BMC Cancer 2009, 9:154 http://www.biomedcentral.com/1471-2407/9/154 tumor activities of BPs have been explored, particularly with zoledronate and pamidronate, through in-vitro as well as in-vivo animal studies [4-6]. These preclinical stud- ies showed that BPs could reduce visceral metastasis as well as bone metastasis. However, the clinical relevance of the antitumor effects of BPs has not been firmly estab- lished. A few small pilot studies investigating the potential roles of BPs in the adjuvant setting were conducted, and their results regarding the antitumor effects of BPs were controversial, due to the non-randomized nature of these studies [7-9]. Recently, Gnant et al. reported that zoledronate, in an adjuvant setting, significantly prolonged disease-free sur- vival beyond the time achieved with endocrine therapy alone (hazard ratio = 0.64, P = 0.01) [10]. Now, several large randomized controlled trials, such as the B-34 trial, the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, and the SWOG 0307 trial, are being con- ducted to clarify the roles of BPs in the adjuvant setting. These studies will assess the direct or indirect antitumor effects of BPs, according to the rate of bone metastasis, other visceral metastasis, and overall survival. The antitumor effects of BPs have not been investigated in the metastatic setting, although BPs are now widely used in metastatic breast cancer. Most studies focused on the development of skeletal related events (SREs) and the quality of life of patients with metastatic bone disease [11]. In this retrospective study, we address the antitumor effect of BPs in breast cancer patients with metastatic bone disease. Our primary objective is to assess the association between BP treatment and overall survival (OS), while adjusting for other factors. The secondary objective is to evaluate the effects of BPs in preventing SREs and the pro- gression of metastatic bone disease. Methods Study population and study assessments This retrospective study included a total of 317 breast can- cer patients with initial bone metastases, whose hormone receptor (HR) status and HER2 status were known, and who were treated between June 2001 and July 2007 at the National Cancer Center Hospital, Korea. Of these, 87 patients (27.4%) had HR negative tumors. A tumor was considered to be HER2 positive if the primary or meta- static tumor was scored 3+ by HER2 immunohistochem- istry (IHC) or by amplification of the HER2 gene by the method of fluorescent in situ hybridization (FISH). If a tumor's score was 2+ by IHC, the tumor was reanalyzed using FISH. Metastatic bone disease (MBD) was diag- nosed mostly by means of radionuclide bone scans per- formed for follow-up. Magnetic resonance imaging was done when patients showed skeletal related symptoms such as pain, fractures, or neurologic signs with equivocal bone scan results. Patients with bone metastases were followed up until August 2008, and their medical records were reviewed for clinical data, including age at the initial diagnosis, age at diagnosis of disease recurrence, initial stage of the disease, pathological type, disease-free interval, number and site of metastases, treatment after diagnosis, especially bisphosphonate treatment, and survival interval from the diagnosis of disease recurrence or initial stage IV presenta- tion. The administered bisphosphonates (BPs) differed accord- ing to the periods of treatment, compliance, tolerability, and insurance strategy. The types of bisphosphonate used were zoledronate or pamidronate. These drugs were given at three or four week intervals. Patients who received more than three consecutive months of bisphosphonate treat- ment were designated as members of the bisphosphonate group (BP group), and other patients were designated as members of the non-bisphosphonate group (non-BP group). For the evaluation of the bisphosphonate effect on bone metastasis, we assessed the progression of bone metasta- sis, time to progression of bone disease (TTP_BD), and development of skeletal related events (SREs). SREs were defined as pathological fractures, or surgery or palliative radiation to bone in order to treat or prevent impending fractures or cord compressions. Disease progression in bone was defined as the appearance of any new bone lesions, or the progression of existing bone metastases, including the development of SREs. To monitor the side effects of bisphosphonate, the serum levels of creatinine and total calcium were regularly checked. Bisphosphonate treatment was temporarily stopped before and after dental procedures. Patients undergoing bisphosphonate treat- ment were instructed to take an oral calcium supplement containing vitamin D. This study protocol was approved by the Institutional Review Board for the National Cancer Center (IRB proto- col number NCCNCS 08-195). Because this was a retro- spective analysis that involved no additional risk to patients, the Institutional Review Board approved a waiver of informed consent. Statistical methods Descriptive statistics, including sample size, median, and range, were reported for continuous variables. Discrete variables were summarized using frequencies and per- centages. Clinical parameters and treatment response were compared using 2-way tables, chi-square, and Mann- Whitney U test. Time to progression of bone disease Page 2 of 9 (page number not for citation purposes)