scholar 

  26. Kuroshima S, Sasaki M, Nakajima K, Tamaki S, Hayano H, Sawase T (2018) Prevalence of bisphosphonate-related osteonecrosis of the jaw-like lesions is increased in a chemotherapeutic dose-dependent manner in mice. Bone. 112:177–186

    CAS  PubMed  Google Scholar 

  27. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G (2008) Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 44(9):857–869

    CAS  PubMed  Google Scholar 

  28. Lungu AE, Lazar MA, Tonea A, Rotaru H, Roman RC, Badea ME (2018) Observational study of the bisphosphonate-related osteonecrosis of jaws. Clujul Med 91(2):209–215

    PubMed  PubMed Central  Google Scholar 

  29. Pelaz A, Junquera L, Gallego L, García-Consuegra L, García-Martínez L, Cutilli T, Olay S (2015) Epidemiology, pharmacology and clinical characterization of bisphosphonate-related osteonecrosis of the jaw. A retrospective study of 70 cases. Acta Otorrinolaringol Esp 66(3):139–147

    PubMed  Google Scholar 

  30. Saussez S, Javadian R, Hupin C, Magremanne M, Chantrain G, Loeb I, Decaestecker C (2009) Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: a Belgian case series. Laryngoscope. 119(2):323–329

    CAS  PubMed  Google Scholar 

  31. Quispe D, Shi R, Burton G (2011) Osteonecrosis of the jaw in patients with metastatic breast cancer: ethnic and socio-economic aspects. Breast J 17(5):510–513

    PubMed  Google Scholar 

  32. Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O (2017) Interventions for managing medication-related osteonecrosis of the jaw. Cochrane Database Syst Rev 10:CD012432

    PubMed  Google Scholar 

  33. Heifetz-Li JJ, Abdelsamie S, Campbell CB, Roth S, Fielding AF, Mulligan JP (2019) Systematic review of the use of pentoxifylline and tocopherol for the treatment of medication-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 128(5):491–497.e2

    PubMed  Google Scholar 

  34. Bodem JP, Schaal C, Kargus S, Saure D, Mertens C, Engel M, Hoffmann J, Freudlsperger C (2016) Surgical management of bisphosphonate-related osteonecrosis of the jaw stages II and III. Oral Surg Oral Med Oral Pathol Oral Radiol 121(4):367–372

    PubMed  Google Scholar 

  35. Rathbone EJ, Brown JE, Marshall HC, Collinson M, Liversedge V, Murden GA, Cameron D, Bell R, Spensley S, Agrawal R, Jyothirmayi R, Chakraborti P, Yuille F, Coleman RE (2013) Osteonecrosis of the jaw and oral health-related quality of life after adjuvant zoledronic acid: an adjuvant zoledronic acid to reduce recurrence trial subprotocol (BIG01/04). J Clin Oncol 31(21):2685–2691

    CAS  PubMed  Google Scholar 

  36. Coleman RE, Collinson M, Gregory W, Marshall H, Bell R, Dodwell D, Keane M, Gil M, Barrett-Lee P, Ritchie D, Bowman A, Liversedge V, De Boer RH, Passos-Coelho JL, O’Reilly S, Bertelli G, Joffe J, Brown JE, Wilson C, Tercero JC, Jean-Mairet J, Gomis R, Cameron D (2018) Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04). J Bone Oncol 13:123–135

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Gnant M, Mlineritsch B, Stoeger H (2011) et al; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 12(7):631–641

    CAS  PubMed  Google Scholar 

  38. Gralow JR, Barlow WE, Paterson AHG, et al (2020) Phase III randomized trial of bisphosphonates as adjuvant therapy in breast cancer: S0307. J Natl Cancer Inst 112(7):698–707

  39. Mauri D, Valachis A, Polyzos IP, Polyzos NP, Kamposioras K, Pesce LL (2009) Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis. Breast Cancer Res Treat 116(3):433–439

    CAS  PubMed  Google Scholar 

  40. Jung SY, Suh HS, Park JW, Kwon JW (2019) Drug holiday patterns and bisphosphonate-related osteonecrosis of the jaw. Oral Dis 25(2):471–480

    PubMed  Google Scholar 

  41. Paterson AH, Anderson SJ, Lembersky BC et al (2012) Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol 13(7):734–742. https://doi.org/10.1016/S1470-2045(12)70226-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Powles T, Paterson A, McCloskey E, Schein P, Scheffler B, Tidy A, Ashley S, Smith I, Ottestad L, Kanis J (2006) Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8(2):R13

    PubMed  PubMed Central  Google Scholar 

  43. Fung P, Bedogni G, Bedogni A, Petrie A, Porter S, Campisi G, Bagan J, Fusco V, Saia G, Acham S, Musto P, Petrucci MT, Diz P, Colella G, Mignogna MD, Pentenero M, Arduino P, Lodi G, Maiorana C, Manfredi M, Hallberg P, Wadelius M, Takaoka K, Leung YY, Bonacina R, Schiødt M, Lakatos P, Taylor T, de Riu G, Favini G, Rogers SN, Pirmohamed M, Nicoletti P, GENVABO Consortium, Fedele S (2017) Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study. Oral Dis 23(4):477–483

    PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the patients who participated in SWOG 0307 and their families. We would also like to thank the Southwest Oncology Group (SWOG) for statistical support.

Funding

This project has been funded with federal funds from NIH/NCI CA180888, CA180819, CA180820, CA180821, CA180868, and CA180863, as well as with funds from the National Cancer Institute, the National Institutes of Health, the Breast Cancer Research Foundation, the Susan G. Komen Foundation, Berlex, Roche/Genentech, and Novartis.

Author information

Authors and Affiliations

  1. The Everett Clinic, Everett, WA, USA

    Darya A. Kizub

  2. SWOG Statistical Center, Seattle, WA, USA

    Jieling Miao & William E. Barlow

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Mark M. Schubert

  4. University of Washington School of Dentistry, Seattle, WA, USA

    Mark M. Schubert

  5. Tom Baker Cancer Center, Calgary, Alberta, Canada

    Alexander H. G. Paterson

  6. Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    Mark Clemons

  7. University of North Carolina, Chapel Hill, NC, USA

    Elizabeth C. Dees

  8. Mayo Clinic, Rochester, MN, USA

    James N. Ingle

  9. Wilmot Cancer Center at the University of Rochester, Rochester, NY, USA

    Carla I. Falkson

  10. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Gabriel N. Hortobagyi

  11. University of Washington School of Medicine, Seattle, WA, USA

    Julie R. Gralow

Authors
  1. Darya A. Kizub
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jieling Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark M. Schubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander H. G. Paterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark Clemons
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elizabeth C. Dees
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James N. Ingle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carla I. Falkson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William E. Barlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gabriel N. Hortobagyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Julie R. Gralow
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JG, MS, AP, MC, CD, JI, CF, WB, and GH contributed to the study conception and design. Material preparation and data collection performed by JG, MS, AP, MC, CD, JI, CF, WB, and GH. Data analysis was performed by JM and WB. The first draft of the manuscript was written by DK and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Darya A. Kizub.

Ethics declarations

Conflict of interest

Dr. Ingle reports grants from U.S. National Cancer Institute, during the conduct of the study. Dr. Falkson reports grants from Seattle Genetics, grants from Pfizer, other from Biotheranostics, other from Agendia, grants from Genentech/Roche, other from ExactSciences/OncotypeDx, outside the submitted work. Dr. Barlow reports grants from the National Cancer Institute, during the conduct of the study. Dr. Hortobagyi reports grants and personal fees from Novartis, outside the submitted work. Dr. Gralow reports other from Roche/Genentech, other from Novartis, other from Radius, other from Astra Zeneca, other from Pfizer, other from Puma, other from Immunomedics, other from Seattle Genetics, other from Sandoz/Hexal AG, outside the submitted work. All other authors declare no conflicts of interest.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. All patients provided written informed consent. The study was approved by the National Cancer Institute Central Institutional Review Board (IRB), as well as by IRBs of participating institutions and monitored by an independent data safety monitoring committee.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

Does not apply

Code availability

Does not apply

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

Kizub, D.A., Miao, J., Schubert, M.M. et al. Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307). Support Care Cancer 29, 2509–2517 (2021). https://doi.org/10.1007/s00520-020-05748-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-020-05748-8

Keywords