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. 2024 Jul 9;7(7):CD013451.
doi: 10.1002/14651858.CD013451.pub2.

Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis

Anne Adams  1 , Tina Jakob  2 , Alessandra Huth  2 , Ina Monsef  3 , Moritz Ernst  3 , Marco Kopp  2 , Julia Caro-Valenzuela  2 , Achim Wöckel  4 , Nicole Skoetz  3
Affiliations

Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis

Anne Adams et al. Cochrane Database Syst Rev. .

Abstract

Background: Bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are amongst the bone-modifying agents used as supportive treatment in women with breast cancer who do not have bone metastases. These agents aim to reduce bone loss and the risk of fractures. Bisphosphonates have demonstrated survival benefits, particularly in postmenopausal women.

Objectives: To assess and compare the effects of different bone-modifying agents as supportive treatment to reduce bone mineral density loss and osteoporotic fractures in women with breast cancer without bone metastases and generate a ranking of treatment options using network meta-analyses (NMAs).

Search methods: We identified studies by electronically searching CENTRAL, MEDLINE and Embase until January 2023. We searched various trial registries and screened abstracts of conference proceedings and reference lists of identified trials.

Selection criteria: We included randomised controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for women with breast cancer without bone metastases.

Data collection and analysis: Two review authors independently extracted data and assessed the risk of bias of included studies and certainty of evidence using GRADE. Outcomes were bone mineral density, quality of life, overall fractures, overall survival and adverse events. We conducted NMAs and generated treatment rankings.

Main results: Forty-seven trials (35,163 participants) fulfilled our inclusion criteria; 34 trials (33,793 participants) could be considered in the NMA (8 different treatment options). Bone mineral density We estimated that the bone mineral density of participants with no treatment/placebo measured as total T-score was -1.34. Evidence from the NMA (9 trials; 1166 participants) suggests that treatment with ibandronate (T-score -0.77; MD 0.57, 95% CI -0.05 to 1.19) may slightly increase bone mineral density (low certainty) and treatment with zoledronic acid (T-score -0.45; MD 0.89, 95% CI 0.62 to 1.16) probably slightly increases bone mineral density compared to no treatment/placebo (moderate certainty). Risedronate (T-score -1.08; MD 0.26, 95% CI -0.32 to 0.84) may result in little to no difference compared to no treatment/placebo (low certainty). We are uncertain whether alendronate (T-score 2.36; MD 3.70, 95% CI -2.01 to 9.41) increases bone mineral density compared to no treatment/placebo (very low certainty). Quality of life No quantitative analyses could be performed for quality of life, as only three studies reported this outcome. All three studies showed only minimal differences between the respective interventions examined. Overall fracture rate We estimated that 70 of 1000 participants with no treatment/placebo had fractures. Evidence from the NMA (16 trials; 19,492 participants) indicates that treatment with clodronate or ibandronate (42 of 1000; RR 0.60, 95% CI 0.39 to 0.92; 40 of 1000; RR 0.57, 95% CI 0.38 to 0.86, respectively) decreases the number of fractures compared to no treatment/placebo (high certainty). Denosumab or zoledronic acid (51 of 1000; RR 0.73, 95% CI 0.52 to 1.01; 55 of 1000; RR 0.79, 95% CI 0.56 to 1.11, respectively) probably slightly decreases the number of fractures; and risedronate (39 of 1000; RR 0.56, 95% CI 0.15 to 2.16) probably decreases the number of fractures compared to no treatment/placebo (moderate certainty). Pamidronate (106 of 1000; RR 1.52, 95% CI 0.75 to 3.06) probably increases the number of fractures compared to no treatment/placebo (moderate certainty). Overall survival We estimated that 920 of 1000 participants with no treatment/placebo survived overall. Evidence from the NMA (17 trials; 30,991 participants) suggests that clodronate (924 of 1000; HR 0.95, 95% CI 0.77 to 1.17), denosumab (927 of 1000; HR 0.91, 95% CI 0.69 to 1.21), ibandronate (915 of 1000; HR 1.06, 95% CI 0.83 to 1.34) and zoledronic acid (925 of 1000; HR 0.93, 95% CI 0.76 to 1.14) may result in little to no difference regarding overall survival compared to no treatment/placebo (low certainty). Additionally, we are uncertain whether pamidronate (905 of 1000; HR 1.20, 95% CI 0.81 to 1.78) decreases overall survival compared to no treatment/placebo (very low certainty). Osteonecrosis of the jaw We estimated that 1 of 1000 participants with no treatment/placebo developed osteonecrosis of the jaw. Evidence from the NMA (12 trials; 23,527 participants) suggests that denosumab (25 of 1000; RR 24.70, 95% CI 9.56 to 63.83), ibandronate (6 of 1000; RR 5.77, 95% CI 2.04 to 16.35) and zoledronic acid (9 of 1000; RR 9.41, 95% CI 3.54 to 24.99) probably increases the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (moderate certainty). Additionally, clodronate (3 of 1000; RR 2.65, 95% CI 0.83 to 8.50) may increase the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (low certainty). Renal impairment We estimated that 14 of 1000 participants with no treatment/placebo developed renal impairment. Evidence from the NMA (12 trials; 22,469 participants) suggests that ibandronate (28 of 1000; RR 1.98, 95% CI 1.01 to 3.88) probably increases the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). Zoledronic acid (21 of 1000; RR 1.49, 95% CI 0.87 to 2.58) probably increases the occurrence of renal impairment while clodronate (12 of 1000; RR 0.88, 95% CI 0.55 to 1.39) and denosumab (11 of 1000; RR 0.80, 95% CI 0.54 to 1.19) probably results in little to no difference regarding the occurrence of renal impairment compared to no treatment/placebo (moderate certainty).

Authors' conclusions: When considering bone-modifying agents for managing bone loss in women with early or locally advanced breast cancer, one has to balance between efficacy and safety. Our findings suggest that bisphosphonates (excluding alendronate and pamidronate) or denosumab compared to no treatment or placebo likely results in increased bone mineral density and reduced fracture rates. Our survival analysis that included pre and postmenopausal women showed little to no difference regarding overall survival. These treatments may lead to more adverse events. Therefore, forming an overall judgement of the best ranked bone-modifying agent is challenging. More head-to-head comparisons, especially comparing denosumab with any bisphosphonate, are needed to address gaps and validate the findings of this review.

Trial registration: ClinicalTrials.gov NCT00295646 NCT00556374 NCT00242203 NCT00525759 NCT00809484 NCT00072020 NCT02616744 NCT01077154 NCT00089661 NCT00375752 NCT00196872 NCT02682693 NCT00049452 NCT00412022 NCT00054418 NCT00512993 NCT01367288 NCT01099436 NCT00332709 NCT00009945 NCT00333229 NCT00375505 NCT00118508 NCT00485953 NCT00082277 NCT00376740 NCT00172068 NCT00127205 NCT00213980 NCT00122356 NCT00022087 NCT00107263 NCT00202059 NCT00247650 NCT00295867 NCT00324714 NCT02051218 NCT03358017 NCT03532087 NCT00050011 NCT00171340 NCT02595138 NCT00859703 NCT03691311 NCT03324932.

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Conflict of interest statement

Action: edits to be checked by the author team

Anne Adams: awarded a grant from the Federal Ministry of Education and Research to perform this systematic review; this did not lead to a conflict of interest, as she is a statistical editor with Cochrane Haematology, but was not involved in the editorial process for this review.

Tina Jakob: awarded a grant from the Federal Ministry of Education and Research to perform this systematic review; this did not lead to a conflict of interest.

Ina Monsef: none known; she is the Information Specialist of Cochrane Haematology, but was not involved in the editorial process for this review.

Alessandra Huth: none known.

Marco Kopp: none known.

Julia Caro‐Valenzuela: none known; a member of Cochrane Haematology, but was not involved in the editorial process for this review.

Moritz Ernst: none known; he is a member of Cochrane Haematology, but was not involved in the editorial process for this review.

Achim Wöckel: received consultancy fees to provide advice on metastatic breast cancer topics for Amgen (until end of 2020), Eli Lilly (ongoing), Hoffman‐La Roche (ongoing), Novartis (ongoing) and Pfizer (ongoing). No relevant relationships were declared in relation to early breast cancer topics.

Nicole Skoetz: none known; she is Co‐ordinating Editor of Cochrane Haematology, but was not involved in the editorial process for this review.

Figures

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Figure 1: Ideal network with all possible comparisons of all treatment options
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Network diagram for outcome: bone mineral density (T‐score). Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients.
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, bone mineral density (T‐score)
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Forest plot for outcome bone mineral density (T‐Score): 
Random‐effects model
Reference treatment: No treatment/placebo
Treatments are ordered by P‐Score (descending). Abbreviations:
CI: confidence interval
MD: mean difference
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Comparison‐adjusted funnel plot for the outcome, bone mineral density (T‐Score)
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Network diagram for outcome: fractures. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients.
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome fractures
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Forest plot for outcome, fractures: 
Random‐effects model
Reference treatment: no treatment/placebo. 
Treatments are ordered by P‐Score (descending). 
Abbreviations:
CI: confidence interval
RR: risk ratio
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Comparison of direct and indirect evidence (in closed loops) for outcome, fractures. 
Abbreviations:
CI: confidence interval
RR: risk ratio
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Network diagram for outcome: vertebral fractures. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, vertebral fractures
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Forest plot for outcome vertebral fractures: Random effects model. Reference treatment: No treatment/placebo. Treatments are ordered by P‐Score (descending). RR: risk ratio. CI: confidence interval.
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Network diagram for outcome: non‐vertebral fractures. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, non‐vertebral fractures
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Forest plot for outcome, non‐vertebral fractures: 
Random‐effects model
Reference treatment: no treatment/placebo
Treatments are ordered by P‐Score (descending). Abbreviations:
CI: confidence interval
RR: risk ratio
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Network diagram for outcome: overall survival. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, overall survival
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Forest plot for outcome, overall survival: 
Random‐effects model
Reference treatment: no treatment/placebo
Treatments are ordered by P‐Score (descending) Abbreviations:
CI: confidence interval
HR: hazard ratio
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Comparison of direct and indirect evidence (in closed loops) for outcome overall survival. HR: hazard ratio. CI: confidence interval.
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Network diagram for outcome: disease‐free survival. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, disease‐free survival
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Forest plot for outcome, disease‐free survival: 
Random‐effects model
Reference treatment: no treatment/placebo
Treatments are ordered by P‐Score (descending) Abbreviations:
CI: confidence interval
HR: hazard ratio
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Comparison of direct and indirect evidence (in closed loops) for outcome, disease‐free survival Abbreviations:
CI: confidence interval
HR: hazard ratio
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Network diagram for outcome, adverse event: osteonecrosis of the jaw. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, adverse event: osteonecrosis of the jaw
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Forest plot for outcome, adverse event: osteonecrosis of the jaw: 
Random‐effects model
Reference treatment: no treatment/placebo
Treatments are ordered by P‐Score (descending). Abbreviations:
CI: confidence interval
RR: risk ratio
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Comparison of direct and indirect evidence (in closed loops) for outcome adverse event: osteonecrosis of the jaw Abbreviations:
CI: confidence interval
RR: risk ratio
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Network diagram for outcome adverse event: renal impairment. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, adverse event: renal impairment
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Forest plot for outcome, adverse event: renal impairment: 
Random‐effects model
Reference treatment: no treatment/placebo
Treatments are ordered by P‐Score (descending). Abbreviations:
CI: confidence interval
RR: risk ratio
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Comparison of direct and indirect evidence (in closed loops) for outcome, adverse event: renal impairment Abbreviations:
CI: confidence interval
RR: risk ratio
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Network diagram for outcome, adverse event: bone pain. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, adverse event: bone pain
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Forest plot for outcome, adverse event: bone pain:
Random‐effects model
Reference treatment: no treatment/placebo
Treatments are ordered by P‐Score (descending). Abbreviations:
CI: confidence interval
RR: risk ratio
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Comparison of direct and indirect evidence (in closed loops) for outcome, adverse event: bone pain Abbreviations:
CI: confidence interval
RR: risk ratio
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Network diagram for outcome, adverse event: hypocalcaemia. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, adverse event: hypocalcaemia
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Forest plot for outcome, adverse event: hypocalcaemia: 
Random‐effects model
Reference treatment: no treatment/placebo
Treatments are ordered by P‐Score (descending). Abbreviations:
CI: confidence interval
RR: risk ratio
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Comparison of direct and indirect evidence (in closed loops) for outcome, adverse event: hypocalcaemia Abbreviations:
CI: confidence interval
RR: risk ratio
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Network diagram for outcome: occurrence of bone metastases. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of studies and node size: number of patients
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Forest plot of pairwise comparisons for the descriptive presentation of studies for outcome, occurrence of bone metastases
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Forest plot for outcome occurrence of bone metastases: Random effects model. Reference treatment: No treatment/placebo. Treatments are ordered by P‐Score (descending). RR: risk ratio. CI: confidence interval.
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Comparison of direct and indirect evidence (in closed loops) for outcome, occurrence of bone metastases Abbreviations:
CI: confidence interval
RR: risk ratio
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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ARIBON 2012 {published data only}
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D‐CARE 2013 {published data only}
    1. Bell R, Goss PE, Barrios CH, Finkelstein D, Iwata H, Martin M, et al. A randomised, double-blind, placebo-controlled multicentre phase 3 study comparing denosumab with placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-care). Asia-Pacific Journal of Clinical Oncology 2011;7:150.
    1. CTRI/2010/091/001297. A phase 3 clinical trial to study the effect of drug product denosumab as adjuvant therapy for women with early-stage breast cancer, who are at high risk of disease recurrence (D-CARE ). https://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=2089&Enc... (first posted 7 September 2010).
    1. Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, et al. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncology 2020;21(1):60-72. - PubMed
    1. Coleman R, Zhou Y, Jandial D, Cadieux B, Chan A. Bone health outcomes from the international, multicenter, randomized, phase 3, placebo-controlled D-CARE study assessing adjuvant denosumab in early breast cancer. Advances in Therapy 2021;38(8):4569-80. - PMC - PubMed
    1. Coleman RE, Barrios C, Bell R, Finkelstein DM, Iwata H, Martin M, et al. Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): an in progress, phase 3 clinical trial. Annals of Oncology 2012;9:ix115.
Delmas 1997 {published data only}
    1. Delmas PD, Balena R, Confravreux E, Hardouin C, Hardy P, Bremond A. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. Journal of Clinical Oncology 1997;15(3):955-62. - PubMed
Diel 1998 {published data only}
    1. Diel IJ, Jaschke A, Solomayer EF, Gollan C, Bastert G, Sohn C, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Annals of Oncology 2008;19(12):2007-11. - PMC - PubMed
    1. Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. New England Journal of Medicine 1998;339(6):357-63. - PubMed
    1. Jaschke A, Bastert G, Solomayer EF, Costa S, Schuetz F, Diel IJ. Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow - a longtime follow-up. Journal of Clinical Oncology 2004;22(14 Suppl):529.
Ellis 2008 {published data only}
    1. Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Fan M, et al. A 24-month subgroup analysis of the effect of denosumab on bone mineral density in women with breast cancer undergoing aromatase inhibitor therapy. Cancer Research 2009;69(2 Suppl):2106. - PubMed
    1. Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Fan M, et al. 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 Research & Treatment 2009;118(1):81-7. - PubMed
    1. Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. Journal of Clinical Oncology 2008;26(30):4875-82. - PubMed
    1. Ellis GK, Bone HG, Chlebowski RT, Paul D, Spadafora S, Smith J, et al. Subgroup analysis of a randomized, phase III study of the effect of denosumab in women with nonmetastatic breast cancer receiving aromatase inhibitor (AI) therapy [abstract no. 546]. Journal of Clinical Oncology 2008;26:17. - PubMed
    1. NCT00089661. AMG 162 in the treatment of bone loss in subjects undergoing aromatase inhibitor therapy for non-metastatic breast cancer. https://clinicaltrials.gov/ct2/show/NCT00089661 (date received 11 August 2004).
EXPAND 2011 {published data only}
    1. EUCTR2004-003888-71-DE. An open phase III trial with Letrozole (Femara®) alone or in combination with zoledronic acid (Zometa®) as extended adjuvant treatment of postmenopausal patients with primary breast cancer [EXpANd]. https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-003888-71/DE (date received 16 May 2016).
    1. Hellriegel M, Mueller M, Reimer T, Baerens DT, Von Der Assen A, Hackmann J, et al. The Expand study - effect of zoledronic acid on prevention of bone loss, during extended adjuvant therapy with letrozole in postmenopausal women with primary hormone receptor positive breast cancer compared to letrozole alone. European Journal of Cancer 2011;1:S390.
FEMZONE 2014 {published data only}
    1. EUCTR2004-004007-37-DE. Neoadjuvant therapy for postmenopausal women with ER and/or PgR positive breast cancer. A randomized open phase II trial evaluating the efficacy of a 6 months preoperative treatment with Letrozole (2.5 mg/day) with or without Zoledronic acid (4 mg every 4 weeks) - FEMZONE. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2004-004007-37-DE (date received 2 March 2006).
    1. Fasching PA, Jud SM, Hauschild M, Kummel S, Schutte M, Warm M, et al. Anticancer activity of letrozole plus zoledronic acid as neoadjuvant therapy for postmenopausal patients with breast cancer: FEMZONE trial results. Cancer Research 2012;72(24 Suppl):PD07-02.
    1. Fasching PA, Jud SM, Hauschild M, Kummel S, Schutte M, Warm M, et al. Anticancer activity of letrozole plus zoledronic acid as neoadjuvant therapy for postmenopausal patients with breast cancer: FEMZONE trial results. Cancer Research 2012;72(24 Suppl):PD07-02.
    1. Fasching PA, Jud SM, Hauschild M, Kummel S, Schutte M, Warm M, et al. FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients. BMC Cancer 2014;14:66. - PMC - PubMed
    1. Lux P, Fasching P, Schulz-Wendtland R, Muth M, Beckmann MW. FEMZONE - a randomized phase II trial evaluating the efficacy of a 6 months preoperative treatment with Letrozole with or without Zoledronic acid in patients with hormone receptor positive breast cancer. Onkologie 2010;33(6):56.
GAIN 2013 {published data only}
    1. Loibl S, Conrad B, Schneeweiss A, Kreienberg R, Solomayer EF, Clemens MR, et al. Pegfilgrastim on day 2 vs. day 4 within the prospective, multi-centered GAIN study: a phase III trial to compare ETC vs. EC-TX and ibandronate vs. observation in patients with node-positive primary breast cancer (GBG 33). Support Care Cancer 2009;7(2-3):256.
    1. Mobus V, Conrad B, Schneeweis A, Kreienberg R, Solomayer EF, Clemens MR, et al. Gain study: a phase III trial to compare ETC versus EC-TX and ibandronate versus observation in patients with node-positive primary breast cancer. Journal of Clinical Oncology 2009;27(15S):568.
    1. Mobus V, Diel IJ, Harbeck N, Elling D, Jackisch C, Thomssen C, et al. GAIN Study: a phase III trial To compare ETC vs. EC-TX and ibandronate vs. observation in patients with node-positive primary breast cancer - 1st interim efficacy analysis. Cancer Research 2011;71(24 Suppl):S2-4.
    1. Mobus V, Diel IJ, Harbeck N, Elling D, Jackisch C, Thomssen C, et al. GAIN study: a phase III trial to compare ETC vs. EC-TX and ibandronate vs. observation in patients with node-positive primary breast cancer - 1st interim efficacy analysis. Cancer Research 2011;71(24 Suppl):S2-4.
    1. Mobus V, Von Minckwitz G, Jackisch C, Luck HJ, Schneeweiss A, Tesch H, et al. German Adjuvant Intergroup Node-positive study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients. Journal of Clinical Oncology 2017;28(8):1803-10. - PubMed
GeparX 2016 {published data only}
    1. Blohmer JU, Link T, Kummel S, Untch M, Just M, Fasching PA, et al. Investigating denosumab as an add-on treatment to neoadjuvant chemotherapy and two different nab-paclitaxel schedules in a 2x2 design in primary breast cancer - first results of the GeparX study. Cancer Research 2020;80(4 Suppl 1):GS3-01.
    1. Blohmer JU, Link T, Reinisch M, Just M, Untch M, Stötzer O, et al. Effect of denosumab added to 2 different nab-paclitaxel regimens as neoadjuvant therapy in patients with primary breast cancer: the GeparX 2 × 2 randomized clinical trial. JAMA Oncology 2022;8(7):1010-8. - PMC - PubMed
    1. EUCTR2015-001755-72-DE. Addition of denosumab to two different neoadjuvant treatment schedules of nab-paclitaxel. https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001755-72/DE (date received 2016).
    1. Kummel S, Von MG, Nekljudova V, Dan CS, Denkert C, Hanusch C, et al. Investigating denosumab as add-on neoadjuvant treatment for hormone receptor-negative, RANK-positive or RANK-negative primary breast cancer and two different nab-paclitaxel schedules - 2x2 factorial design (GeparX). Journal of Clinical Oncology 2016;34(15 Suppl):TPS635.
    1. Link T, Blohmer JU, Just M, Untch M, Stotzer O, Fasching PA. GeparX: Denosumab (Dmab) as add-on to different regimen of nab-paclitaxel (nP)-anthracycline based neoadjuvant chemotherapy (NACT) in early breast cancer (BC): subgroup analyses by RANK expression and HR status. Annals of Oncology 2020;31(Suppl 4):308-9.
Hershman 2008 {published data only}
    1. Hershman DL, McMahon D, Crew K, Cremers S, Irani D, Cucchiara G, et al. Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early stage breast cancer. Journal of Clinical Oncology 2008;26:4739-45. - PMC - PubMed
    1. Hershman DL, McMahon D, Crew KD, Shao T, Cremers S, Brafman L, et al. Evaluation of the protective effects of zoledronic acid on bone mass in premenopausal women undergoing adjuvant chemotherapy following treatment discontinuation. Journal of Clinical Oncology 2009;27:562.
    1. Hershman DL, McMahon DJ, Crew KD, Cremers S, Irani D, Cucchiara G, et al. Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. Journal of Clinical Oncology 2008;26(29):4739-45. - PMC - PubMed
    1. Hershman DL, McMahon DJ, Crew KD, Shao T, Cremers S, Brafman L, et al. Prevention of bone loss by zoledronic acid in premenopausal women undergoing adjuvant chemotherapy persist up to one year following discontinuing treatment. Journal of Clinical Endocrinology and Metabolism 2010;95(2):559-66. - PMC - PubMed
    1. NCT00049452. Zoledronate in preventing bone loss in premenopausal women receiving chemotherapy after surgery for early stage breast cancer. https://clinicaltrials.gov/ct2/show/NCT00049452 (date received 27 January 2003).
H‐FEAT 2011 {published data only}
    1. JPRN-UMIN000005568. A randomized phase II study of efficacy of risendronate for the prevention of letrozole-induced bone mineral loss in post-menopausal breast cancer patients. http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000005568 (date received 2011).
    1. Kadoya T, Masumoto N, Shigematsu H, Emi A, Kajitani K, Kobayashi Y, et al. Prevention of letrozole-induced bone loss using risedronate in postmenopausal women with hormone receptor positive breast cancer: a multicenter randomized clinical trial. Cancer Research 2016;76(4 Suppl):P1-15-03.
HOBOE 2019 {published data only}
    1. Gravina A, De Laurentis M, De Placido S, Orditura M, Orlando L, Riccardi F, et al. The HOBOE multicenter randomized phase III trial in premenopausal patients (pts) with hormonereceptor positive early breast cancer (EBC) comparing triptorelin plus either tamoxifen (T) or letrozole (L) or zoledronic acid + letrozole (ZL): 8yr efficacy analysis. Tumori 2022;108(4):2-3.
    1. Morabito A, Rossi E, Di Rella F, Esposito G, Gravina A, Labonia V, et al. Endocrine effects of adjuvant letrozole versus tamoxifen in hormone responsive postmenopausal early breast cancer patients: results from the HOBOE randomized trial. Cancer Research 2009;69(2 Suppl):1150. - PubMed
    1. NCT00412022. HOBOE: A phase 3 study of adjuvant triptorelin and tamoxifen, letrozole, or letrozole and zoledronic acid in premenopausal patients with breast cancer. https://clinicaltrials.gov/ct2/show/NCT00412022 (date received 15 December 2006).
    1. Nuzzo F, Gallo C, Lastoria S, Di Maio M, Piccirillo MC, Gravina A, et al. Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study. Annals of Oncology 2012;23(8):2027-33. - PubMed
    1. Perrone F, De Laurentiis M, De Placido S, Orditura M, Cinieri S, Riccardi F, et al. Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. European Journal of Cancer 2019;118:178-86. - PubMed
JONIE 2017 {published data only}
    1. Hasegawa Y, Kohno N, Horiguchi J, Miura D, Ishikawa T, Hayashi M, et al. A randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer. Cancer Research 2012;72(24 Suppl):PD07-05.
    1. Hasegawa Y, Tanino H, Horiguchi J, Miura D, Ishikawa T, Hayashi M, et al. Randomized controlled trial of zoledronic acid plus chemotherapy versus chemotherapy alone as neoadjuvant treatment of HER2-negative primary breast cancer (JONIE study). PLOS One 2015;10(12):e0143643. - PMC - PubMed
    1. Horiguchi J, Hasegawa Y, Miura D, Ishikawa T, Hayashi M, Takao S, et al. A randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer. Journal of Clinical Oncology 2013;31(15 Suppl):1029.
    1. Ishikawa T, Akazawa K, Hasegawa Y, Tanino H, Horiguchi J, Miura D, et al. Survival outcomes of neoadjuvant chemotherapy with zoledronic acid for HER2-negative breast cancer. Journal of Surgical Research 2017;220:46-51. - PubMed
    1. Ishikawa T, Akazawa K, Hasegawa Y, Tanino H, Horiguchi J, Miura D, et al. Zoledronic acid combined with neoadjuvant chemotherapy for HER2-negative early breast cancer (JONIE 1 trial): survival outcomes of a randomized multicenter phase 2 trial. Cancer Research 2017;77(4 Suppl 1):P5-16-10.
Kanis 1996 {published data only}
    1. Kanis JA, Powles T, Paterson AHG, McCloskey EV, Ashley S. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 1996;19:663-7. - PubMed
    1. Powles TJ, Paterson A, Ashley S, Tidy A, McCloskey E, Nevantaus A, et al. Adjuvant clodronate will reduce the incidence of bone metastases in patients with primary operable breast cancer. Breast Cancer Research & Treatment 1998;50(3):234.
Kristensen 2008 {published data only}
    1. Kristensen B, Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Bjerregaard B, et al. Bisphosphonate treatment in primary breast cancer: results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer. Acta Oncologica (Stockholm, Sweden) 2008;47(4):740-6. - PubMed
Mardiak 2000 {published data only}
    1. Mardiak J, Bohunick L, Chovanec J, lek T, Koza I, Slovak Clodronate Collaborative Group. Adjuvant clodronate therapy in patients with locally advanced breast cancer - long term results of a double blind randomized trial.. Neoplasma 2000;47(3):177-80. - PubMed
Monda 2017 {published data only}
    1. Monda V, Lupoli GA, Messina G, Peluso R, Panico A, Villano I, et al. Improvement of bone physiology and life quality due to association of risedronate and anastrozole. Frontiers in Pharmacology 2017;8:00632. - PMC - PubMed
N02C1 2009 {published data only}
    1. Hines SL, Mincey BA, Sloan JA, Thomas SP, Chotinner EG, Loprinzi CL, et al. N02C1: a phase III randomized, placebo-controlled, double-blind trial of risedronate for prevention of bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer (BC) [abstract no. 525]. Journal of Clinical Oncology 2008;26:12. - PMC - PubMed
    1. Hines SL, Mincey BA, Sloan JA, Thomas SP, Chottiner E, Loprinzi CL, et al. Phase III randomized, placebo-controlled, double-blind trial of risedronate for the prevention of bone loss in premenopausal women undergoing chemotherapy for primary breast cancer. Journal of Clinical Oncology 2009;27(7):1047-53. - PMC - PubMed
    1. NCT00054418. Risedronate in preventing bone loss in premenopausal women receiving chemotherapy for primary breast cancer. Https://clinicaltrials.gov/show/NCT00054418 (date received 6 February 2003).
NATAN 2016 {published data only}
    1. NCT00512993. Postoperative use of zoledronic acid in breast cancer patients after neoadjuvant chemotherapy. https://clinicaltrials.gov/ct2/show/NCT00512993 (date received 8 August 2007).
    1. Von Minckwitz G, Rezai M, Eidtmann H, Tesch H, Huober J, Gerber B, et al. Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclines-taxane-based chemotherapy for primary breast cancer - the phase III NATAN study (GBG 36/ABCSG XX). Cancer Research 2013;73(24 Suppl):S5-05.
    1. Von Minckwitz G, Rezai M, Tesch H, Huober J, Gerber B, Zahm DM, et al. Zoledronate for patients with invasive residual disease after anthracyclines-taxane-based chemotherapy for early breast cancer - the Phase III NeoAdjuvant Trial Add-oN (NaTaN) study (GBG 36/ABCSG 29). European Journal of Cancer 2016;64:12-21. - PubMed
    1. Von Minckwitz G, Zahm MD, Eidtmann H, Tesch H, Du Bois A, Schwedler K, et al. Zoledronic acid (ZOL) as add-on therapy in patients with tumour residuals after neoadjuvant chemotherapy for primary breast cancer - first interim safety analysis of the NATAN study (GBG 36). European Journal of Cancer 2010;8(3 Suppl):65.
NEOZOL 2018 {published data only}
    1. Lelievre L, Clezardin P, Magaud L, Roche L, Tubiana-Mathieu N, Tigaud JD, et al. Comparative study of neoadjuvant chemotherapy with and without zometa for management of locally advanced breast cancer with serum VEGF as primary endpoint: the NEOZOL study. Clinical Breast Cancer 2018;18(6):e1311-21. - PubMed
    1. Mathevet P, Magaud L, Clezardin P. Adding zoledronic acid to neo-adjuvant chemotherapy may improve the efficiency of chemotherapy in locally advanced breast cancer: results from the prospective randomized study NEOZOL. Cancer Research 2016;76(4 Suppl):P6-13-19.
    1. NCT01367288. Comparative study of neoadjuvant chemotherapy with and without Zometa for management of locally advanced breast cancers. https://clinicaltrials.gov/show/NCT01367288 (date received 7 June 2010). - PubMed
NEO‐ZOTAC BOOG 2010 {published data only}
    1. Charehbili A, Hamdy NA, Smit VT, Kessels L, Van Bochove A, Van Laarhoven HW, et al. Vitamin d (25-0H D3) status and pathological response to neoadjuvant chemotherapy in stage II/III breast cancer: data from the NEOZOTAC trial (BOOG 10-01). Breast (Edinburgh, Scotland) 2016;25:69-74. - PubMed
    1. Charehbili A, Hamdy NAT, Smit VM, Liefers GJ, Putter H, Meershoek-Klein Kranenbarg E, et al. Changes in circulating vitamin D levels as a predictor for pathological response to neoadjuvant chemotherapy (NAC) in breast cancer (BC): a Dutch breast cancer trialists group (BOOG) side-study. Cancer Research 2013;73(24 Suppl):P1-08-19.
    1. Charehbili A, Van De Ven S, Liefers GJ, Smit VT, Wasser MN, Meershoek-Klein Kranenbarg EM, et al. Clinical and pathological response after neoadjuvant chemotherapy with or without zoledronic acid for patients with HER2-negative large resectable or stage II or III breast cancer. European Journal of Cancer 2013;49:S401.
    1. Charehbili A, Van De Ven S, Liefers GJ, Smit VTHBM, Putter H, Heijns JB, et al. NEOZOTAC: efficacy results from a phase III randomized trial with neoadjuvant chemotherapy (TAC) with or without zoledronic acid for patients with HER2-negative large resectable or stage II or III breast cancer (BC)-a Dutch Breast Cancer Trialists' Group (BOOG) study. Journal of Clinical Oncology 2013;31(15 Suppl):1028.
    1. Charehbili A, Van de Ven, Smit VT, Meershoek-Klein Kranenbarg E, Hamdy NA, Putter H, et al. Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010-01). Annals of Oncology 2014;25(5):998-1004. - PubMed
Novartis I 2006 {published data only}
    1. NCT00332709. Safety/efficacy of letrozole monotherapy or in combination with zoledronic acid as extended adjuvant treatment of postmenopausal patients with primary breast cancer. https://clinicaltrials.gov/ct2/show/NCT00332709 (date received 2 June 2006).
NSABP B‐34 2012 {published data only}CDR0000068426
    1. NCT00009945. Clodronate with or without chemotherapy and/or hormonal therapy in treating women with stage I or stage II breast cancer. https://clinicaltrials.gov/ct2/show/NCT00009945 (date received 27 January 2003).
    1. Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, et al. 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. Oncology 2012;13(7):734-42. - PMC - PubMed
    1. Paterson AHG, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, et al. NSABP Protocol B-34: a clinical trial comparing adjuvant clodronate vs. placebo in early stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapy - final analysis 6. Cancer Research 2011;71(24 Suppl):S2-3.
    1. Paterson AHG, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, et al. NSABP protocol B-34: a clinical trial comparing adjuvant clodronate vs. placebo in early stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapy - final analysis. Cancer Research 2011;71(24 Suppl):S2-3.
    1. Paterson AHG, Lucas PC, Anderson SJ, Mamounas EP, Brufsky A, Baez-Diaz L, et al. MAF amplification and adjuvant clodronate outcomes in early-stage breast cancer in NSABP B-34 and potential impact on clinical practice. JNCI Cancer Spectrum 2021;5(4):08. - PMC - PubMed
Powles 2006 {published data only}ISRCTN83688026
    1. Atula S, Powles T, Paterson A, McCloskey E, Nevalainen J, Kanis J. Extended safety profile of oral clodronate after long-term use in primary breast cancer patients. Drug Safety 2003;26(9):661-71. - PubMed
    1. Atula ST, Paterson AHG, Powles TJ, McCloskey EV, Nevalamen JI, Kants JA. Safety profile of oral clodronate during long-term use in primary breast cancer patients. Bone 2002;30(3):46S. - PubMed
    1. ISRCTN83688026. A randomised controlled clinical trial to evaluate the anti-osteolytic agent clodronate for the prevention of the development of bone metastases in patients with primary breast cancer. https://www.isrctn.com/ISRCTN83688026 (date received 1 February 2006).
    1. McCloskey E, Paterson A, Kanis J, Tahtela R, Powles T. Effect of oral clodronate on bone mass, bone turnover and subsequent metastases in women with primary breast cancer. European Journal of Cancer 2010;46(3):558-65. - PubMed
    1. McCloskey E, Paterson AH, Powles TJ. Oral clodronate maintains bone mass in women with primary breast cancer. Journal of Clinical Oncology 2005;23(16 Suppl):12S.
ProBONE I 2005 {published data only}
    1. EUCTR2004-002831-14-DE. Influence of zoledronic acid (Zometa®) on bone mineral density and bone ultrasonometry in premenopausal women with hormone receptor negative breast cancer and adjuvant chemotherapeutic treatment. https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-002831-14/DE (date received 2005).
    1. Hadji P, Kauka A, Bauer T, Kalder M, Albert U, Birkholz K, et al. Influence of zoledronic acid on BMD in premenopausal women with breast cancer and neoadjuvant or adjuvant chemotherapy and/or endocrine treatment - the Probone studies. Cancer Research 2011;71(24 Suppl):P2-19-03.
ProBONE II 2015 {published data only}
    1. Hadji P, Kauka A, Bauer T, Kalder M, Albert U, Birkholz K, et al. Influence of zoledronic acid on BMD in premenopausal women with breast cancer and neoadjuvant or adjuvant chemotherapy and/or endocrine treatment - the Probone studies. Cancer Research 2011;71(24 Suppl):P2-19-03.
    1. Hadji P, Kauka A, Bauer T, Kalder M, Albert US, Birkholz K, et al. The ProBone study: influence of zoledronic acid on bone mineral density in premenopausal women with breast cancer and neoadjuvant or adjuvant chemotherapy and/or endocrine treatment. Journal of Cancer Research and Clinical Oncology 2012;138:62.
    1. Hadji P, Kauka A, Kalder M, Bauer T, Albert U, Muth M, et al. Influence of zoledronic acid on bone mineral density in premenopausal women with hormone receptor positive or negative breast cancer and neoadjuvant or adjuvant chemotherapy or endocrine treatment. European Journal of Cancer 2010;8(3 Suppl):62.
    1. Hadji P, Kauka A, Ziller M, Birkholz K, Baier M, Muth M, et al. Effect of adjuvant endocrine therapy on hormonal levels in premenopausal women with breast cancer: the ProBONE II study. Breast Cancer Research & Treatment 2014;144(2):343-51. - PubMed
    1. Hadji P, Kauka A, Ziller M, Birkholz K, Baier M, Muth M, et al. Effects of zoledronic acid on bone mineral density in premenopausal women receiving neoadjuvant or adjuvant therapies for HR+ breast cancer: the ProBONE II study. Osteoporosis International 2014;25(4):1369-78. - PubMed
REBBeCA 2008 {published data only}
    1. Greenspan SL, Bhattacharya RK, Sereika SM, Brufsky A, Vogel VG. Prevention of bone loss in survivors of breast cancer: a randomized, double-blind, placebo-controlled clinical trial. Journal of Clinical Endocrinology and Metabolism 2007;92(1):131-6. - PubMed
    1. Greenspan SL, Brufsky A, Lembersky BC, Bhattacharya R, Vujevich KT, Perera S, et al. Risedronate prevents bone loss in breast cancer survivors: 2-year, randomized, double-blind, placebo-controlled clinical trial. Journal of Clinical Oncology 2008;26(16):2644-52. - PMC - PubMed
    1. Langmann G, Vujevich K, Medich D, Miller M, Perera S, Greenspan SL. Heel ultrasound can assess maintenance of bone mass in women with breast cancer. Journal of Bone and Mineral Research 2010;1:398. - PMC - PubMed
    1. NCT00118508. The prevention of osteoporosis in premenopausal and newly postmenopausal (up to 8 years) women with breast cancer following chemotherapy (REBBeCA study). https://www.clinicaltrials.gov/ct2/show/NCT00118508 (date received 11 July 2005).
    1. Van Londen G, Perera S, Vujevich K, Sereika S, Bhattacharya R, Vogel V, et al. The effect of risedronate on hip structural geometry in chemotherapy-induced postmenopausal women on SERMS versus aromatase inhibitors: a 2-year trial. Bone 2007;46(3):3655-9. - PMC - PubMed
REBBeCA II 2016 {published data only}
    1. Anonymous. Once-weekly risedronate benefits postmenopausal breast-cancer survivors. Nature Clinical Practice Endocrinology and Metabolism 2008;4:478.
    1. Greenspan S, Perera S, Vujevich K, Van Londen G, Brufsky A, Lembersky B, et al. Prevention of bone loss in breast cancer survivors on aromatase inhibitors: results of the Rebbeca II trial. Journal of Bone and Mineral Research (conference abstracts) 2013;28:S18.
    1. Greenspan SL, Vujevich KT, Brufsky A, Lembersky BC, Van Londen GJ, Jankowitz RC, et al. Prevention of bone loss with risedronate in breast cancer survivors: a randomized, controlled clinical trial. Osteoporosis International 2015;26(6):1857-64. - PMC - PubMed
    1. Langmann GA, Vujevich KT, Medich D, Miller ME, Perera S, Greenspan SL. Heel ultrasound can assess maintenance of bone mass in women with breast cancer. Journal of Clinical Densitometry 2012;15(3):290-4. - PMC - PubMed
    1. NCT00485953. Effect of bisphosphonate on bone loss in postmenopausal women with breast cancer initiating aromatase inhibitor therapy. Https://clinicaltrials.gov/show/NCT00485953 (date received 13 June 2007).
Rhee 2013 {published data only}
    1. Rhee Y, Song K, Lim SK, Park BW. Efficacy of a combined alendronate and calcitriol agent in Korean postmenopausal women with early breast cancer receiving aromatase inhibitor: a double-blind, randomized, placebo-controlled study. Osteoporosis International 2010;5:S760-1. - PubMed
    1. Rhee Y, Song K, Park S, Park HS, Lim SK, Park BW. Efficacy of a combined alendronate and calcitriol agent (maxmarvil) in Korean postmenopausal women with early breast cancer receiving aromatase inhibitor: a double-blind, randomized, placebo-controlled study. Endocrine Journal 2013;60(2):167-72. - PubMed
Saarto 2004 {published data only}
    1. Leppa S, Saarto T, Vehmanen L, Blomqvist C, Elomaa I. Clodronate treatment influences MMP-2 associated outcome in node positive breast cancer. Breast Cancer Research & Treatment 2005;90(2):117-25. - PubMed
    1. Saarto T, Blomqvist C, Valimaki M, Makela P, Elomaa I. Clodronate improves bone mineral density in early breast cancer patients. A randomized study [abstract no: 51]. European Journal of Cancer 1995;31A(Suppl 5):S12.
    1. Saarto T, Blomqvist C, Valimaki M, Makela P, Elomaa I. Clodronate improves bone mineral density in early breast cancer patients. A randomized study. European Journal of Cancer 1995;31A(Suppl 5):S12. - PMC - PubMed
    1. Saarto T, Blomqvist C, Valimaki M, Makela P, Sarna S, Elomaa I. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. Journal of Clinical Oncology 1997;15(4):1341-7. - PubMed
    1. Saarto T, Blomqvist C, Valimaki M, Makela P, Sarna S, Elomaa I. Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antioestrogens. British Journal of Cancer 1997;75(4):602-5. - PMC - PubMed
SABRE 2010 {published data only}
    1. NCT00082277. Anastrozole biphosphonate study in postmenopausal women with hormone-receptor-positive early breast cancer. https://clinicaltrials.gov/ct2/show/NCT00082277 (date received 6 May 2004).
    1. Van Poznak C, Hannon R, Clack G, Campone M, Mackey JR, Apffelstaedt J, et al. Managing cancer treatment-induced bone loss: 24-month results from the Study of Anastrozole with the Bisphosphonate Risedronate. Cancer Research 2009;69(2 Suppl):1137.
    1. Van Poznak C, Hannon R, Clack G, Campone M, Mackey JR, Apffelstaedt J, et al. Managing cancer treatment-induced bone loss: 24-month results from the study of anastrozole with the bisphosphonate risedronate (SABRE). Cancer Research 2009;69(2 Suppl):1137.
    1. Van Poznak C, Hannon RA, Clack G, Campone M, Mackey JR, Apffelstaedt J, et al. The SABRE (Study of Anastrozole with the Bisphosphonate RisedronatE) study: 12-month analysis. Breast Cancer Research and Treatment 2007;106:S37.
    1. Van Poznak C, Hannon RA, Mackey JR, Campone M, Apffelstaedt JP, Clack G, et al. Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. Journal of Clinical Oncology 2010;28(6):967-75. - PubMed
Safra 2011 {published data only}
    1. Greenberg J, Stemmer SM, Bernstein-Molho R, Pelles-Avraham S, Stephansky I, Inbar MJ, et al. The protective effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole: 36-month follow-up. Journal of Clinical Oncology 2011;29(15 Suppl 1):e11111. - PubMed
    1. NCT00376740. Effectiveness of zoledronic acid in the prevention of osteoporosis in early breast cancer patients receiving letrozole. https://clinicaltrials.gov/ct2/show/NCT00376740 (date received 15 September 2006).
    1. Safra T, Bernstein Molho R, Stephansky I, Yaal-Hahoshen N, Inbar M, Ackerstein A, et al. Effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole. Journal of Clinical Oncology 2009;27(15S):599. - PubMed
    1. Safra T, Bernstein-Molho R, Greenberg J, Pelles-Avraham S, Stephansky I, Sarid D, et al. 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 2011;81(5-6):298-305. - PubMed
Saito 2015 {published data only}
    1. Saito M, Matsuoka J. Open-label randomized parallel controlled study comparing bone mineral density between alendronate plus alfacalcidol combination and single administration of alfacalcidol in postmenopausal women receiving aromatase inhibitor as adjuvant therapy. Cancer Research 2015;75(9 Suppl):P5-15-06.
Solomayer 2012 {published data only}
    1. Banys M, Solomayer EF, Gebauer G, Janni W, Krawczyk N, Lueck HJ, et al. Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial. BMC Cancer 2013;13:480. - PMC - PubMed
    1. NCT00172068. Zoledronic acid in the treatment of breast cancer with minimal residual disease in the bone marrow. https://www.clinicaltrials.gov/ct2/show/NCT00172068 (date received 15 September 2005).
    1. Solomayer E, Gebauer G, Hirnle P, Janni W, Lück H, Becker S, et al. Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients. Cancer Research 2009;69(2 Suppl):2048. - PubMed
    1. Solomayer EF, Banys M, Krawczyk N, Gebauer G, Wallwiener D, Hirnle P, et al. Bisphosphonates may improve survival of breast cancer patients with disseminated tumor cells in bone marrow. Journal of Cancer Research and Clinical Oncology 2012;1:90.
    1. Solomayer EF, Gebauer G, Hirnle P, Janni W, Luck HJ, Becker S, et al. Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Annals of Oncology 2012;23(9):2271-7. - PubMed
Sun 2016 {published data only}
    1. Sun S, Wang F, Dou H, Zhang L, Li J. Preventive effect of zoledronic acid on aromatase inhibitor-associated bone loss for postmenopausal breast cancer patients receiving adjuvant letrozole. Oncotargets and Therapy 2016;9:6029-36. - PMC - PubMed
SWOG S0307 2019 {published data only}
    1. Gralow J, Barlow WE, Paterson AHG, Lew D, Stopeck A, Hayes DF, et al. Phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: sWOG/Alliance/ECOG-ACRIN/NCIC Clinical Trials Group/NRG Oncology study S0307. Journal of Clinical Oncology 2015;33(15 Suppl):503.
    1. Gralow J, Barlow WE, Paterson AHG, Lew D, Stopeck A, Hayes DF, et al. SWOG S0307 phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: comparison of toxicities and patient-stated preference for oral versus intravenous delivery. Journal of Clinical Oncology 2014;32(15 Suppl):558.
    1. Gralow JR, Barlow WE, Paterson AH, Miao JL, Lew DL, Stopeck AT, et al. Phase III randomized trial of bisphosphonates as adjuvant therapy in breast cancer: S0307. Journal of the National Cancer Institute 2019;112(7):698-707. - PMC - PubMed
    1. Kizub D, Miao J, Stopeck A, Thompson P, Paterson AH, Clemons M, et al. Statin use, site of recurrence, and survival among post-menopausal women taking bisphosphonates as adjuvant therapy for breast cancer (SWOG S0307). Cancer Research 2019;79(4 Suppl):P1-17-03.
    1. Kizub DA, Miao J, Schubert MM, Paterson AHG, Clemons M, Dees EC, et al. Factors associated with osteonecrosis of the jaw in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG 0307 trial. Journal of Clinical Oncology 2019;37(Suppl 15):552.
Team IIB 2006 {published data only}
    1. ISRCTN17633610. TEAM II: a randomised, multicentre, prospective, phase III trial investigating neoadjuvant hormonal therapy with exemestane for three versus six months (TEAM IIa) and/or the efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in post-menopausal women with hormone receptor positive early breast cancer (TEAM IIb). http://www.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN17633610 (date received 28 December 2006).
    1. NTR785. TEAM II A randomised, multicentre, prospective, phase III trial investigating TEAM IIa: neoadjuvant hormonal therapy with exemestane for three versus six months. and / or TEAM IIb: the efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone receptor positive early breast cancer. http://www.who.int/trialsearch/Trial2.aspx?TrialID=NTR785 (date received 2006).
    1. Vliek SB, Meershoek-Klein Kranenbarg E, Van Rossum AG, Tanis BC, Putter H, Van Der Velden AW, et al. The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone-receptor positive early breast cancer. First results of the TEAM IIB trial (BOOG 2006-04). Cancer Research 2017;77(4 Suppl 1):S6-02.
    1. Vliek SB, Noordhoek I, Meershoek-Klein Kranenbarg E, Van Rossum AGJ, Dezentje VO, Jager A, et al. Daily oral ibandronate with adjuvant endocrine therapy in postmenopausal women with estrogen receptor-positive breast cancer (BOOG 2006-04): randomized phase III TEAM-IIB trial. Journal of Clinical Oncology 2022;40(25):2934-45 Erratum in: Journal of Clinical Oncology 2022; 40(28):3352. - PubMed
Tevaarwerk 2007 {published data only}
    1. Leal T, Tevaarwerk A, Love R, Stewart J, Binkley N, Eickhoff J, et al. Randomized trial of adjuvant zoledronic acid in postmenopausal women with high-risk breast cancer. Clinical Breast Cancer 2010;10(6):471-6. - PMC - PubMed
    1. NCT00213980. Bone mineral density effects of zoledronate in postmenopausal women with breast cancer. https://clinicaltrials.gov/show/NCT00213980 (date received 21 September 2005).
    1. Tevaarwerk A, Stewart JA, Love R, Binkley NC, Black S, Eickhoff J, et al. Randomized trial to assess bone mineral density (BMD) effects of zoledronic acid (ZA) in postmenopausal women (PmW) with breast cancer. Journal of Clinical Oncology 2007;25(18 Suppl):19558.

References to studies excluded from this review

Ahmad 2007 {published data only}
    1. Ahmad K. Zoledronic acid prevents bone loss. Lancet Oncology 2007;8(5):375. - PubMed
Ahn 2009 {published data only}
    1. Ahn J, Jung K, Kim S, Lee K, Ro J, Park Y, et al. Zoledronic acid prevents bone loss in premenopausal women with early breast cancer undergoing adjuvant chemotherapy: a phase III study of Korean Cancer Study Group (KCSG-BR06-01). Cancer Research 2009;69(24 Suppl):2104. - PubMed
    1. Kim JE, Ahn JH, Jung KH, Kim SB, Kim HJ, Lee KS, et al. Zoledronic acid prevents bone loss in premenopausal women with early breast cancer undergoing adjuvant chemotherapy: a phase III trial of the Korean Cancer Study Group (KCSG-BR06-01). Breast Cancer Research and Treatment 2011;125(1):99-106. - PubMed
BATMAN 2005 {published data only}
    1. NCT00122356. Bisphosphonate and anastrozole trial - bone maintenance algorithm assessment. https://clinicaltrials.gov/ct2/show/NCT00122356 (date received 22 July 2005).
CALGB 79809 {published data only}
    1. Anonymous. CALGB 78909: phase III trial of intravenous zoledronic acid in the prevention of bone loss in localized breast cancer patients with chemotherapy-induced ovarian failure. Clinical Advances in Hematology & Oncology 2005;3:105-6. - PubMed
    1. NCT00022087. Zoledronate, calcium, and vitamin D in preventing bone loss in women receiving adjuvant chemotherapy for breast cancer. Https://clinicaltrials.gov/show/NCT00022087 (date received 27 January 2003).
    1. Shapiro CL, Halabi S, Gibson G, Weckstein DJ, Kirshner J, Sikov WM, et al. Effect of zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who develop ovarian failure (OF) due to adjuvant chemotherapy (AdC): first results from CALGB trial 7980. Journal of Clinical Oncology 2008;26(15 Suppl):512.
    1. Shapiro CL, Halabi S, Hars V, Archer L, Weckstein D, Kirshner J, et al. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. European Journal of Cancer 2011;47(5):683-9. - PMC - PubMed
Chen 2011 {published data only}
    1. Chen J, Liu ZY, Zhao L. Effects of zoledronic acid in the treatment of breast cancer. Chung-hua Chung Liu Tsa Chih [Chinese Journal of Oncology] 2011;33:318-9. - PubMed
Ciardo 2020 {published data only}
    1. Ciardo D, Casciaro E, Ciccarese M, Conversano F, Forcignano R, Lombardi F, et al. Rems technology for short-term monitoring of denosumab therapeutic effect in breast cancer patients receiving aromatase inhibitors based therapy. Osteoporosis International 2020;31(Suppl 1):S372-3.
Fuleihan 2005 {published data only}
    1. Fuleihan G, Salamoun M, Mourad YA, Chehal A, Salem Z, Mahfoud Z, et al. Pamidronate in the prevention of chemotherapy-induced bone loss in premenopausal women with breast cancer: a randomized controlled trial. Journal of Clinical Endocrinology & Metabolism 2005;90(6):3209-14. - PubMed
Gessner 2000 {published data only}
    1. Gessner U, Koeberle D, Thuerlimann B, Bacchus L, Horisberger B. Economic analysis of terminal care for patients with malignant osteolytic bone disease and pain treated with pamidronate. Supportive Care in Cancer 2000;8(2):115-22. - PubMed
Gucalp 1994 {published data only}
    1. Gucalp R, Theriault R, Gill I, Madajewicz S, Chapman R, Navari R, et al. Treatment of cancer-associated hypercalcemia. Double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone. Archives of Internal Medicine 1994;154(17):1935-44. - PubMed
Hines 2010 {published data only}
    1. Hines SL, Sloan JA, Atherton PJ, Perez EA, Dakhil SR, Johnson DB, et al. Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy. Breast 2010;19(2):92-6. - PMC - PubMed
    1. Majithia N, Atherton PJ, Lafky JM, Wagner-Johnston N, Olson J, Dakhil SR, et al. Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up. Supportive Care in Cancer 2016;24(3):1219-26. - PubMed
IBIS 3 FEASIBILITY {published data only}ISRCTN93764730
    1. EUCTR2014-004430-26-GB. Feasibility of the International Breast Intervention Study 3 (IBIS 3). Prevention of late recurrence in hormone receptor positive breast cancer survivors following 5 years of treatment. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-004430-26-GB (date received 2015).
    1. ISRCTN93764730. Feasability of IBIS 3. An international breast intervention study investigating prevention of late recurrence in ER+ breast cancer survivors following 5 years of adjuvant treatment. https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-004430-26/re... (date received 2014).
IBIS II 2003 {published data only}
    1. Sestak I, Blake G, Patel R, Cuzick J, Howell A, Coleman R, et al. Off-treatment bone mineral density changes in postmenopausal women receiving anastrozole for 5 years: 7-year results from the IBIS-II prevention trial. British Journal of Cancer 2021;124(8):1373-8. - PMC - PubMed
    1. Sestak I, Cuzick J, Blake G, Patel R, Coleman R, Eastell R. Effect of risedronate on bone loss due to anastrozole given to prevent breast cancer: 5-year results from the IBISII prevention trial. Journal of Bone and Mineral Research 2016;31(Suppl 1):S102.
    1. Sestak I, Cuzick J. Off-treatment bone mineral density changes in postmenopausal women after 5 years of anastrozole. Journal of Bone and Mineral Research 2018;33(Suppl 1):102-3.
    1. Singh S, Cuzick J, Blake GM, Mesher D, Patel R, Truscott J, et al. One year effect of anastrozole and risedronate on bone mineral density: first results from the IBIS-II bone sub-study. Bone 2011;48(1):S24.
JPRN‐UMIN000004375 {published data only}
    1. JPRN-UMIN000004375. Study on preventive effect of risedronate administration on aromatase inhibitor-induced bone mineral loss in the endoclinical therapy for postmenopausal breast cancer patients. http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000004375 (date received 2010).
Lee 2011 {published data only}
    1. Lee SA, Hwang SH, Ahn SG, Lee HM, Jeong J, Lee H. Effects of zoledronic acid on bone mineral density during aromatase inhibitor treatment of Korean postmenopausal breast cancer patients. Breast Cancer Research and Treatment 2011;130:863-70. - PubMed
Lipton 1999 {published data only}
    1. Lipton A, Berenson J, Knight R, Grace Hu, Levvy E. Phase 2 trial of zoledronate vs pamidronate in multiple myeloma and breast cancer. In: European Cancer Conference 10, Vienna. Vol. 35 Suppl 4. 1999:S360.
N03CC {published data only}
    1. Hines SL, Mincey B, Dentchev T, Sloan JA, Perez EA, Johnson DB, et al. Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen - N03CC. Breast Cancer Research & Treatment 2009;117(3):603-9. - PMC - PubMed
    1. Hines SL, Mincey BA, Sloan JA, Thomas SP, Chottiner E, Loprinzi CL, et al. Phase III randomized, placebo-controlled, double-blind trial of risedronate for the prevention of bone loss in premenopausal women undergoing chemotherapy for primary breast cancer. Journal of Clinical Oncology 2009;27(7):1047-53. - PMC - PubMed
    1. Mincey BA, Dentchev T, Sloan JA, Hines SL, Perez EA, Johnson DB, et al. N03CC - a randomized, controlled, open-label trial of upfront vs. delayed zoledronic acid for prevention of bone loss in postmenopausal (PM) women with primary breast cancer (PBC) starting letrozole after tamoxifen. Journal of Clinical Oncology 2008;26(15 Suppl):564.
    1. NCT00107263. Zoledronate in preventing bone loss in postmenopausal women who are receiving letrozole for stage I, stage II, or stage IIIA breast cancer. https://clinicaltrials.gov/show/NCT00107263 (date received 6 April 2005).
Nakatsukasa 2019 {published data only}
    1. Nakatsukasa K, Koyama H, Ouchi Y, Ono H, Sakaguchi K, Matsuda T, et al. Effect of denosumab on low bone mineral density in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results. Breast Cancer (Tokyo, Japan) 2019;26(1):106-12. - PubMed
NCT00196859 {published data only}
    1. NCT00196859. Study in elderly patients with early breast cancer (ICE). https://clinicaltrials.gov/show/NCT00196859 (date received 20 September 2005).
NCT00202059 {published data only}
    1. NCT00202059. Effects of zometa and physical activity on bone density in women receiving chemotherapy for breast cancer. https://clinicaltrials.gov/ct2/show/NCT00202059 (date received 20 September 2005).
NCT00247650 {published data only}
    1. NCT00247650. Comparison study of letrozole alone or letrozole with zoledronic acid in early breast cancer, neoadjuvant therapy. https://www.clinicaltrials.gov/ct2/show/NCT00247650 (date received 1 November 2005).
NCT00295867 {published data only}
    1. NCT00295867. Zoledronate in treating bone marrow micrometastases in women with stage I, stage II, or stage III breast cancer. https://www.clinicaltrials.gov/ct2/show/NCT00295867 (date received 24 February 2006).
NCT00324714 {published data only}
    1. NCT00324714. Risedronate in improving bone mineral density and bone health in postmenopausal women with ductal carcinoma in situ enrolled in clinical trial CRUK-IBIS-II-DCIS. https://clinicaltrials.gov/ct2/show/NCT00324714 (date received 11 May 2006).
NCT00873808 {published data only}
    1. NCT00873808. S0307A, long-term bone quality in women with breast cancer enrolled on clinical trial SWOG-S0307. https://clinicaltrials.gov/ct2/show/NCT00873808 (date received 2 April 2009).
NCT02051218 {published data only}
    1. NCT02051218. Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks. https://clinicaltrials.gov/ct2/show/NCT02051218 (date received 31 January 2014).
NCT03358017 {published data only}
    1. NCT03358017. Neoadjuvant zoledronate and atorvastatin in triple negative breast cancer (YAPPETIZER). https://clinicaltrials.gov/ct2/show/NCT03358017 (date received 30 November 2017).
NCT03664687 {published data only}
    1. NCT03664687. Comparing a single-dose vs. twice yearly zoledronate in patients with early stage breast cancer (REaCT-ZOL). https://clinicaltrials.gov/ct2/show/NCT03664687 (date received 10 September 2018).
NCT05164952 {published data only}
    1. NCT05164952. Delayed versus immediate use of zoledronic acid for postmenopausal patients with ER/PR positive early breast cancer who are using adjuvant letrozole. https://clinicaltrials.gov/ct2/show/NCT05164952 (date received 21 December 2021).
PERIDENO {published data only}
    1. EUCTR2016-005210-22-NL. The influence of denosumab on the immune system in women after the menopause with HER2 negative breast cancer. https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-005210-22/NL (date received 2017).
    1. NCT03532087. Study to identify the impact of denosumab on the immune system in patients with HER2 negative breast cancer. Https://clinicaltrials.gov/show/NCT03532087 (date received 22 May 2018).
Purohit 1995 {published data only}
    1. Purohit OP, Radstone CR, Anthony C, Kanis JA, Coleman RE. A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. British Journal of Cancer 1995;72(5):1289-93. - PMC - PubMed
Ralston 1997 {published data only}
    1. Ralston SH, Thiebaud D, Herrmann Z, Steinhauer EU, Thurlimann B, Walls J, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. British Journal of Cancer 1997;75(2):295-300. - PMC - PubMed
Rizzoli 1996 {published data only}
    1. Rizzoli R, Forni M, Schaad MA, Slosman DO, Sappino AP, Garcia J, et al. Effects of oral clodronate on bone mineral density in patients with relapsing breast cancer. Bone 1996;18(6):531-7. - PubMed
Smith 1999 {published data only}
    1. Smith TJ, Hillner BE. Clodronate reduced the incidence of bony and visceral metastases in patients with breast cancer and tumour cells in the bone marrow. Evidence Based Medicine 1999;4(2):43.
SUCCESS {published data only}
    1. Andergassen U, Kasprowicz NS, Hepp P, Schindlbeck C, Harbeck N, Kiechle M, et al. Participation in the success - a trial improves intensity and quality of care for patients with primary breast cancer. Geburtshilfe und Frauenheilkunde 2013;73(1):63-9. - PMC - PubMed
    1. Andergassen U, Rack B, Schindlbeck C, Raber G, Ulmer H, Heinrich G, et al. Evaluation of CA 27.29 as prognostic marker in primary breast cancer patients - results of the German SUCCESS trial. Cancer Research 2009;69(24 Suppl):3023.
    1. Bauer ECA, Neugebauer JK, Andergassen U, Jaeger B, Jueckstock JK, Fasching PA, et al. Evaluation of prevalence, number, and temporal changes of circulating tumor cells as assessed after 2 and 5 years of follow-up in patients with early breast cancer in the SUCCESS: a study. Journal of Clinical Oncology 2013;31(15 Suppl):11042.
    1. Bauer ECA, Schochter F, Widschwendter P, DeGregorio A, Andergassen U, Friedl TWP, et al. Prevalence of circulating tumor cells in early breast cancer patients 2 and 5 years after adjuvant treatment. Breast Cancer Research & Treatment 2018;171(3):571-80. - PubMed
    1. De Gregorio A, Rack B, Fasching PA, Haberle L, Friedl TWP, Tesch H, et al. Persistence of circulating tumor cells in high-risk early breast cancer patients during follow-up care suggests poor prognosis: results from the adjuvant SUCCESS A trial. Clinical and Experimental Metastasis 2018;35(3):202.
Takahashi 2012 {published data only}
    1. Kohno N, Hasegawa Y, Horiguchi J, Ishikawa T, Miura D, Hayashi M, et al. Randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer. Journal of Clinical Oncology (conference abstracts) 2012;30(15 Suppl):TPS1141.
    1. Takahashi S, Iwase T, Kohno N, Ishikawa T, Kim SJ, Hosoda M, et al. Efficacy of zoledronic acid in postmenopausal Japanese women with early breast cancer receiving adjuvant letrozole: 36-month results. Journal of Clinical Oncology 2013;31(15 Suppl):e20510.
    1. Takahashi S, Iwase T, Kohno N, Ishikawa T, Taguchi T, Takahashi M, et al. Efficacy of zoledronic acid in postmenopausal Japanese women with early breast cancer receiving adjuvant letrozole: 12-month results. Breast Cancer Research & Treatment 2012;133(2):685-93. - PubMed
    1. Takahashi S, Iwase T, Kohno N, Ishikawa T, Taguchi T, Takahashi M, et al. Zoledronic acid inhibits adjuvant letrozole-associated bone loss in postmenopausal Japanese women with early breast cancer. Journal of Clinical Oncology 2011;29:829-36.
    1. UMIN-CTR700207118. Assessment of the efficacy of the use of zoledronic acid in the prevention of aromatase inhibitor-associated bone loss in postmenopausal women with hormone receptor-positive breast cancer who received letrozole as adjuvant therapy. https://adisinsight.springer.com/trials/700207118 (date received 2008).
Toulis 2016 {published data only}
    1. Toulis K, Iliadou P, Mandanas S, Kazila P, Margaritidou E, Georgopoulos K, et al. Calcium homeostasis in women with non-metastatic breast cancer with osteoporosis after a single dose of denosumab: a pilot study. Hormones 2016;15:560-2. - PubMed
Van Hellemond 2019 {published data only}
    1. Van Hellemond IEG, Smorenburg CH, Peer PGM, Swinkels ACP, Seynaeve CM, Van der Sangen MJC, et al. Assessment and management of bone health in women with early breast cancer receiving endocrine treatment in the DATA study. International Journal of Cancer 2019;145(5):1325-33. - PMC - PubMed
Vinholes 1995 {published data only}
    1. Purohit OP, Radstone CR, Anthony C, Kanis JA, Coleman RE. A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. British Journal of Cancer 1995;72(5):1289-93. - PMC - PubMed
    1. Vinholes J, Purohit OP, Guo CY, Eastell R, Vinholes AP, Coleman R. Randomised double-blind comparison of pamidronate or clodronate for hypercalcaemia of malignancy: effects on bone metabolism markers. European Journal of Cancer 1995;31A(Suppl 5):S253.
Vriens 2017 {published data only}
    1. Vriens B, Keymeulen K, Kroep JR, Charehbili A, Peer PG, De Boer M, et al. Axillary staging in breast cancer patients treated with neoadjuvant chemotherapy in two Dutch phase III studies. Oncotarget 2017;8(28):46557-64. - PMC - PubMed
Z‐FAST 2012 {published data only}
    1. Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore H, et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: the Z-FAST study 36-month follow-up. Clinical Breast Cancer 2009;29(2):77-85. - PubMed
    1. Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore H, et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: the Z-FAST study 36-month follow-up. In: 30th Annual San Antonio Breast Cancer Symposium. 2007. - PubMed
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ZO‐FAST 2013 {published data only}
    1. Llombart A, Frassoldati A, Paija O, Sleeboom HP, Jerusalem G, Mebis J, et al. 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. Clinical Breast Cancer 2012;12(1):40-8. - PubMed
    1. Bundred NJ, Campbell ID, Davidson N, DeBoer RH, Eidtmann H, Monnier A, et al. Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST study results. Cancer 2008;112(5):1001-10. - PubMed
    1. Coleman R, De Boer R, Eidtmann H, Llombart A, Davidson N, Neven P, et al. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Annals of Oncology 2013;24(2):398-405. - PubMed
    1. Coleman R, De Boer R, Eidtmann H, Neven P, Von Minckwitz G, Martin N, et al. Influence of delayed zoledronic acid initiation on disease-free survival in postmenopausal women with endocrine receptor-positive early breast cancer receiving adjuvant letrozole: exploratory analyses from the ZO-FAST trial. Cancer Research 2011;71(24 Suppl):P2-17-01.
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ZOLMENO 2017 {published data only}
    1. ISRCTN15749696. Does zoledronic acid alter levels of reproductive hormones and how does this affect the tumour and bone in pre- and post-menopausal women with early breast cancer? https://www.isrctn.com/ISRCTN15749696 (date received 3 October 2017).
    1. Theodoulou E, Wilson C, Brown JE, Holen I. The ZOLMENO study-exploring the effects of ZOLedronic Acid and MENOpausal status in patients with early breast cancer. Journal of Bone and Mineral Research Plus 2019;3(Suppl 3):62-3. [ISRCTN: 15749696]

References to studies awaiting assessment

ACTRN12616001051437 {published data only}
    1. ACTRN12616001051437. A randomised, double-blind, placebo controlled trial to examine the effects of total oestradiol depletion on bone microstructure and the efficacy of denosumab in preventing microstructural bone decay in premenopausal women with early breast cancer. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12616001... (date received 5 August 2016).
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ADAIDO {published data only}
    1. EUCTR2020-005343-23-IT. Study of the antiresorptive treatment with alendronate versus no treatment after denosumab and aromatase inhibitors discontinuation in low fracture risk osteopenic postmenopausal women with non metastatic hormonal receptor positive breast cancer. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-005343-23/IT (date received 2021).
ChiCTR‐TRC‐09000408 {published data only}
    1. ChiCTR-TRC-09000408. A clinical study of the effects of zoledronic acid in the prevention of metastasis of breast cancer to bone, and impact for disease process of breast cancer patients. https://www.chictr.org.cn/showprojEN.html?proj=9125 (date received 27 April 2009).
El‐Ibrashi 2016 {published data only}
    1. El-Ibrashi MM, El-Sadda WM, Abdel-Halim II, Elashri MS. Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients. Cancer Research 2016;76(4 Suppl):P5-15-04.
Gunmalm 2018 {published data only}
    1. Gunmalm V, Rasmussen AQ, Lund-Jacobson T, Andersson M, Brons C, Schwarz P. Bone and calcium metabolic changes during anti-resorptive treatment in early breast cancer. Calcified Tissue International 2018;102(1 Suppl 1):75.
NCT02595138 {published data only}
    1. NCT02595138. Zoledronic acid as adjuvant treatment of triple-negative breast cancer. https://clinicaltrials.gov/show/NCT02595138 (date received 3 November 2015).
Rhee 2011 {published data only}
    1. Rhee Y, Jung Chung Y, Kim SH, Lim SK, Park BW. Aromatase inhibitor significantly increased circulating sclerostin level in patients with endocrine-responsive breast cancer. Journal of Bone and Mineral Research 2011;26(Suppl 1):S223.
RISAROS 2009 {published data only}
    1. EUCTR2006-006943-29. Randomized, double-blind, placebo-controlled trial evaluating the effectiveness of oral risedronate 35 mg per week in the prevention of bone loss in women with breast cancer treated with aromatase inhibitors - Risaros [Essai randomise, en double aveugle contre placebo evaluant l'efficacite du risedronate oral 35 mg par semaine dans la prevention de la perte osseuse chez la femme atteinte d'un cancer du sein traite par inhibiteurs de l'aromatase - Risaros]. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_nu... (date received 2009).
    1. NCT00859703. Study to assess efficacy of risedronate in preventing bone loss in postmenopausal women treated for breast cancer. https://clinicaltrials.gov/ct2/show/NCT00859703 (date received 11 March 2009).
Xu 2010 {published data only}
    1. Xu L, Hao X, Zhang M, Zhang J. Clinical trial on the efficacy of zoledronic acid in preventing bone loss induced by aromatase inhibitor in breast cancer. Chinese Journal of Clinical Oncology 2010;37:392-4.
Yonehara 2007 {published data only}
    1. Yonehara Y, Iwamoto I, Kosha S, Rai Y, Sagara Y, Douchi T. Aromatase inhibitor-induced bone mineral loss and its prevention by bisphosphonate administration in postmenopausal breast cancer patients. Journal of Obstetrics and Gynaecology Research 2007;33:696-9. - PubMed

References to ongoing studies

D‐BIOMARK {published data only}
    1. EUCTR2016-002678-11-ES. An open label biomarker pilot study of the antitumoral acrivity of denosumab in the pre-operative setting of early breast cancer. https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002678-11/ES (date received 2018).
    1. Ippoliti G, Vethencourt A, Eva T, Feu Llaurado A, Taco C, Guerra E, et al. Denosumab as inmunomodulator in early breast cancer: preliminary results of a randomized window of opportunity clinical trial DBIOMARK (NCT03691311). Virchows Archiv 2021;479(Suppl 1):68‐9.
    1. NCT03691311. Biomarker study of the antitumoral activity of denosumab in the pre-operative setting of early breast cancer. Https://clinicaltrials.gov/show/NCT03691311 (date received 1 October 2018).
    1. Vethencourt A, Trinidad EM, Petit A, Soler-Monso MT, Aleza CG, Urruticochea A, et al. First results of the randomized window of opportunity clinical trial D-Biomark: immunomodulatory effect of denosumab in early breast cancer. Cancer Research 2022;82(4 Suppl):P2-08-10.
    1. Vethencourt AC, Trinidad EM, Gomez Aleza C, Pernas Simon S, Petit A, Soler T, et al. 14P Immunomodulatory effect of denosumab in early breast cancer: preliminary results of a randomized window-opportunity clinical trial D-Biomark. Annals of Oncology 2021;32:26.
ENDEAVOR {published data only}
    1. JprnUminR000024427. A multicenter, cooperative, randomized, comparative study regarding the efficacy of denosumab for bone loss related to postoperative endocrine therapy in postmenopausal patients with hormone-sensitive breast cancer. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R0000... (date received 2016).
    1. NCT03324932. Efficacy of denosumab on normal BMD in women receiving adjuvant aromatase inhibitors for early breast cancer. https://clinicaltrials.gov/ct2/show/NCT03324932 (date received 30 October 2017).
    1. Sakaguchi K, Ono H, Nakatsukasa K, Ishikawa T, Hasegawa Y, Takahashi M, et al. Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer. Medicine 2019;98(32):e16770. - PMC - PubMed

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