Top

Breast Cancer Research and Treatment

Published in:

01-06-2020 | Bisphosphonate | Review

Bone modifying agents for bone loss in patients with aromatase inhibitor as adjuvant treatment for breast cancer; insights from a network meta-analysis

Authors: Hirotaka Miyashita, Sera Satoi, Toshiki Kuno, Christina Cruz, Stephen Malamud, Se-Min Kim

Published in: Breast Cancer Research and Treatment | Issue 2/2020

Abstract

Purpose

The data of head-to-head comparisons of the anti-fracture efficacy of bone modifying agents (BMAs) in patients with hormone receptor-positive breast cancer receiving aromatase inhibitor (AI) are not available. Therefore, we conducted a network meta-analysis to compare the efficacy of different BMAs in patients with breast cancer receiving adjuvant AI.

Methods

We performed a network meta-analysis to compare the change of bone mineral densities (BMDs) and the risk of fracture in the selected studies using a random effect model. The primary outcomes are the change of BMD of lumbar spine (LS) and total hip (TH) from the baseline (ΔBMD, %) at 1 and 2 years and the risk of fracture.

Results

We identified and included a total of 16 randomized controlled trials for this analysis. All BMAs included (risedronate, zoledronate, and denosumab) were associated with a significant increase in BMD of LS and TH at 1 and 2 years compared with no upfront treatment group. Among BMAs, zoledronate and denosumab use resulted in significantly higher BMD of LS and TH at 1 and 2 years compared with risedronate. The risk of fracture was significantly lower in the patients who received denosumab or risedronate compared with the patients without upfront treatment (Relative risk (RR) [95% CI] 0.51 [0.38–0.67] and 0.54 [0.35–0.83], respectively).

Conclusion

Among the bisphosphonates, zoledronate increased BMD the most, but risedronate, not zoledronate, use was associated with lower risk of fracture. Denosumab increased BMD not only of LS but also of the cortical-bone-rich hip, and showed a significant reduction of fracture risk.

Available only for authorised users

Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin 70:7–30. https://doi.org/10.3322/caac.21590 CrossRefPubMed

American Cancer Society Facts & Figures. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed 18 Jan 2019

Burstein HJ, Lacchetti C, Anderson H et al (2016) Adjuvant Endocrine therapy for women with hormone receptor-positive breast cancer: American society of clinical oncology clinical practice guideline update on ovarian suppression. J Clin Oncol 34:1689–1701. https://doi.org/10.1200/JCO.2015.65.9573 CrossRefPubMed

Hadji P, Aapro MS, Body JJ et al (2017) Management of aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol 7:1–12CrossRef

Osteoporosis International Consensus Development Statement (1997) Who are candidates for prevention and treatment for osteoporosis? Osteoporos Int 7(1):1–6. https://doi.org/10.1007/bf01623453 CrossRef

Hadji P (2009) Aromatase inhibitor-associated bone loss in breast cancer patients is distinct from postmenopausal osteoporosis. Crit Rev Oncol Hematol 69:73–82. https://doi.org/10.1016/j.critrevonc.2008.07.013 CrossRefPubMed

Howell A, Cuzick J, Baum M et al (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62. https://doi.org/10.1016/S0140-6736(04)17666-6 CrossRefPubMed

Kanis JA, Johnell O, Oden A et al (2001) Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 12:989–995. https://doi.org/10.1007/s001980170006 CrossRef

Kuno T, Takagi H, Sugiyama T et al (2019) Antithrombotic strategies after transcatheter aortic valve implantation: Insights from a network meta-analysis. Catheter Cardiovasc Interv. https://doi.org/10.1002/ccd.28498 CrossRefPubMed

10.

Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. https://doi.org/10.1371/journal.pmed.1000100 CrossRefPubMedPubMedCentral

11.

Higgins JPT, Altman DG, Gøtzsche PC et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. https://doi.org/10.1136/bmj.d5928 CrossRefPubMedPubMedCentral

12.

Rücker G (2012) Network meta-analysis, electrical networks and graph theory. Res Synth Methods 3:312–324. https://doi.org/10.1002/jrsm.1058 CrossRefPubMed

13.

Gnant M, Pfeiler G, Dubsky PC et al (2015) Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433–443. https://doi.org/10.1016/S0140-6736%2815%2960995-3 CrossRefPubMed

14.

Sestak I, Blake GM, Patel R et al (2019) Comparison of risedronate versus placebo in preventing anastrozole-induced bone loss in women at high risk of developing breast cancer with osteopenia. Bone 124:83–88. https://doi.org/10.1016/j.bone.2019.04.016 CrossRefPubMedPubMedCentral

15.

Greenspan SL, Vujevich KT, Brufsky A et al (2015) Prevention of bone loss with risedronate in breast cancer survivors: a randomized, controlled clinical trial. Osteoporos Int 26:1857–1864. https://doi.org/10.1007/s00198-015-3100-7 CrossRefPubMedPubMedCentral

16.

Coleman R, De Boer R, Eidtmann H et al (2013) Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 24:398–405. https://doi.org/10.1093/annonc/mds277 CrossRefPubMed

17.

Brufsky AM, Harker WG, Beck JT et al (2012) Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer 118:1192–1201. https://doi.org/10.1002/cncr.26313 CrossRefPubMed

18.

Llombart A, Frassoldati A, Paija O et al (2012) Immediate administration of zoledronic acid reduces aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer: 12-month analysis of the E-ZO-FAST trial. Clin Breast Cancer 12:40–48. https://doi.org/10.1016/j.clbc.2011.08.002 CrossRefPubMed

19.

Takahashi S, Iwase T, Kohno N et al (2012) Efficacy of zoledronic acid in postmenopausal Japanese women with early breast cancer receiving adjuvant letrozole: 12-month results. Breast Cancer Res Treat 133:685–693. https://doi.org/10.1007/s10549-012-1973-0 CrossRefPubMed

20.

Van Poznak C, Hannon RA, Mackey JR et al (2010) Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. J Clin Oncol 28:967–975. https://doi.org/10.1200/JCO.2009.24.5902 CrossRefPubMed

21.

Ellis GK, Bone HG, Chlebowski R et al (2009) Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat 118:81–87. https://doi.org/10.1007/s10549-009-0352-y CrossRefPubMed

22.

Greenspan SL, Brufsky A, Lembersky BC et al (2008) Risedronate prevents bone loss in breast cancer survivors: a 2-year, randomized, double-blind, placebo-controlled clinical trial. J Clin Oncol 26:2644–2652. https://doi.org/10.1200/JCO.2007.15.2967 CrossRefPubMedPubMedCentral

23.

Monda V, Lupoli GA, Messina G et al (2017) Improvement of bone physiology and life quality due to association of risedronate and anastrozole. Front Pharmacol. https://doi.org/10.3389/fphar.2017.00632 CrossRefPubMedPubMedCentral

24.

Sun S, Wang F, Dou H et al (2016) Preventive effect of zoledronic acid on aromatase inhibitor-associated bone loss for postmenopausal breast cancer patients receiving adjuvant letrozole. Onco Targets Ther 9:6029–6036. https://doi.org/10.2147/OTT.S115058 CrossRefPubMedPubMedCentral

25.

Nuzzo F, Gallo C, Lastoria S et al (2012) Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study. Ann Oncol 23:2027–2033. https://doi.org/10.1093/annonc/mdr600 CrossRefPubMed

26.

Safra T, Bernstein-Molho R, Greenberg J et al (2011) The protective effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole: a prospective, randomized, phase II trial. Oncology 81:298–305. https://doi.org/10.1159/000334456 CrossRefPubMed

27.

Markopoulos C, Tzoracoleftherakis E, Polychronis A et al (2010) Management of anastrozole-induced bone loss in breast cancer patients with oral risedronate: results from the ARBI prospective clinical trial. Breast Cancer Res 12:R24. https://doi.org/10.1186/bcr2565 CrossRefPubMedPubMedCentral

28.

Wagner-Johnston ND, Sloan JA, Liu H et al (2015) 5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: n03CC (Alliance) trial. Cancer 121:2537–2543. https://doi.org/10.1002/cncr.29327 CrossRefPubMedPubMedCentral

29.

Su G, Xiang Y, He G et al (2014) Bisphosphonates may protect against bone loss in postmenopausal women with early breast cancer receiving adjuvant aromatase inhibitor therapy: results from a meta-analysis. Arch Med Res 45:570–579. https://doi.org/10.1016/j.arcmed.2014.10.007 CrossRefPubMed

30.

Zhao X, Zhou C, Chen H et al (2017) Efficacy and safety of medical therapy for low bone mineral density in patients with Crohn disease. Medicine 96:e6378CrossRef

31.

Sanderson J, Martyn-St James M, Stevens J et al (2016) Clinical effectiveness of bisphosphonates for the prevention of fragility fractures: a systematic review and network meta-analysis. Bone 89:52–58. https://doi.org/10.1016/j.bone.2016.05.013 CrossRefPubMed

32.

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 386:1353–1361. https://doi.org/10.1016/S0140-6736(15)60908-4 CrossRef

33.

O’Carrigan B, Wong MHF, Willson ML et al (2017) (2017) Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst, Rev

34.

Beaudoin C, Jean S, Bessette L et al (2016) Denosumab compared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture: a systematic review and meta-analysis. Osteoporos Int 27:2835–2844CrossRef

35.

Brown JP, Roux C, Ho PR et al (2014) Denosumab significantly increases bone mineral density and reduces bone turnover compared with monthly oral ibandronate and risedronate in postmenopausal women who remained at higher risk for fracture despite previous suboptimal treatment with an oral bisphosphonate. Osteoporos Int 25:1953–1961. https://doi.org/10.1007/s00198-014-2692-7 CrossRefPubMed

36.

Abdel-Rahman O (2016) Denosumab versus zoledronic acid to prevent aromatase inhibitors-associated fractures in postmenopausal early breast cancer; a mixed treatment meta-analysis. Expert Rev Anticancer Ther 16:885–891. https://doi.org/10.1080/14737140.2016.1192466 CrossRefPubMed

37.

Edwards BJ, Sun M, West DP et al (2016) Incidence of atypical femur fractures in cancer patients: the MD Anderson Cancer Center experience. J Bone Miner Res 31:1569–1576. https://doi.org/10.1002/jbmr.2818 CrossRefPubMed

38.

Takahashi M, Ozaki Y, Kizawa R et al (2019) Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy: a retrospective study and systematic review. BMC Cancer. https://doi.org/10.1186/s12885-019-6236-6 CrossRefPubMedPubMedCentral

Title: Bone modifying agents for bone loss in patients with aromatase inhibitor as adjuvant treatment for breast cancer; insights from a network meta-analysis
Authors: Hirotaka Miyashita
Sera Satoi
Toshiki Kuno
Christina Cruz
Stephen Malamud
Se-Min Kim
Publication date: 01-06-2020
Publisher: Springer US
Keywords: Bisphosphonate
Breast Cancer
Breast Cancer
Denosumab
Denosumab
Published in: Breast Cancer Research and Treatment / Issue 2/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-020-05640-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2020

Phyllodes tumors of the breast: a retrospective analysis of 57 cases

Mechanistic basis for PI3K inhibitor antitumor activity and adverse reactions in advanced breast cancer

Discrepancy between FDG-PET/CT and contrast-enhanced CT in the staging of patients with inflammatory breast cancer: implications for treatment planning

Expression of epithelial-mesenchymal transition-related markers and phenotypes during breast cancer progression

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women

Keynote webinar | Spotlight on antibody–drug conjugates in cancer