Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis
Antonis Valachis, Nikolaos P Polyzos, Robert E Coleman, Michael Gnant, Holger Eidtmann, Adam M Brufsky, Rebecca Aft, Amye J Tevaarwerk, Karen Swenson, Pehr Lind, Davide Mauri, Antonis Valachis, Nikolaos P Polyzos, Robert E Coleman, Michael Gnant, Holger Eidtmann, Adam M Brufsky, Rebecca Aft, Amye J Tevaarwerk, Karen Swenson, Pehr Lind, Davide Mauri
Abstract
Background: The purpose of the study was to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I-III) breast cancer.
Materials and methods: We performed a systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus nonuse, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible. Standard meta-analytic procedures were used to analyze the study outcomes.
Results: Fifteen studies were considered eligible and were further analyzed. The use of zoledronic acid resulted in a statistically significant better overall survival outcome (five studies, 6,414 patients; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94). No significant differences were found for the disease-free survival outcome (seven studies, 7,541 patients; HR, 0.86; 95% CI, 0.70-1.06) or incidence of bone metastases (seven studies, 7,543 patients; odds ratio [OR], 0.94; 95% CI, 0.64-1.37). Treatment with zoledronic acid led to a significantly lower overall fracture rate (OR, 0.78; 95% CI, 0.63-0.96). Finally, the rate of osteonecrosis of the jaw was 0.52%.
Conclusion: Zoledronic acid as adjuvant therapy in breast cancer patients appears to not only reduce the fracture risk but also offer a survival benefit over placebo or no treatment.
Conflict of interest statement
Disclosures of potential conflicts of interest may be found at the end of this article.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3639520/bin/onc9991112540001.jpg)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3639520/bin/onc9991112540002.jpg)
Figure 3.
Forest plot for disease-free survival…
Figure 3.
Forest plot for disease-free survival outcome. Squares represent hazard ratios and size of…
Figure 4.
Forest plot for fracture rates.…
Figure 4.
Forest plot for fracture rates. Squares represent odds ratios and size of squares…
- Zoledronic acid and its accentuating effect on tumor radiosensitivity.Kapoor S. Kapoor S. Oncologist. 2013;18(8):e21. doi: 10.1634/theoncologist.2013-0054. Oncologist. 2013. PMID: 23986343 Free PMC article.
- γδ T cells predict outcome in zoledronate-treated breast cancer patients.Welton JL, Martí S, Mahdi MH, Boobier C, Barrett-Lee PJ, Eberl M. Welton JL, et al. Oncologist. 2013;18(8):e22-3. doi: 10.1634/theoncologist.2013-0097. Oncologist. 2013. PMID: 23986344 Free PMC article.
- Adjuvant therapy with zoledronic Acid and menopausal status.Zheng YY, Zhu JH. Zheng YY, et al. Oncologist. 2013;18(8):e24. doi: 10.1634/theoncologist.2013-0109. Oncologist. 2013. PMID: 23986345 Free PMC article.
- Role of zoledronate in aromatase activity should be considered in future studies.Ghobadifar MA. Ghobadifar MA. Oncologist. 2013;18(8):e25. doi: 10.1634/theoncologist.2013-0208. Oncologist. 2013. PMID: 23986346 Free PMC article.
- In reply.Valachis A, Polyzos NP. Valachis A, et al. Oncologist. 2013;18(8):e26-7. doi: 10.1634/theoncologist.2013-0235. Oncologist. 2013. PMID: 23986347 Free PMC article.
- Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial.Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, Keane M, Gil M, Burkinshaw R, Grieve R, Barrett-Lee P, Ritchie D, Liversedge V, Hinsley S, Marshall H; AZURE investigators. Coleman R, et al. Lancet Oncol. 2014 Aug;15(9):997-1006. doi: 10.1016/S1470-2045(14)70302-X. Epub 2014 Jul 15. Lancet Oncol. 2014. PMID: 25035292 Clinical Trial.
- Adjuvant zoledronic acid therapy for patients with early stage breast cancer: an updated systematic review and meta-analysis.He M, Fan W, Zhang X. He M, et al. J Hematol Oncol. 2013 Oct 23;6(1):80. doi: 10.1186/1756-8722-6-80. J Hematol Oncol. 2013. PMID: 24283946 Free PMC article. Review.
- Bisphosphonates and other bone agents for breast cancer.O'Carrigan B, Wong MH, Willson ML, Stockler MR, Pavlakis N, Goodwin A. O'Carrigan B, et al. Cochrane Database Syst Rev. 2017 Oct 30;10(10):CD003474. doi: 10.1002/14651858.CD003474.pub4. Cochrane Database Syst Rev. 2017. PMID: 29082518 Free PMC article. Review.
- The efficacy of zoledronic acid in breast cancer adjuvant therapy: a meta-analysis of randomised controlled trials.Yan T, Yin W, Zhou Q, Zhou L, Jiang Y, Du Y, Shao Z, Lu J. Yan T, et al. Eur J Cancer. 2012 Jan;48(2):187-95. doi: 10.1016/j.ejca.2011.10.021. Epub 2011 Nov 17. Eur J Cancer. 2012. PMID: 22100904 Review.
- Phase III Randomized Trial of Bisphosphonates as Adjuvant Therapy in Breast Cancer: S0307.Gralow JR, Barlow WE, Paterson AHG, M'iao JL, Lew DL, Stopeck AT, Hayes DF, Hershman DL, Schubert MM, Clemons M, Van Poznak CH, Dees EC, Ingle JN, Falkson CI, Elias AD, Messino MJ, Margolis JH, Dakhil SR, Chew HK, Dammann KZ, Abrams JS, Livingston RB, Hortobagyi GN. Gralow JR, et al. J Natl Cancer Inst. 2020 Jul 1;112(7):698-707. doi: 10.1093/jnci/djz215. J Natl Cancer Inst. 2020. PMID: 31693129 Free PMC article. Clinical Trial.
- Bisphosphonates and breast cancer survival: a meta-analysis and trial sequential analysis of 81508 participants from 23 prospective epidemiological studies.Liu Y, Zhao S, Zhang Y, Onwuka JU, Zhang Q, Liu X. Liu Y, et al. Aging (Albany NY). 2021 Aug 10;13(15):19835-19866. doi: 10.18632/aging.203395. Epub 2021 Aug 10. Aging (Albany NY). 2021. PMID: 34375305 Free PMC article.
- Bone metastases in thyroid cancer.Iñiguez-Ariza NM, Bible KC, Clarke BL. Iñiguez-Ariza NM, et al. J Bone Oncol. 2020 Feb 19;21:100282. doi: 10.1016/j.jbo.2020.100282. eCollection 2020 Apr. J Bone Oncol. 2020. PMID: 32154098 Free PMC article. Review.
- Immune system and bone microenvironment: rationale for targeted cancer therapies.Gnoni A, Brunetti O, Longo V, Calabrese A, Argentiero AL, Calbi R, Solimando Antonio G, Licchetta A. Gnoni A, et al. Oncotarget. 2020 Jan 28;11(4):480-487. doi: 10.18632/oncotarget.27439. eCollection 2020 Jan 28. Oncotarget. 2020. PMID: 32064051 Free PMC article. Review.
- Antiresorptive agents' bone-protective and adjuvant effects in postmenopausal women with early breast cancer.Chukir T, Liu Y, Farooki A. Chukir T, et al. Br J Clin Pharmacol. 2019 Jun;85(6):1125-1135. doi: 10.1111/bcp.13834. Epub 2019 Jan 25. Br J Clin Pharmacol. 2019. PMID: 30536446 Free PMC article. Review.
- Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Bone Metastasis in Breast Cancer.Ubellacker JM, Baryawno N, Severe N, DeCristo MJ, Sceneay J, Hutchinson JN, Haider MT, Rhee CS, Qin Y, Gregory WM, Garrido-Castro AC, Holen I, Brown JE, Coleman RE, Scadden DT, McAllister SS. Ubellacker JM, et al. Cancer Res. 2018 Sep 15;78(18):5300-5314. doi: 10.1158/0008-5472.CAN-18-0548. Epub 2018 Jul 31. Cancer Res. 2018. PMID: 30065048 Free PMC article.
- Meta-Analysis
- Systematic Review
- Breast Neoplasms / drug therapy*
- Breast Neoplasms / pathology
- Chemotherapy, Adjuvant*
- Diphosphonates / administration & dosage*
- Diphosphonates / adverse effects
- Disease-Free Survival
- Female
- Fractures, Bone / complications
- Fractures, Bone / drug therapy
- Fractures, Bone / pathology
- Humans
- Imidazoles / administration & dosage*
- Imidazoles / adverse effects
- Neoplasm Staging
- Osteoporosis / complications
- Osteoporosis / drug therapy
- Osteoporosis / pathology
- Randomized Controlled Trials as Topic
- Treatment Outcome
- Zoledronic Acid
- Diphosphonates
- Imidazoles
- Zoledronic Acid
- Full Text Sources
- Other Literature Sources
- Medical
NCBI Literature Resources
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![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3639520/bin/onc9991112540003.jpg)
Figure 4.
Forest plot for fracture rates.…
Figure 4.
Forest plot for fracture rates. Squares represent odds ratios and size of squares…
- Zoledronic acid and its accentuating effect on tumor radiosensitivity.Kapoor S. Kapoor S. Oncologist. 2013;18(8):e21. doi: 10.1634/theoncologist.2013-0054. Oncologist. 2013. PMID: 23986343 Free PMC article.
- γδ T cells predict outcome in zoledronate-treated breast cancer patients.Welton JL, Martí S, Mahdi MH, Boobier C, Barrett-Lee PJ, Eberl M. Welton JL, et al. Oncologist. 2013;18(8):e22-3. doi: 10.1634/theoncologist.2013-0097. Oncologist. 2013. PMID: 23986344 Free PMC article.
- Adjuvant therapy with zoledronic Acid and menopausal status.Zheng YY, Zhu JH. Zheng YY, et al. Oncologist. 2013;18(8):e24. doi: 10.1634/theoncologist.2013-0109. Oncologist. 2013. PMID: 23986345 Free PMC article.
- Role of zoledronate in aromatase activity should be considered in future studies.Ghobadifar MA. Ghobadifar MA. Oncologist. 2013;18(8):e25. doi: 10.1634/theoncologist.2013-0208. Oncologist. 2013. PMID: 23986346 Free PMC article.
- In reply.Valachis A, Polyzos NP. Valachis A, et al. Oncologist. 2013;18(8):e26-7. doi: 10.1634/theoncologist.2013-0235. Oncologist. 2013. PMID: 23986347 Free PMC article.
- Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial.Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, Keane M, Gil M, Burkinshaw R, Grieve R, Barrett-Lee P, Ritchie D, Liversedge V, Hinsley S, Marshall H; AZURE investigators. Coleman R, et al. Lancet Oncol. 2014 Aug;15(9):997-1006. doi: 10.1016/S1470-2045(14)70302-X. Epub 2014 Jul 15. Lancet Oncol. 2014. PMID: 25035292 Clinical Trial.
- Adjuvant zoledronic acid therapy for patients with early stage breast cancer: an updated systematic review and meta-analysis.He M, Fan W, Zhang X. He M, et al. J Hematol Oncol. 2013 Oct 23;6(1):80. doi: 10.1186/1756-8722-6-80. J Hematol Oncol. 2013. PMID: 24283946 Free PMC article. Review.
- Bisphosphonates and other bone agents for breast cancer.O'Carrigan B, Wong MH, Willson ML, Stockler MR, Pavlakis N, Goodwin A. O'Carrigan B, et al. Cochrane Database Syst Rev. 2017 Oct 30;10(10):CD003474. doi: 10.1002/14651858.CD003474.pub4. Cochrane Database Syst Rev. 2017. PMID: 29082518 Free PMC article. Review.
- The efficacy of zoledronic acid in breast cancer adjuvant therapy: a meta-analysis of randomised controlled trials.Yan T, Yin W, Zhou Q, Zhou L, Jiang Y, Du Y, Shao Z, Lu J. Yan T, et al. Eur J Cancer. 2012 Jan;48(2):187-95. doi: 10.1016/j.ejca.2011.10.021. Epub 2011 Nov 17. Eur J Cancer. 2012. PMID: 22100904 Review.
- Phase III Randomized Trial of Bisphosphonates as Adjuvant Therapy in Breast Cancer: S0307.Gralow JR, Barlow WE, Paterson AHG, M'iao JL, Lew DL, Stopeck AT, Hayes DF, Hershman DL, Schubert MM, Clemons M, Van Poznak CH, Dees EC, Ingle JN, Falkson CI, Elias AD, Messino MJ, Margolis JH, Dakhil SR, Chew HK, Dammann KZ, Abrams JS, Livingston RB, Hortobagyi GN. Gralow JR, et al. J Natl Cancer Inst. 2020 Jul 1;112(7):698-707. doi: 10.1093/jnci/djz215. J Natl Cancer Inst. 2020. PMID: 31693129 Free PMC article. Clinical Trial.
- Bisphosphonates and breast cancer survival: a meta-analysis and trial sequential analysis of 81508 participants from 23 prospective epidemiological studies.Liu Y, Zhao S, Zhang Y, Onwuka JU, Zhang Q, Liu X. Liu Y, et al. Aging (Albany NY). 2021 Aug 10;13(15):19835-19866. doi: 10.18632/aging.203395. Epub 2021 Aug 10. Aging (Albany NY). 2021. PMID: 34375305 Free PMC article.
- Bone metastases in thyroid cancer.Iñiguez-Ariza NM, Bible KC, Clarke BL. Iñiguez-Ariza NM, et al. J Bone Oncol. 2020 Feb 19;21:100282. doi: 10.1016/j.jbo.2020.100282. eCollection 2020 Apr. J Bone Oncol. 2020. PMID: 32154098 Free PMC article. Review.
- Immune system and bone microenvironment: rationale for targeted cancer therapies.Gnoni A, Brunetti O, Longo V, Calabrese A, Argentiero AL, Calbi R, Solimando Antonio G, Licchetta A. Gnoni A, et al. Oncotarget. 2020 Jan 28;11(4):480-487. doi: 10.18632/oncotarget.27439. eCollection 2020 Jan 28. Oncotarget. 2020. PMID: 32064051 Free PMC article. Review.
- Antiresorptive agents' bone-protective and adjuvant effects in postmenopausal women with early breast cancer.Chukir T, Liu Y, Farooki A. Chukir T, et al. Br J Clin Pharmacol. 2019 Jun;85(6):1125-1135. doi: 10.1111/bcp.13834. Epub 2019 Jan 25. Br J Clin Pharmacol. 2019. PMID: 30536446 Free PMC article. Review.
- Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Bone Metastasis in Breast Cancer.Ubellacker JM, Baryawno N, Severe N, DeCristo MJ, Sceneay J, Hutchinson JN, Haider MT, Rhee CS, Qin Y, Gregory WM, Garrido-Castro AC, Holen I, Brown JE, Coleman RE, Scadden DT, McAllister SS. Ubellacker JM, et al. Cancer Res. 2018 Sep 15;78(18):5300-5314. doi: 10.1158/0008-5472.CAN-18-0548. Epub 2018 Jul 31. Cancer Res. 2018. PMID: 30065048 Free PMC article.
- Meta-Analysis
- Systematic Review
- Breast Neoplasms / drug therapy*
- Breast Neoplasms / pathology
- Chemotherapy, Adjuvant*
- Diphosphonates / administration & dosage*
- Diphosphonates / adverse effects
- Disease-Free Survival
- Female
- Fractures, Bone / complications
- Fractures, Bone / drug therapy
- Fractures, Bone / pathology
- Humans
- Imidazoles / administration & dosage*
- Imidazoles / adverse effects
- Neoplasm Staging
- Osteoporosis / complications
- Osteoporosis / drug therapy
- Osteoporosis / pathology
- Randomized Controlled Trials as Topic
- Treatment Outcome
- Zoledronic Acid
- Diphosphonates
- Imidazoles
- Zoledronic Acid
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3639520/bin/onc9991112540004.jpg)
Source: PubMed