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Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer

Powles, T., Paterson, A., McCloskey, E., Schein, P., Scheffler, B., Tidy, A., Ashley, S., Smith, I., Ottestad, L. and Kanis, J. (2006) Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer. Breast Cancer Research, 8 (2). R13. ISSN 1465-5411

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Experimental and clinical data show that the oral bisphosphonate clodronate (Bonefos®) can inhibit tumor-induced osteoclastic bone resorption. This randomized, double-blind, placebo-controlled, multicenter trial was designed to determine if the addition of oral clodronate to standard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival.


1,069 patients with primary operable stage I-III breast cancer were randomized to receive oral clodronate (1,600 mg/day) or placebo for 2 years, in conjunction with standard treatment for primary breast cancer including surgery, radiotherapy, adjuvant chemotherapy, and/or tamoxifen. All patients were assessed for bone metastases at two and five years and additionally when clinically indicated. Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years. The treatment arms were compared using the unstratified log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated.


Oral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period (51 patients versus 73 patients with placebo; HR = 0.692, P = 0.043); the difference was also statistically significant over the 2 year medication period (19 patients versus 35 patients with placebo; HR = 0.546, P = 0.031). These differences were most pronounced in patients with stage II/III disease (39 patients versus 64 patients with placebo, HR = 0.592, P = 0.009 over 5 years; 16 patients versus 32 patients with placebo, HR= 0.496, P = 0.020 over 2 years). Survival data also favoured the clodronate arm (HR for all patients = 0.768, P = 0.048; HR for stage II/III disease = 0.743, P = 0.041), although this was not significant due to multiple analyses. Oral clodronate was well tolerated, with mild-to-moderate diarrhoea being the most frequently reported adverse event.


These results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer.

Item Type: Article
Copyright, Publisher and Additional Information: © 2006 Powles et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield)
Depositing User: Sheffield Import
Date Deposited: 08 Oct 2009 12:53
Last Modified: 08 Oct 2009 12:53
Published Version: http://breast-cancer-research.com/content/8/2/R13
Status: Published
Publisher: BioMed Central
Identification Number: 10.1186/bcr1384
URI: http://eprints.whiterose.ac.uk/id/eprint/9732

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