BMC Cancer 2009, 9:154 http://www.biomedcentral.com/1471-2407/9/154 Discussion BPs have been used for more than 15 years to improve the outcomes of patients with bone metastases from solid tumors, as well as hematologic malignancies. In bone metastases, the cancer cells invade the bone marrow cavity and produce parathyroid hormone-related protein (PTH- rP), which stimulates osteoclastic resorption by increasing the production of the receptor activator of the nuclear fac- tor-κB ligand (RANKL) by osteoblast and stromal cells. The RANKL binds to its receptor, RANK, on osteoclast lin- eage cells, induces differentiation into mature osteoclasts, and stimulates osteoclast activity [12,13]. Nitrogen-con- taining BPs (N-BPs) such as zoledronate, pamidronate, and ibandronate affect osteoclast activity and survival through inhibiting farnesyl diphosphonate synthase in the mevalonate pathway [13]. This inhibition also seems to account for the antitumor effects of N-BPs in vitro [14]. N-BPs also have anti-angiogenic effects, decreasing the serum VEGF of patients with a variety of solid tumors [15]. Inhibition by N-BPs enhanced the antitumor activity of known cytotoxic agents that were commonly used in clinical settings [16]. Among various BPs, N-BPs, espe- cially zoledronate, have the strongest antitumor effect in vitro [17]. In contrast to the consistent preclinical antitumor effects of BPs, the results of clinical studies in breast cancer have shown conflicting findings. Diel and Powles indicated that clodronate treatment prevented skeletal metastases with no effect on visceral metastases, and improved over- all survival [7,18-20]. However, Saarto reported that clodronate treatment worsened survival, especially in hor- mone negative patients, among whom significantly more patients on clodronate experienced non-skeletal metas- tases than among the control group [8]. In this study, we investigated the effect of BP in a meta- static setting, specifically in patients with metastatic bone disease from breast cancer. The most important limitation of this retrospective study is that the use of BPs was based on the clinical decision to prevent complications such as pathological fracture, bone pain, and hypercalcemia. Patients who had experienced SREs secondary to bone metastasis tended to be put on bisphosphonate more often. Consequently, patients with BP group in this study developed more often progression of bone disease and SREs, because BP treated group had more advanced and complicated bone disease at the outset of BP use. Con- versely, patients with bone metastasis who did not have symptoms or had only minimal tumor burden tended not to receive BP treatment. Therefore, patients with more indolent bone disease had greater propensity to be included in the non-BP group. With these inherent unbal- ances, TTP_BD was not significantly different according to BP treatment in both HR positive and HR negative groups. In the first analysis, including all patients with metastatic bone disease, favorable OS was expected in the BP group, as a result of an imbalance in hormone receptor status, the presence of visceral organs involvement, and other impor- tant prognostic factors. It was still possible that BP treat- ment was an important factor for survival because far more patients with HR positive tumors received BP treat- ment. In the next analysis, we corrected for this confound- ing factor by looking separately at patients with HR positive tumors within the BP-treated vs. untreated groups. In these patients, HER2 positivity and visceral organ involvement were important factors for OS, but there was no significant difference in OS with or without BP treatment. In HR negative patients, on the contrary, an OS difference was significant in favor of the BP treatment. HR negative patients' characteristics were well balanced between the BP treated and untreated groups. There was no concern for a possible interaction between hormonal therapy and BPs in HR negative patients. These results are contrary to those of Saarto's clodronate study. In that study, 10-year disease free survival was much worse in the clodronate treatment group, especially in estrogen receptor (ER) negative patients [8]. It was assumed that antiestrogen might have opposed the detri- mental effect of BPs. However, this proposition lacks a biological rationale. To the best of our knowledge, no published studies explored the relationship between hor- mone receptor status and the effect of BP treatment in patients with bone metastasis. Cross et al. observed a more frequent expression of RANKL in estrogen negative patients with a high histologic grade breast cancer. They observed a significant negative relation between the expression of RANKL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [21]. In other words, estrogen negative tumors showed higher RANKL expres- sion and lower TRAIL expression. Therefore, BP treatment could be more beneficial to ER negative tumors through suppressing RANKL production by osteoblast and other stromal cells. In this study, it may appear that there were unexpected interactions of anti-hormonal treatment with BPs in HR positive patients. Recently, studies of the role of zoledro- nate in preventing treatment-induced bone loss in pre- and post-menopausal breast cancer patients were per- formed. They showed that hormonal treatment combined with zoledronate did not influence the survival or disease progression in hormone responsive breast cancer [22,23]. Further studies are needed to fully elucidate the effects of BPs in HR positive tumors. Another limitation of this study was that patients receiv- ing different N-BPs were included. Variation in the N-BPs made it difficult to compare the efficiency among the N- Page 7 of 9 (page number not for citation purposes)