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Meta-Analysis
. 2017 Oct 30;10(10):CD003474.
doi: 10.1002/14651858.CD003474.pub4.

Bisphosphonates and other bone agents for breast cancer

Brent O'Carrigan  1 , Matthew Hf Wong, Melina L Willson, Martin R Stockler, Nick Pavlakis, Annabel Goodwin
Affiliations
Meta-Analysis

Bisphosphonates and other bone agents for breast cancer

Brent O'Carrigan et al. Cochrane Database Syst Rev. .

Abstract

Background: Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab inhibit other key bone metabolism pathways. We have studied these agents in both early breast cancer and advanced breast cancer settings. This is an update of the review originally published in 2002 and subsequently updated in 2005 and 2012.

Objectives: To assess the effects of bisphosphonates and other bone agents in addition to anti-cancer treatment: (i) in women with early breast cancer (EBC); (ii) in women with advanced breast cancer without bone metastases (ABC); and (iii) in women with metastatic breast cancer and bone metastases (BCBM).

Search methods: In this review update, we searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 19 September 2016.

Selection criteria: We included randomised controlled trials (RCTs) comparing: (a) one treatment with a bisphosphonate/bone-acting agent with the same treatment without a bisphosphonate/bone-acting agent; (b) treatment with one bisphosphonate versus treatment with a different bisphosphonate; (c) treatment with a bisphosphonate versus another bone-acting agent of a different mechanism of action (e.g. denosumab); and (d) immediate treatment with a bisphosphonate/bone-acting agent versus delayed treatment of the same bisphosphonate/bone-acting agent.

Data collection and analysis: Two review authors independently extracted data, and assessed risk of bias and quality of the evidence. The primary outcome measure was bone metastases for EBC and ABC, and a skeletal-related event (SRE) for BCBM. We derived risk ratios (RRs) for dichotomous outcomes and the meta-analyses used random-effects models. Secondary outcomes included overall survival and disease-free survival for EBC; we derived hazard ratios (HRs) for these time-to-event outcomes where possible. We collected toxicity and quality-of-life information. GRADE was used to assess the quality of evidence for the most important outcomes in each treatment setting.

Main results: We included 44 RCTs involving 37,302 women.In women with EBC, bisphosphonates were associated with a reduced risk of bone metastases compared to placebo/no bisphosphonate (RR 0.86, 95% confidence interval (CI) 0.75 to 0.99; P = 0.03, 11 studies; 15,005 women; moderate-quality evidence with no significant heterogeneity). Bisphosphonates provided an overall survival benefit with time-to-event data (HR 0.91, 95% CI 0.83 to 0.99; P = 0.04; 9 studies; 13,949 women; high-quality evidence with evidence of heterogeneity). Subgroup analysis by menopausal status showed a survival benefit from bisphosphonates in postmenopausal women (HR 0.77, 95% CI 0.66 to 0.90; P = 0.001; 4 studies; 6048 women; high-quality evidence with no evidence of heterogeneity) but no survival benefit for premenopausal women (HR 1.03, 95% CI 0.86 to 1.22; P = 0.78; 2 studies; 3501 women; high-quality evidence with no heterogeneity). There was evidence of no effect of bisphosphonates on disease-free survival (HR 0.94, 95% 0.87 to 1.02; P = 0.13; 7 studies; 12,578 women; high-quality evidence with significant heterogeneity present) however subgroup analyses showed a disease-free survival benefit from bisphosphonates in postmenopausal women only (HR 0.82, 95% CI 0.74 to 0.91; P < 0.001; 7 studies; 8314 women; high-quality evidence with no heterogeneity). Bisphosphonates did not significantly reduce the incidence of fractures when compared to placebo/no bisphosphonates (RR 0.77, 95% CI 0.54 to 1.08, P = 0.13, 6 studies, 7602 women; moderate-quality evidence due to wide confidence intervals). We await mature overall survival and disease-free survival results for denosumab trials.In women with ABC without clinically evident bone metastases, there was no evidence of an effect of bisphosphonates on bone metastases (RR 0.96, 95% CI 0.65 to 1.43; P = 0.86; 3 studies; 330 women; moderate-quality evidence with no heterogeneity) or overall survival (RR 0.89, 95% CI 0.73 to 1.09; P = 0.28; 3 studies; 330 women; high-quality evidence with no heterogeneity) compared to placebo/no bisphosphonates however the confidence intervals were wide. One study reported a trend towards an extended period of time without a SRE with bisphosphonate compared to placebo (low-quality evidence). One study reported quality of life and there was no apparent difference in scores between bisphosphonate and placebo (moderate-quality evidence).In women with BCBM, bisphosphonates reduced the SRE risk by 14% (RR 0.86, 95% CI 0.78 to 0.95; P = 0.003; 9 studies; 2810 women; high-quality evidence with evidence of heterogeneity) compared with placebo/no bisphosphonates. This benefit persisted when administering either intravenous or oral bisphosphonates versus placebo. Bisphosphonates delayed the median time to a SRE with a median ratio of 1.43 (95% CI 1.29 to 1.58; P < 0.00001; 9 studies; 2891 women; high-quality evidence with no heterogeneity) and reduced bone pain (in 6 out of 11 studies; moderate-quality evidence) compared to placebo/no bisphosphonate. Treatment with bisphosphonates did not appear to affect overall survival (RR 1.01, 95% CI 0.91 to 1.11; P = 0.85; 7 studies; 1935 women; moderate-quality evidence with significant heterogeneity). Quality-of-life scores were slightly better with bisphosphonates than placebo at comparable time points (in three out of five studies; moderate-quality evidence) however scores decreased during the course of the studies. Denosumab reduced the risk of developing a SRE compared with bisphosphonates by 22% (RR 0.78, 0.72 to 0.85; P < 0.001; 3 studies, 2345 women). One study reported data on overall survival and observed no difference in survival between denosumab and bisphosphonate.Reported toxicities across all settings were generally mild. Osteonecrosis of the jaw was rare, occurring less than 0.5% in the adjuvant setting (high-quality evidence).

Authors' conclusions: For women with EBC, bisphosphonates reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates. There is preliminary evidence suggestive that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate. This was not a planned subgroup for these early trials, and we await the completion of new large clinical trials assessing benefit for postmenopausal women. For women with BCBM, bisphosphonates reduce the risk of developing SREs, delay the median time to an SRE, and appear to reduce bone pain compared to placebo or no bisphosphonate.

PubMed Disclaimer

Conflict of interest statement

BOC: none known MW: none known MLW: none known MS: none known NP: none known AG: none known

Figures

1
1
Study flow diagram
 ABC: advanced breast cancer; ASCO: American Society of Clinical Oncology; BCBM: breast cancer with bone metastases; EBC: early breast cancer; SABCS: San Antonio Breast Cancer Symposium
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Forest plot of comparison: 3 Early breast cancer (EBC), outcome: 3.1 Incidence of bone metastases in EBC: bisphosphonate versus control
4
4
Forest plot of comparison: 1 Early Breast Cancer (EBC), outcome: 1.7 Overall survival: time‐to‐event outcome.
5
5
Funnel plot of comparison: 1 Early Breast Cancer (EBC), outcome: 1.7 Overall survival: time‐to‐event outcome.
6
6
Forest plot of comparison: 1 Early Breast Cancer (EBC), outcome: 1.11 Overall survival by menopausal status: time‐to‐event outcome.
7
7
Funnel plot of comparison: 1 Early Breast Cancer (EBC), outcome: 1.13 Disease‐free survival: time‐to‐event outcome.
8
8
Forest plot of comparison: 2 Advanced breast cancer (ABC), outcome: 2.1 Incidence of bone metastases in ABC (Stage III/IV)
9
9
Forest plot of comparison: 1 Breast cancer and Bone Metastases (BCBM), outcome: 1.2 Overall risk of SREs in BCBM: bisphosphonate versus control (excluding hypercalcaemia).
10
10
Forest plot of comparison: 1 Breast cancer with bone metastases (BCBM), outcome: 1.3 Overall risk of skeletal events in BCBM: denosumab versus bisphosphonate
See this image and copyright information in PMC

Update of

References

References to studies included in this review

ABCSG‐12 2011 {published data only}
    1. Gnant M, Mlineritsch B, Luschin‐Ebengreuth G, Stoeger H, Dubsky P, Jakesz R, et al. Long‐term follow‐up in ABCSG‐12: significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine‐receptor‐positive early breast cancer. Cancer Research 2011;71:S1‐2.
    1. Gnant M, Mlineritsch B, Schippinger W, Luschin‐Ebengreuth G, Pöstlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. New England Journal of Medicine 2009;360(7):679‐91. - PubMed
    1. Gnant M, Mlineritsch B, Stoeger H, Luschin‐Ebengreuth G, Heck D, Menzel C, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early‐stage breast cancer: 62‐month follow‐up from the ABCSG‐12 randomised trial. Lancet Oncology 2011;12(7):631‐41. - PubMed
    1. Gnant M, Mlineritsch B, Stoeger H, Luschin‐Ebengreuth G, Knauer M, Moik M, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozole plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Annals of Oncology 2015; Vol. 26, issue 2:313‐20. - PubMed
    1. Gnant M, Mlineritsch B, Stoeger H, Luschin‐Ebengreuth G, Poestlberger S, Dubsky PC, et al. Mature results from ABCSG‐12: adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine‐responsive early breast cancer. Journal of Clinical Oncology 2010;28(15 Suppl):533.
ABCSG‐18 2015 {published data only}
    1. Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. Adjuvant denosumab in breast cancer (ABCSG‐18): a multicentre, randomised, double‐blind, placebo‐controlled trial. Lancet 2015;386(9992):433–43. [NCT00556374] - PubMed
    1. Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. Adjuvant denosumab in breast cancer: results from 3,425 post‐menopausal patients of the ABCSG18 trial. Journal of Clinical Oncology 2015;33(15 Suppl):504. [0732‐183X]
    1. Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. The impact of adjuvant denosumab on disease‐free survival: results from 3,425 postmenopausal patients of the ABCSG‐18 trial. Cancer Research 2016;76(4 Suppl):S2‐02. [0008‐5472]
Aft 2012 {published data only}
    1. Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez‐MacGregor M, et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncology 2010;11(5):421‐8. - PMC - PubMed
    1. Aft RL, Naughton M, Trinkaus K, Weilbaecher K. Effect of (neo)adjuvant zoledronic acid on disease‐free and overall survival in clinical stage II/III breast cancer. British Journal of Cancer 2012;107(1):7‐11. - PMC - PubMed
AREDIA 1998 {published data only}
    1. Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C, et al. Long‐term prevention of skeletal complications of metastatic breast cancer with pamidronate. Journal of Clinical Oncology 1998;16(6):2038‐44. - PubMed
    1. Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. New England Journal of Medicine 1996;335(24):1785‐91. - PubMed
    1. Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. Cancer 2000;88(5):1082‐90. - PubMed
    1. Theriault RL, Lipton A, Hortobagyi GN, Leff R, Gluck S, Stewart JF, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomised, placebo‐controlled trial. Journal of Clinical Oncology 1999;17(3):846‐54. - PubMed
AZURE 2014 {published data only}
    1. Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, et al. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open‐label phase 3 trial. Lancet Oncology 2014;15(9):997‐1006. - PubMed
    1. Coleman R, Woodward E, Brown J, Cameron D, Bell R, Dodwell D, et al. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01‐04) for women with stage II/III breast cancer. Breast Cancer Research and Treatment 2011;127(2):429‐38. - PubMed
    1. Coleman R, Woodward E, Turner L, Marshall H, Collinson M, Dodwell D, et al. Impact of zoledronic acid on fractures, bone mineral density and bone remodeling in the AZURE trial (BIG 01‐04). Cancer Research 2011;71(24 Suppl):P2‐19‐01.
    1. Coleman RE, Marshall H, Cameron D, Dodwell D, Burkinshaw R, Keane M, et al. Breast‐cancer adjuvant therapy with zoledronic acid. New England Journal of Medicine 2011;365(15):1396‐405. - PubMed
    1. Coleman RE, Rathbone EJ, Marshall HC, Wilson C, Brown JE, Gossiel F, et al. Vitamin D, but not bone turnover markers, predict relapse in women with early breast cancer: an AZURE translational study. Cancer Research 2012;72(24 Suppl):S6‐4.
Body 2003 {published data only}
    1. Body JJ, Diel IJ, Lichinitser MR, Kreuser ED, Dornoff W, Gorbunova VA, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Annals of Oncology 2003;14(9):1399‐405. - PubMed
    1. Body JJ, Lichinitser MR, Diehl I, Schlosser K, Pfarr E, Cavalli F, et al. Double‐blind placebo‐controlled trial of intravenous ibandronate in breast cancer metastatic to bone. Annual Meeting of the American Society of Clinical Oncology (ASCO); 1999; Chicago. Chicago: American Society of Clinical Oncology, 1999; Vol. 18:575a.
    1. Diel IJ, Body JJ, Lichinitser MR, Kreuser ED, Dornoff W, Gorbunova VA, et al. Improved quality of life after long‐term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer. European Journal of Cancer 2004;40(11):1704‐12. - PubMed
    1. Lyubimova N, Kushlinksky NE, Lichinitser MR. Long‐term treatment with intravenous ibandronate does not affect renal function in breast cancer patients with metastatic bone disease. 15th Annual Multinational Association of Supportive Care in Cancer (MASCC) Meeting; 2003. New York: Supportive Care in Cancer, 2003.
Body 2004 {published data only}
    1. Body JJ, Diel I, Bell R, Pecherstorfer M, Lichinitser M, Lazarev A, et al. Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 2004;111(3):306‐12. - PubMed
    1. Body JJ, Diel IJ, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo‐controlled phase III studies. British Journal of Cancer 2004;90(6):1133‐7. - PMC - PubMed
CALGB‐70604 2015 {published data only}
    1. Himelstein AL, Qin R, Novotny PJ, Seisler DK, Khatcheressian JL, Roberts JD, et al. CALGB 70604 (Alliance): a randomized phase III study of standard dosing vs. longer interval dosing of zoledronic acid in metastatic cancer. Journal of Clinical Oncology 2015; Vol. 33, issue 15 Suppl:9501. [0732‐183X]
    1. NCT00869206. Zoledronic acid in treating patients with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma with bone involvement. clinicaltrials.gov/ct2/show/NCT00869206 Date first received: 24 March 2009.
Conte 1996 {published data only}
    1. Conte PF, Giannessi PG, Latreille J, Mauriac L, Koliren L, Cabresi F, et al. Delayed progression of bone metastases with pamidronate therapy in breast cancer patients: a randomised, multicenter phase III trial. Annals of Oncology 1994;5(Suppl 7):41‐4. - PubMed
    1. Conte PF, Latrielle J, Mauriac L, Calbresi F, Santos R, Campos D, et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomised controlled trial. Journal of Clinical Oncology 1996;14(9):2552‐9. - PubMed
Diel 1998 {published data only}
    1. Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallweiner 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. 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):2007‐201. - PMC - PubMed
    1. Jaschke A, Bastert G, Solomayer EF, Costa S, Scheutz F, Diel JJ. Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow: a long‐term follow‐up. Journal of Clinical Oncology 2004;22(14 Suppl):529.
Diel 1999 {published data only}
    1. Diel IJ, Marschner N, Kindler M, Lange O, Untach M, Hurtz HJ, et al. Continual oral versus intravenous interval therapy with bisphosphonates in patients with breast cancer and bone metastases (abstract 488). Annual Meeting of the American Society of Clinical Oncology (ASCO); 1999; Chicago. Chicago: American Society of Clinical Oncology, 1999.
Elomaa 1983 {published data only}
    1. Elomaa I, Blomqvist C, Grohn P, Porkka L, Kairento A‐L, Selander K, et al. Long‐term controlled trial with diphosphonate in patients with osteolytic bone metastases. Lancet 1983;1(8317):146‐9. - PubMed
    1. Elomaa I, Blomqvist C, Porkka, Holtstrom T, Taube T, Lamberg‐Allardt C, et al. Clodronate for osteolytic metastases due to breast cancer. Biomedicine and Pharmacotherapy 1988;42(2):111‐6. - PubMed
    1. Elomma I, Blomqvist L, Porkka L, Lamberg‐Allardt C, Borgstrom GH. Treatment of skeletal disease in breast cancer: a controlled clodronate trial. Bone 1987;8(Suppl 1):53‐6. - PubMed
E‐ZO‐FAST 2012 {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. Llombarto A, Frassoldati A, Paija O, Sleeboom HP, Jerusalem G, Mebis J, et al. Effect of zoledronic acid on aromatase inhibitor‐associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: E‐ZO‐FAST 36‐month follow‐up. ASCO Breast Cancer Symposium; 2009; Chicago. Chicago: American Society of Clinical Oncology, 2009.
Fizazi 2009 {published and unpublished data}
    1. Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. Journal of Clinical Oncology 2009;27(10):1564‐71. - PubMed
    1. Suarez T, Fizazi K, Rahim Y, Wilson J, Fan M, Jun S, et al. A randomized trial of denosumab (AMG 162) versus intravenous (IV) bisphosphonates (BP) in cancer patients (pts) with bone metastases (BM) on established IV BP and evidence of elevated bone resorption. Journal of Clinical Oncology 2006;24(18 Suppl):8562.
GAIN 2013 {published and unpublished data}
    1. Moebus VJ, Minckwitz G, Jackisch C, Lueck H‐J, Schneeweiss A, Tesch H, et al. German Adjuvant Intergroup Node Positive (GAIN) study: a phase III trial to compare IDD‐ETC versus EC‐TX in patients with node‐positive primary breast cancer‐final efficacy analysis. Journal of Clinical Oncology 2014;32(5 Suppl):1009.
    1. Möbus V, Diel I J, 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):S2‐4.
    1. NCT00196872. A study to compare ETC vs EC‐TX and ibandronate vs observation in patients with node‐positive primary breast cancer. clinicaltrials.gov/ct2/show/NCT00196872 Date first received: 12 September 2005.
    1. Minckwitz G, Mobus V, Schneeweiss A, Huober J, Thomssen C, Untch M, et al. German Adjuvant Intergroup Node‐positive study: a phase III trial to compare oral ibandronate versus observation in patients with high‐risk early breast cancer. Journal of Clinical Oncology 2013;31(28):3531‐9. - PubMed
Heras 2009 {published data only}
    1. Heras P, Hatzopoulos A, Mitsibounas D. Efficacy of ibandronate for the prevention of skeletal‐related events in breast cancer patients with metastatic bone disease. European Journal of Cancer 2005;3(2):121.
    1. Heras P, Kritikos K, Hatzopoulos A, Georgopoulou AP. Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancer. European Journal of Cancer Care 2009;18(6):653‐6. - PubMed
Hershman 2008 {published data only}
    1. Hershman DL, McMahon DJ, Crew KD, Cremers S, Irani D, Cucchiara G, 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. 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
Hultborn 1999 {published data only}
    1. Hultborn R, Gundersen S, Ryden S, Holmberg E, Carstensen J, Wallgren UB, et al. Efficacy of pamidronate in breast cancer with bone metastases: a randomised, double‐blind placebo‐controlled multicenter study. Anticancer Research 1999;19(4C):3383‐92. - PubMed
Kanis 1996 {published data only}
    1. Kanis JA, Powles T, Paterson AH, McCloskey EV, Ashley S. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 1996;19(6):663‐7. - PubMed
Kohno 2005 {published data only}
    1. Kohno N, Aogi K, Minami H, Nakamura S, Asaga T, Iino Y, et al. Zolendronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomised, placebo‐controlled trial. Journal of Clinical Oncology 2005;23(15):3314‐21. - PubMed
Kristensen 1999 {published data only}
    1. Kristensen B, Ejlertsen B, Groenvold M, Hein S, Loft H, Mouridsen HT. Oral clodronate in breast cancer patients with bone metastases: a randomised study. Journal of Internal Medicine 1999;246(1):67‐74. - PubMed
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 2008;47(4):740‐6. - PubMed
Lipton 2008 {published data only}
    1. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal‐Celigny P, Body JJ, et al. Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clinical Cancer Research 2008;14(20):6690‐6. - PubMed
    1. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal‐Celigny P, Body JJ, et al. Randomized active‐controlled phase II study of denosumab efficacy and safety in patients with breast cancer‐related bone metastases. Journal of Clinical Oncology 2007;25(28):4431‐7. - PubMed
Mardiak 2000 {published data only}
    1. Mardiak J, Bohunicky L, Chovanec J, Salek T, Koza I. Adjuvant clodronate therapy in patients with locally advanced breast cancer ‐ long term results of a double blind randomised trial. Neoplasma 2000;47(3):177‐80. - PubMed
Martoni 1991 {published data only}
    1. Martoni A, Guaraldi M, Camera P, Biagi R, Marri S, Beghe F, et al. Controlled clinical study on the use of dichloromethylene diphosphonate in patients with breast carcinoma metastasizing to the skeleton. Oncology 1991;48(2):97‐101. - PubMed
NATAN 2016 {published data only}
    1. 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. NCT00512993. Postoperative use of zoledronic acid in breast cancer patients after neoadjuvant chemotherapy (NATAN). clinicaltrials.gov/ct2/show/NCT00512993 Date first received: 3 August 2007.
    1. 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.
NSABP‐34 2012 {published data only}
    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; Vol. 13, issue 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. Cancer Research 2011;71(24 Suppl):S2‐3.
OPTIMIZE‐2 2014 {published data only}
    1. Hortobagyi GN, Lipton A, Chew HK, Gradishar WJ, Sauter NP, Mohanlal RW, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: results of the OPTIMIZE‐2 trial. Journal of Clinical Oncology 2014;32(5 Suppl):LBA9500.
    1. NCT00320710. Efficacy and safety of zoledronic acid (every 4 weeks vs every 12 weeks) in patients with documented bone metastases from bone cancer. clinicaltrials.gov/ct2/show/NCT00320710 Date first received: 28 April 2006.
Paterson 1993 {published data only}
    1. Paterson AHG, Kanis JA, Powles TJ, McCloskey EV, Archabault WT, Kurman MR, et al. A re‐analysis of a trial of clodronate in patients with breast cancer and bone metastases. Anthra Pharmaceuticals.
    1. Paterson AHG, Powles TJ, Kanis JA, McCloskey E, Hanson J, Ashley S. Double‐blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. Journal of Clinical Oncology 1993;11(1):59‐65. - PubMed
Powles 2006 {published data only}
    1. Atula ST, Paterson AHG, Powles TJ, McLoskey EV, Nevalainen JI, Kanis JA. Extended safety profile of oral clodronate after long‐term use in primary breast cancer patients. Drug Safety 2003;26(9):661‐71. - PubMed
    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 2009;46(3):558‐65. - PubMed
    1. Powles T, McCloskey E, Kurkilahti M, Kurkilahti M, Kanis J. Oral clodronate for the adjuvant treatment of operable breast cancer: results of a randomised, double‐blind, placebo‐controlled multicenter trial. Journal of Clinical Oncology 2004;22(14 Suppl):528.
    1. Powles T, Paterson A, McCloskey E, Schein P, Scheffler B, Tidy A, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer. Breast Cancer Research 2006;8(2):13. - PMC - PubMed
    1. Powles T, Paterson S, Kanis JA, McCloskey E, Ashley S, Tidy A, et al. Randomized, placebo‐controlled trial of clodronate in patients with primary operable breast cancer. Journal of Clinical Oncology 2002;20(15):3219‐24. - PubMed
Rosen 2004 {published and unpublished data}
    1. Rosen L, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Long term efficacy and safety of zolendronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma. Cancer 2003;98(8):1735‐44. - PubMed
    1. Rosen LS, Gordon D, Dugan W, Major P, Eisenberg PD, Provencher L, et al. Zolendronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100(1):36‐43. - PubMed
    1. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Zolendronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double‐blind, comparative trial. Cancer 2001;7(5):377‐87. - PubMed
Saarto 2004 {published data only}
    1. Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node‐positive breast cancer patients: 5 year results of a randomised controlled study. Journal of Clinical Oncology 2001;19(1):10‐17. - PubMed
    1. Saarto T, Vehmanen L, Virkkunen P, Blomqvist C. Ten‐year follow‐up of a randomized controlled trial of adjuvant clodronate treatment in node‐positive breast cancer patients. Acta Oncologica 2004;43(7):650‐6. - PubMed
Stopeck 2010 {published data only}
    1. Body JJ, Moos R, Stopeck A, Qian Y, Braun A, Chung K. Health resource utilization of subjects receiving denosumab and zoledronic acid in a randomized phase 3 trial of advanced breast cancer patients with bone metastases. Value in Health 2010;13:A279.
    1. Cleeland CS, Body JJ, Stopeck A, Moos R, Fallowfield L, Mathias SD, et al. Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double‐blind study of denosumab and zoledronic acid. Cancer 2013;119(4):832‐8. - PubMed
    1. Boer R, Steger G, Moos R, Martin M, Stopeck A, Tonkin K, et al. A number needed to treat (NNT) analysis of the benefit of denosumab therapy among patients with breast cancer and bone metastases (BMS). Journal of Oncology Pharmacy Practice 2012;18:22.
    1. Boer RH, Stopeck A, Fallowfield L, Patrick D, Cleeland CS, Steger GG, et al. Pain in patients with metastatic breast cancer: results from a phase III trial of denosumab versus zoledronic acid. Asia‐Pacific Journal of Clinical Oncology 2012;8:40.
    1. Boer RH, Stopeck AT, Lipton A, Martin M, Body JJ, Paterson A, et al. Denosumab in patients with breast cancer and bone metastases previously treated with zoledronic acid or denosumab: a pre‐specified two year open‐label extension treatment phase of a pivotal phase iii study. Asia‐Pacific Journal of Clinical Oncology 2012;8:44.
SWOG‐S0307 2015 {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. [0732‐183X]
    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 Oncoloy 2014;32(15 Suppl):558.
    1. NCT00127205. Zoledronate, clodronate, or ibandronate in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer. clinicaltrials.gov/ct2/show/NCT00127205 (accessed 30 April 2011); Vol. Date first received: 3 August 2005.
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. Tevaarwerk A, Stewart JA, Love R, Binkley NC, Black S, Eickhoff S, 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.
Tripathy 2004 {published data only}
    1. Tripathy D, Lichinitzer M, Lazarev A, MacLachian A, Apffelstaedt J, Budde M, et al. Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomised, double‐blind, placebo‐controlled trial. Annals of Oncology 2004;15(5):743‐50. - PubMed
Tubiana‐Hulin 2001 {published data only}
    1. Tubiana‐Hulin M, Beuzeboc P, Mauriac L, Barbet N, Frenay M, Monnier A, et al. Double‐blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases. Bulletin du Cancer 2001;88(7):701‐7. - PubMed
Van‐Holten 1987 {published data only}
    1. Cleton FJ, Holten‐Verzantvoort AT, Bijvoet OLM. Effect of long‐term bisphosphonate treatment on morbidity due to bone metastases in breast cancer patients. Recent Results in Cancer Research. Vol. 116, Berlin‐Heidelberg: Springer‐Verlag, 1989:73‐8. - PubMed
    1. Holten‐Vaerzantvoort ATM, Kroon HM, Bijvoet OLM, Cleton FJ, Beex LVAM, Blijham G, et al. Palliative pamidronate treatment in patients with bone metastases from breast cancer. Journal of Clinical Oncology 1993;11(3):491‐8. - PubMed
    1. Holten‐Verzantvoort AT, Bijvoet OLM, Cleton FJ, Hermans J, Kroon HM, Harinck HIJ, et al. Reduced morbidity from skeletal metastases in breast cancer patients during long‐term bisphosphonate (APD) treatment. Lancet 1987;330(8566):983‐5. - PubMed
    1. Holten‐Verzantvoort ATM, Zwinderman AH, Aaronson NK, Hermans J, Emmerik B, Dam FSAM, et al. The effect of supportive pamidronate treatment on aspects of quality of life of patients with advanced breast cancer. European Journal of Cancer 1991;27(5):544‐9. - PubMed
Van‐Holten 1996 {published data only}
    1. Holten‐Verzantvoort AT, Hermans J, Beex LVAM, Blijham G, Cleton FJ, Eck‐Smit BCF, et al. Does supportive pamidronate treatment prevent or delay the first manifestations of bone metastases in breast cancer patients?. European Journal of Cancer 1996;32A(3):450‐4. - PubMed
von Au 2016 {published data only}
    1. Au A, Milloth E, Diel I, Stefanovic S, Hennigs A, Wallwiener M, et al. Intravenous pamidronate versus oral and intravenous clodronate in bone metastatic breast cancer: a randomized, open‐label, non‐inferiority phase III trial. OncoTargets and Therapy 2016; Vol. 2016, issue 9:4173‐80. - PMC - PubMed
Z‐FAST 2012 {published data only}
    1. Brufsky A, Bundred N, Coleman R, Lambert‐Falls R, Mena R, Hadji P, et al. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor‐associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 2008;13(5):503‐14. - PubMed
    1. Brufsky A, Harker WG, Beck JT, Carroll R, Tan‐Chiu E, Seidler C, et al. Zoledronic acid inhibits adjuvant letrozole‐induced bone loss in postmenopausal women with early breast cancer. Journal of Clinical Oncology 2007;25(7):829‐36. - PubMed
    1. Brufsky AM, Harker WG, Beck JT, Bosserman L, Vogel C, Seidler C, et al. Final 5‐year results of Z‐FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer 2012;118(5):1192‐201. - PubMed
    1. Brufsky AM, Bosserman LD, Caradonna RR, Haley BB, Jones CM, Moore HC, et al. Zoledronic acid effectively prevents aromatase inhibitor‐associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z‐FAST study 36‐month follow‐up results. Clinical Breast Cancer 2009;9(2):77‐85. - PubMed
ZICE 2014 {published data only}
    1. Barrett‐Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, et al. Erratum [Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non‐inferiority phase 3 trial]. Lancet Oncology 2014;15(2):e52‐3. - PubMed
    1. Barrett‐Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non‐inferiority phase 3 trial. Lancet Oncology 2014;15(1):114‐22. - PubMed
    1. Barrett‐Lee PJ, Casbard A, Abraham J, Grieve R, Wheatley D, Simmons P, et al. Zoledronate versus ibandronate comparative evaluation (ZICE) trial‐first results of a UK NCRI 1,405 patient phase III trial comparing oral ibandronate versus intravenous zoledronate in the treatment of breast cancer patients with bone metastases. Cancer Research 2012;72(24 Suppl):PD07‐09.
    1. NCT00326820. Ibandronate or zoledronate in treating patients with newly diagnosed bone metastases from breast cancer. clinicaltrials.gov/ct2/show/NCT00326820 Date first received: 16 May 2006.
    1. Nelson A, Fenlon D, Morris J, Sampson C, Harrop E, Murray N, et al. QUALZICE: a QUALitative exploration of the experiences of the participants from the ZICE clinical trial (metastatic breast cancer) receiving intravenous or oral bisphosphonates. Trials 2013;14:325. - PMC - PubMed
ZO‐FAST 2013 {published data only}
    1. Coleman R, 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, Boer R, Eidtmann H, Neven P, 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 analysis from the ZO‐FAST trial. Cancer Research 2011;71(24 Suppl):P2‐17‐01.
    1. Boer R, Bundred N, Eidtmann H, Neven P, Minckwitz G, Martin N, et al. Long‐term survival outcomes among postmenopausal women with hormone receptor‐positive early breast cancer receiving adjuvant letrozole and zoledronic acid: 5‐year follow‐up of ZO‐FAST. Cancer Research 2011;71(24 Suppl):S1‐3.
    1. Boer R, Martin M, Steger GG, Moos R, Stopeck A, Tonkin K, et al. Assessing the benefit of denosumab therapy among patients with breast cancer and bone metastases (BMs): a number‐needed‐to‐treat (NNT) analysis. Asia‐Pacific Journal of Clinical Oncology 2011;7(3 Suppl):9.
    1. Eidtmann H, Boer R, Bundred N, Llombart‐Cussac A, Davidson N, Neven P, et al. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36‐month results of the ZO‐FAST Study. Annals of Oncology 2010;21(11):2188‐94. - PubMed
ZOOM 2013 {published data only}
    1. Amadori D, Aglietta M, Alessi B, Gianni L, Ibrahim T, Farina G, et al. Efficacy and safety of 12‐weekly versus 4‐weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open‐label, randomised, non‐inferiority trial. Lancet Oncology 2013;14(7):663‐70. - PubMed
    1. NCT00375427. Safety and efficacy of zoledronic acid in patients with breast cancer with metastatic bone lesions. clinicaltrials.gov/ct2/show/NCT00375427 Date first received: 12 September 2006.

References to studies excluded from this review

ANZAC 2013 {published data only}
    1. NCT00525759. Investigating the biological effects of the addition of zoledronic acid to pre‐operative chemotherapy in breast cancer (ANZAC). clinicaltrials.gov/ct2/show/NCT00525759 Date first received: 5 September 2007.
    1. Winter MC, Wilson C, Syddall SP, Cross SS, Evans A, Ingram CE, et al. Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer‐‐a randomized biomarker pilot study. Clinical Cancer Research 2013;19(10):2755‐65. - PubMed
Berenson 2001 {published data only}
    1. Berenson JR, Rosen LS, Howell A, Porter L, Coleman RE, Morley W, et al. Zolendronic acid reduces skeletal‐related events in patients with osteolytic metastases: a double‐blind, randomised dose‐response study. Cancer 2001;91(7):1191‐200. - PubMed
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
Fuleihan 2005 {published data only}
    1. Fuleihan G, Salamoun M, Mourad Y, Chehal A, Salem Z, Mahfoud Z, et al. Pamidronate in the prevention of chemotherapy‐induced bone loss in premenopausal women with breast cancer: a randomised controlled trial. Journal of Endocrinology and Metabolism 2005;90(6):3209‐14. - PubMed
Greenspan 2008 {published data only}
    1. Greenspan S, Perera S, Vujevich K, 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 2013;28(1 Suppl):1050.
    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
Hines 2009 {published data only}
    1. Hines S, Mincey B, Sloan J, Thomas S, Chottiner E, Loprinzi C, 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
Jagdev 2001 {published data only}
    1. Jagdev SP, Purohity P, Heatley S, Herling C, Coleman RE. Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Annals of Oncology 2001;12(10):1433‐8. - PubMed
Kokufu 2010 {published data only}
    1. Kokufu I, Kohno N, Yamamoto M, Takao S. Adjuvant pamidronate therapy prevents the development of bone metastases in breast cancer patients with four or more positive nodes. Oncology Letters 2010;1(2):247‐52. - PMC - PubMed
Leppa 2005 {published data only}
    1. Leppa S, Saarto T, Vehmanen L, Blomqvist C, Elomaa I. Clondronate treatment influences MMP‐2 associated outcome in node positive breast cancer. Breast Cancer Research and Treatment 2005;90:117‐25. - PubMed
Mathevet 2016 (NEOZOL) {published data only}
    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. [0008‐5472]
McCloskey 2009 {published data only}
    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 2009;46(3):558‐65. - PubMed
ProBONE II 2015 {published data only}
    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;144:343‐51. - 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
    1. Kalder M, Kyvernitakis I, Albert US, Baier‐Ebert M, Hadji P. Effects of zoledronic acid versus placebo on bone mineral density and bone texture analysis assessed by the trabecular bone score in premenopausal women with breast cancer treatment‐induced bone loss: results of the ProBONE II substudy. Osteoporosis International 2015;26(1):353‐60. - PubMed
Saarto 2005 {published data only}
    1. Saarto T, Taube T, Blomqvist C, Vehmanen L, Elomaa I. Three‐year oral clodronate treatment does not impair mineralization of newly formed bone‐a histomorphometric study. Calcified Tissue International 2005;77(2):84‐90. - PubMed
    1. Saarto T, Vehmanen L, Virkkunen P, Blomqvist C. Ten‐year follow‐up of a randomised controlled trial of adjuvant clodronate treatment in node‐positive breast cancer patients. Acta Oncology 2004;43(7):650‐6. - PubMed
Scotti 2014 (BONADIUV) {published data only}
    1. Livi L, Meattini I, Scotti V, Saieva C, Desideri I, Carta GA, et al. BONADIUV trial: a single blind, randomized placebo controlled phase II study using oral ibandronate for osteopenic women receiving adjuvant aromatase inhibitors: final safety analysis. Journal of Clinical Oncology 2016;34(15 Suppl):e12043. [1527‐7755]
    1. Scotti V, Meattini I, Cecchini S, Feo ML, Saieva C, Luca Cardillo C, et al. A single‐blind, randomized, placebo‐controlled phase II study to evaluate the impact of oral bisphosphonate treatment on bone mineral density in osteopenic women receiving adjuvant aromatase inhibitors: Interim analysis of "BONADIUV" trial. Journal of Clinical Oncology 2014;32:TPS658.
Sestak 2014 (IBIS‐II) {published data only}
    1. Sestak I, Singh S, Cuzick J, Blake GM, Patel R, Gossiel F, et al. Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS‐II bone substudy: an international, double‐blind, randomised, placebo‐controlled trial. Lancet Oncology 2014;15(13):1460‐8. [ISRCTN31488319] - PubMed
    1. Sestak I, Singh S, Cuzick J, Blake GM, Patel R, Gossiel F, et al. Correction to Lancet Oncology 2014; 15: 1464. Lancet Oncology 2014;15(13):e587.
Siris 1983 {published data only}
    1. Siris ES, Hyman GA, Canfield RE. Effects of dichloromethylene diphosphonate in women with breast carcinoma metastatic to the skeleton. American Journal of Medicine 1983;74(3):401‐6. - PubMed
Vehmanen 2001 {published data only}
    1. Vehmanen L, Saarto T, Elomaa I, Makela P, Valimaki M, Blomqvist C. Long‐term impact of chemotherapy‐induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment. Breast Cancer Research and Treatment 2001;37:2373‐8. - PubMed
Vehmanen 2004 {published data only}
    1. Vehmanen L, Saarto T, Risteli J, Risteli L, Blomqvist C, Elomaa I. Short‐term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy‐induced ovarian failure. Breast Cancer Research and Treatment 2004;87:181‐8. - PubMed
Weinfurt 2004 {published data only}
    1. Weinfurt KP, Catel LD, Li Y, Timie JW, Glendenning GA, Schulman KA. Health‐related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions. Medical Care 2004;42(2):164‐75. - PubMed

References to studies awaiting assessment

BISMARK 2012 {published data only}
    1. Coleman RE, Wright J, Houston S, Agrawal R, Purohit OP, Hayward L, et al. Randomized trial of marker‐directed versus standard schedule zoledronic acid for bone metastases from breast cancer. Journal of Clinical Oncology 2012;30(15 Suppl (May 2012)):511.
    1. NCT00458796. Comparison of two schedules of zoledronic acid in treating patients with breast cancer that has spread to the bone. clinicaltrials.gov/ct2/show/NCT00458796 Date first received: 9 April 2007.

References to ongoing studies

Amir 2013 {published data only}
    1. Addison CL, Zhao H, Mazzarello S, Mallick R, Amir E, Tannock I, et al. Effects of de‐escalated bisphosphonate therapy on bone turnover or metastasis markers and their correlation with risk of skeletal related events ‐ a biomarker analysis in conjunction with the REFORM study. Cancer Research 2012;72(24 Suppl):P2‐05‐12.
    1. Amir E, Freedman O, Carlsson L, Dranitsaris G, Tomlinson G, Laupacis A, et al. Randomized feasibility study of de‐escalated (Every 12 wk) versus standard (every 3 to 4 wk) intravenous pamidronate in women with low‐risk bone metastases from breast cancer. American Journal of Clinical Oncology 2013;36(5):436‐42. - PubMed
    1. Amir E, Freedman O, Carlsson L, Usmani T, Lee E, Dranitsaris G, et al. Pilot randomized trial of de‐escalated (q12 weekly) versus standard (q3‐4 weekly) intravenous bisphosphonates in women with low‐risk bone metastases from breast cancer. Cancer Research 2011;71(24 Suppl):P4‐16‐08.
D‐CARE 2011 {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. Goss PE, Barrios CH, Bell R, Finkelstein D, Iwata H, Martin M, et al. A phase 3 randomized, double‐blind, placebo‐controlled multicenter 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). Cancer Research 2011;71(24 Suppl):OT1‐01.
    1. Goss PE, Barrios CH, Bell R, Finkelstein D, Iwata H, Martin M, et al. A randomized, double‐blind, placebo‐controlled multicenter phase III 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). Journal of Clinical Oncology 2011;29(15 Suppl):published online before print.
    1. Goss PE, Barrios CH, Bell R, Finkelstein DM, Iwata H, Martin M, et al. Denosumab versus placebo as adjuvant treatment for women with early‐stage breast cancer who are at high risk of disease recurrence (D‐CARE): an international, randomized, double‐blind, placebo‐controlled phase III clinical trial. Journal of Clinical Oncology 2012;30(15 Suppl):Published online before print.
    1. Goss PE, Barrios CH, Chan A, 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): a global, placebo‐controlled, randomized, double‐blind, phase 3 clinical trial. Cancer Research 2013;73:OT2‐6.
El‐Ibrashi 2016 {published data only}
    1. El‐Ibrashi MM, El‐Sadda WM, bdel‐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. [0008‐5472]
Fallowfield 2015 {published data only}
    1. Fallowfield L, Patrick DL, Moos R, Cleeland CS, Zhou Y, Balakumaran A, et al. The impact of skeletal‐related events on pain interference in patients with advanced breast cancer and bone metastases. Cancer Research 2015;75(9 Suppl):P5‐16‐03.
FEMZONE 2014 {published data only}
    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
HOBOE 2013 {published data only}
    1. NCT00412022. HOBOE: a phase 3 study of adjuvant triptorelin and tamoxifen, letrozole, or letrozole and zoledronic acid in premenopausal patients with breast cancer. clinicaltrials.gov/ct2/show/NCT00412022 Date first received: 14 December 2006.
    1. Nuzzo F, Gallo C, Lastoria S, 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;23:2027‐33. - PubMed
Jacobs 2014 (ODYSSEY) {published data only}
    1. Jacobs CM, Kuchuk I, Smith S, Mazzarello S, Vandermeer L, Bouganim N, et al. A randomized, double‐blind trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronate in patients with high‐risk bone metastases from breast cancer (The Odyssey Study). Journal of Clinical Oncology 2014;32(31 Suppl):155. [Clinicaltrials.gov: NCT01907880] - PubMed
Jiang 2016 {published data only}
    1. Jiang Z, Shao Z, Zhang Q, Yao Y, He J, Liao W, et al. Efficacy and safety of denosumab from a phase III, randomized, active‐controlled study compared with zoledronic acid in patients of Asian ancestry with bone metastases from solid tumors. Journal of Clinical Oncology 2016;34(15 Suppl):10116. [1527‐7755]
JONIE‐1 2013 {published data only}
    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. Miura D, Hasegawa Y, Horiguchi J, Ishikawa T, Hayashi M, Takao S, et al. Disease‐free survival and Ki67 analysis of a randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2‐negative primary breast cancer (JONIE‐1 study). Cancer Research 2013;73(24 Suppl):PD3‐7.
    1. Sangai T, Ishikawa T, Kohno N, Miura D, Sato E, Kaise H, et al. Exploring biomarkers of response to zoledronic acid in breast cancer from clinical trial result of neoadjuvant chemotherapy with zoledronic acid: JONIE‐1 study. Cancer Research 2015;75(9 Suppl):P6‐01‐02. [0008‐5472]
    1. Sangai T, Sato E, Ishikawa T, Kaise H, Hasegawa Y, Miura D, et al. Exploring immunomodulatory effects of zoledronic acid in breast cancer from clinical trial result of neoadjuvant chemotherapy with zoledronic acid: JONIE‐1 study. Cancer Research 2016; Vol. 76, issue 4 Suppl:P4‐09‐25. [0008‐5472]
Kummel 2016 (GeparX) {published data only}
    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. [1527‐7755]
NCT00196895 {published data only}
    1. NCT00196859. Study in elderly patients with early breast cancer (ICE). clinicaltrials.gov/ct2/show/NCT00196859 Date first received: 12 September 2005.
NCT00301886 {published data only}
    1. NCT00301886. Zoledronate or ibandronate in preventing bone problems in women with stage IV breast cancer that has spread to the bone. clinicaltrials.gov/ct2/show/NCT00301886 (accessed 30 April 2011).
NCT00524849 {published data only}
    1. NCT00524849. Zometa and circulating vascular endothelial growth factor (VEGF) in breast cancer patients with bone metastasis. clinicaltrials.gov/ct2/show/NCT00524849 (accessed 30 April 2011).
NCT01129336 {published data only}
    1. NCT01129336. Effect of zoledronic acid as anti‐cancer treatment in metastatic breast cancer patients (Z‐ACT 1). clinicaltrials.gov/ct2/show/NCT01129336 (accessed 30 April 2011).
NEOZOTAC {published data only}
    1. Charehbili A, Hamdy NAT, Smit VTHB, Kessels L, Bochove A, 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 2016;25:69‐74. [0960‐9776] - PubMed
    1. Charehbili A, Hamdy NAT, Smit VTHB, 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, Ven S, 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
    1. Dekker TJA, Charehbili A, Smit VTHB, Ten DP, Meershoek‐Klein KE, Ven S, et al. Disorganised stroma determined on pre‐treatment breast cancer biopsies is associated with poor response to neoadjuvant chemotherapy: results from the NEOZOTAC trial. Molecular Oncology 2015;9(6):1120‐8. [1574‐7891] - PMC - PubMed
    1. Dekker TJA, Charehbili A, Smit VTHB, Wasser MNJM, Heijns JB, Warmerdam LJ, et al. The predictive value of tumor‐stroma ratio for radiological and pathological response to neoadjuvant chemotherapy in breast cancer (BC): a Dutch breast cancer trialists group (BOOG) side‐study. Cancer Research 2013;73(24 Suppl):P1‐06‐04.
SAKK 96/12 2014 {published data only}
    1. NCT02051218. Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks. clinicaltrials.gov/ct2/show/NCT02051218 Date first received: 29 January 2014.
    1. Templeton AJ, Stalder L, Bernhard J, Brauchli P, Gillessen S, Hayoz S, et al. Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks: a noninferiority phase III trial (SAKK 96/12, REDUSE). Journal of Clinical Oncology 2014;32(15 Suppl):published online before print.
SUCCESS 2013 {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. Tumor Diagnostik und Therapie 2013;34:140‐6. - PMC - PubMed
    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. Janni W, Rack B, Fasching P, Haeberle L, Friedl T, 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. Cancer Research 2016;76(4 Suppl):S2‐03. [0008‐5472]
    1. NCT02181101. Simultaneous study of gemcitabine‐docetaxel combination adjuvant treatment, as well as extended bisphosphonate and surveillance‐trial SUCCESS‐Trial. clinicaltrials.gov/ct2/show/NCT02181101 Date first received: 4 June 2014.
TRIUMPH 2012 {published data only}
    1. Addison CL, Bouganim N, Hilton J, Vandermeer L, Dent S, Amir E, et al. A phase II multicentre trial evaluating the efficacy of de‐escalated bisphosphonate therapy in metastatic breast cancer patients at low‐risk of skeletal‐related events. Breast Cancer Research and Treatment 2014;144(3):615‐624. - PMC - PubMed
    1. Bouganim N, Hilton J, Vandermeer L, Hopkins S, Spencer P, Robbins D, et al. A multicentre study assessing 12‐weekly intravenous bisphosphonate therapy in women with low risk bone metastases from breast cancer ‐ the TRIUMPH trial. Cancer Research 2011;71(24 Suppl):OT1‐01‐02.
    1. Bouganim N, Vandermeer L, Kuchuk I, Dent S, Hopkins S, Song X, et al. Evaluating efficacy of de‐escalated bisphosphonate therapy in metastatic breast cancer patients at low‐risk of skeletal related events. TRIUMPH: a pragmatic multicentre trial. Cancer Research 2012;72(24 Suppl):P3‐13‐05. - PMC - PubMed

Additional references

Addison 2014
    1. Addison CL, Bouganim N, Hilton J, Vandermeer L, Dent S, Amir E, et al. A phase II multicentre trial evaluating the efficacy of de‐escalated bisphosphonate therapy in metastatic breast cancer patients at low‐risk of skeletal‐related events. Breast Cancer Research and Treatment 2014;144(3):615‐624. - PMC - PubMed
Aft 2010
    1. Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez‐MacGregor M, et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncology 2010;11(5):421‐8. - PMC - PubMed
Andersen 1982
    1. Andersen PK, Gill RD. Cox's regression model for counting processes: a large sample study. Annals of Statistics 1982;10(4):1100‐20.
ASCO Guidelines 2011
    1. Poznak CHV, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone‐modifying agents in metastatic breast cancer. Journal of Clinical Oncology 2011; Vol. 29, issue 9:1221‐7. - PubMed
ASCO Guidelines 2017
    1. Dhesy‐Thind S, Fletcher GG, Blanchette PS, Clemons MJ, Dillmon MS, Frank ES, et al. Use of adjuvant bisphosphonates and other bone‐modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology 2017;35(18):2062‐81. - PubMed
Bloomfield 1998
    1. Bloomfield DJ. Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence‐based review. Journal of Clinical Oncology 1998;16(3):1218‐25. - PubMed
Body 1998
    1. Body JJ, Bartl R, Burckhardt P, Delmas PD, Diel IJ, Fleisch H, et al. Current use of bisphosphonates in oncology. Journal of Clinical Oncology 1998;16(12):3890‐9. - PubMed
Body 1999
    1. Body JJ, Lichinitser MR, Diehl I, Schlosser K, Pfarr E, Cavalli F, et al. Double‐blind placebo‐controlled trial of intravenous ibandronate in breast cancer metastatic to bone. Annual Meeting of the American Society of Clinical Oncology (ASCO); 1999; Chicago. Chicago: American Society of Clinical Oncology, 1999; Vol. 18:575a.
Coleman 1985
    1. Coleman RE, Rubens RD. Bone metastases and breast cancer. Cancer Treatment Reviews 1985;12:251‐70. - PubMed
Coleman 1987
    1. Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. British Journal of Cancer 1987;55(1):61‐6. - PMC - PubMed
Coleman 2009
    1. Coleman R, Bundred N, Boer R, Llombart A, Campbell I, Neven P, et al. Impact of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z‐FAST, ZO‐FAST, and E‐ZO‐FAST. 32nd Annual San Antonio Breast Cancer Symposium; 2009 Dec 9‐13; San Antonio. San Antonio: San Antonio Breast Cancer Symposium (SABCS), 2009.
Coleman 2010
    1. Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti‐tumour activity in breast cancer. British Journal of Cancer 2010;102(7):1099‐105. - PMC - PubMed
Colleoni 2000
    1. Colleoni M, O'Neill A, Goldhirsch A, Gelber RD, Bonetti M, Thurlimann B, et al. Identifying breast cancer patients at high risk for bone metastases. Journal of Clinical Oncology 2000;18(23):3925‐35. - PubMed
Cook 2001
    1. Cook RJ, Major P. Methodology for treatment evaluation in patients with cancer metastatic to bone. Journal of the National Cancer Institute 2001;93(7):534‐8. - PubMed
Deeks 2011
    1. Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Diel 2008
    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):2007‐201. - PMC - PubMed
EBCTCG 2015
    1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta‐analyses of individual patient data from randomised trials. Lancet 3;386(10001):1353‐61. - PubMed
Elomaa 1988
    1. Elomaa I, Blomqvist C, Porkka, Holtstrom T, Taube T, Lamberg‐Allardt C, et al. Clodronate for osteolytic metastases due to breast cancer. Biomedicine and Pharmacotherapy 1988;42(2):111‐6. - PubMed
Elomma 1987
    1. Elomma I, Blomqvist L, Porkka L, Lamberg‐Allardt C, Borgstrom GH. Treatment of skeletal disease in breast cancer: a controlled clodronate trial. Bone 1987;8(Suppl 1):53‐6. - PubMed
ESMO Clinical Practice Guidelines 2014
    1. Coleman R, Body JJ, Aapro M, Hadji P, Herrstedt J. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology 2014; Vol. 25, issue suppl 3:iii124‐37. - PubMed
Ferlay 2015
    1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 2015;136:E259‐86. - PubMed
Fizazi 2011
    1. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration‐resistant prostate cancer: a randomised, double‐blind study. Lancet 2011;377(9768):813‐22. - PMC - PubMed
GRADEpro GDT 2015 [Computer program]
    1. McMaster University (developed by Evidence Prime). GRADEpro GDT. Version accessed 19 September 2016. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015.
Harvey 1997
    1. Harvey HA. Issue concerning the role of chemotherapy and hormonal therapy of bone metastases from breast cancer. Cancer 1997;80(8):1646‐56. - PubMed
Higgins 2003
    1. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327:557‐60. - PMC - PubMed
Higgins 2011
    1. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Hiraga 2004
    1. Hiraga T, Williams PJ, Ueda A, Tamura D, Yoneda T. Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clinical Cancer Research 2004;10(13):4559‐67. - PubMed
Hortobagyi 2014
    1. Hortobagyi GN, Lipton A, Chew HK, Gradishar WJ, Sauter NP, Mohanlal RW, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: results of the OPTIMIZE‐2 trial. Journal of Clinical Oncology 2014;32(5 Suppl):LBA9500.
Kanis 1995
    1. Kanis JA. Bone and cancer: pathophysiology and treatment of metastases. Bone 1995;17(Suppl 2):101‐5. - PubMed
Kozlow 2005
    1. Kozlow W, Guise T. Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. Journal of Mammary Gland Biology and Neoplasia 2005;10(2):169‐80. - PubMed
Michiels 2005
    1. Michiels S, Piedbois P, Burdett S, Syz N, Stewart L, Pignon JP. Meta‐analysis when only the median survival times are known: a comparison with individual patient data results. International Journal of Technology Assessment in Health Care 2005;21(1):119‐25. - PubMed
Moher 2009
    1. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta‐Analyses: The PRISMA Statement. PLoS Medicine 2009;6(7):e1000097. [DOI: 10.1371/journal.pmed1000097] - DOI - PMC - PubMed
Mundy 1991
    1. Mundy GR. Mechanisms of osteolytic bone destruction. Bone 1991;12(Suppl 1):1‐6. - PubMed
Mundy 1997
    1. Mundy GR. Mechanisms of bone metastases. Cancer 1987;80(8):1546‐56. - PubMed
RevMan 2014 [Computer program]
    1. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Rogers 1997
    1. Rogers MJ, Watts DJ, Russell RGG. Overview of bisphosphonates. Cancer 1997;80(8):1652‐60. - PubMed
Russell 1999
    1. Russell RGG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999;25(1):97‐106. - PubMed
Saarto 2001
    1. Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node‐positive breast cancer patients: 5 year results of a randomised controlled study. Journal of Clinical Oncology 2001;19(1):10‐17. - PubMed
Scheid 1986
    1. Scheid V, Buzdar AU, Smith TL, Hortobagyi GN. Clinical course of breast cancer patients with osseous metastases treated with combination chemotherapy. Cancer 1986;58:2589‐93. - PubMed
Schultz 2010
    1. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332. [DOI: 10.1136/bmj.c332] - DOI - PMC - PubMed
Schünemann 2011a
    1. Schunemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glaziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors). Cochrane Handbook of Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org..
Schünemann 2011b
    1. Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and ‘Summary of findings' tables. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Sterne 2011
    1. Sterne JAC, Egger M, Moher D (editors). Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Templeton 2014
    1. Templeton AJ, Stalder L, Bernhard J, Brauchli P, Gillessen S, Hayoz S, et al. Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks: a noninferiority phase III trial (SAKK 96/12, REDUSE). Journal of Clinical Oncology 2014;32(15 Suppl):published online before print.
Theriault 1999
    1. Theriault RL, Lipton A, Hortobagyi GN, Leff R, Gluck S, Stewart JF, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomised, placebo‐controlled trial. Journal of Clinical Oncology 1999;17(3):846‐54. - PubMed
Tierney 2007
    1. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time‐to‐event data into meta‐analysis. Trials 2007;8:16. - PMC - PubMed
Van Holten‐Verzantvoort 1987
    1. Holten‐Verzantvoort AT, Bijvoet OLM, Cleton FJ, Hermans J, Kroon HM, Harinck HIJ, et al. Reduced morbidity from skeletal metastases in breast cancer patients during long‐term bisphosphonate (APD) treatment. Lancet 1987;330(8566):983‐5. - PubMed
Van Holten‐Verzantvoort 1991
    1. Holten‐Verzantvoort ATM, Zwinderman AH, Aaronson NK, Hermans J, Emmerik B, Dam FSAM, et al. The effect of supportive pamidronate treatment on aspects of quality of life of patients with advanced breast cancer. European Journal of Cancer 1991;27(5):544‐9. - PubMed
WHO 2003
    1. World Health Organization (WHO). World Cancer Report. The International Agency for Research on Cancer 2003.

References to other published versions of this review

Pavlakis 2002
    1. Pavlakis N, Stockler M. Bisphosphonates for breast cancer. Cochrane Database of Systematic Reviews 2002, Issue 1. [DOI: 10.1002/14651858.CD003474] - DOI - PubMed
Pavlakis 2005
    1. Pavlakis N, Schmidt RL, Stockler MR. Bisphosphonates for breast cancer. Cochrane Database of Systematic Reviews 2005, Issue 3. [DOI: 10.1002/14651858.CD003474.pub2] - DOI - PubMed
Wong 2012
    1. Matthew HF Wong, Martin Stockler, Nick Pavlakis. Bisphosphonates and other bone agents for breast cancer. Cochrane Database of Systematic Reviews 2012, Issue 2. [DOI: 10.1002/14651858.CD003474.pub3; PUBMED: 22336790] - DOI - PubMed

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