br Conclusion br Acknowledgments br Introduction The bone is

Conclusion
Acknowledgments
Introduction The bone is the most common site of tumor metastasis, in about 20–25% of cancer patients [1]. Bone metastases are most common from carcinomas of the breast, lung, prostate, kidney, and thyroid. Some bone metastases are osteoclastic, whereas others are osteoblastic or mixed, resulting from reactive bone formation. Zoledronic order ceramide (Zometa, Novartis) is the only bisphosphonate indicated for the management of solid tumors with bone metastases at the time of writing [2]. It is about 100–1000 times more potent than other bisphosphonates such as clodronate, pamidronate, risedronate, alendronic acid, or etidronate [3–13]. Zoledronic acid inhibits farnesyl diphosphate synthase, an enzyme in the mevalonate pathway, reducing the post-translational prenylation of proteins such as small GTPases, and resulting in the disruption of metabolic pathways essential for cancer cell survival [3,14]. Zoledronic acid may also exert indirect anti-tumor effects by modulating the immune system. It is structurally similar to low-molecular-weight, non-peptide compounds with a phosphate residue, which is recognized by gamma delta T cells in the mediation of immune responses directed against tumor cells [3]. Several dosing schedules of zoledronic acid for the treatment of osteoporosis and bone metastases have been proposed [15,16]. Several dosing schedules of zoledronic acid have been studied, including conventional dosing (4mg intravenously every 3–4 weeks), maintenance dosing (4mg intravenously every 3–6 months), and metronomic dosing (1mg intravenously weekly). Different dosing schedules may have different anti-tumor effects.
Conventional dosing Zoledronic acid has been demonstrated in vitro and in vivo to have anti-tumor activity. Although the approved dosing schedules of zoledronic acid (4mg intravenously every 3–4 weeks) and pamidronate (90mg intravenously monthly) have reduced the risk of skeletal morbidity in patients with bone metastases, the anti-tumor activity of zoledronic acid in breast cancer patients still needs to be optimized. Levels of circulating vascular endothelial growth factor (VEGF), an critical biomarker of tumor angiogenesis, may be useful in the optimization of bisphosphonate use. Increased levels of circulating VEGF correlate with poor prognosis and negative clinical outcomes, including shortened survival, in multiple tumor types. Furthermore, preclinical studies have demonstrated that bisphosphonates are able to inhibit angiogenesis. Promising data from 2 clinical studies in patients with metastatic bone disease demonstrated that a single dose of zoledronic acid (4mg) or pamidronate (90mg) can reduce levels of circulating VEGF. In patients with bone metastases from late-stage solid tumors, circulating VEGF levels were analyzed after monthly treatment with zoledronic acid [16]. VEGF levels decreased 7 days after zoledronic acid infusion [16]. Similarly, in breast cancer patients with bone metastases (N=42), zoledronic acid significantly reduced basal VEGF levels 3 weeks post infusion (p<0.0001) [17]. Furthermore, these reductions correlated with delayed time to bone disease progression (58 versus 34 weeks; p=0.0024) and delayed time to first skeleton related events (SRE) (76 versus 39 weeks; p=0.0002) compared with patients whose VEGF levels remained elevated. Zoledronic acid has been clinically evaluated for potential antiangiogenic effects in patients with bone metastases from advanced cancers [15]. In patients who received zoledronic acid, circulating levels of VEGF decreased after 1 week (p=0.04) [15]. This inhibition persisted throughout the 84-day observation period of the study (p≤0.014). Since changes in levels of serum VEGF correlated with clinical outcomes, zoledronic acid-mediated suppression of serum VEGF levels may decrease tumor burden in patients with advanced and metastatic cancers. The anti-tumor activity of conventional zoledronic acid was also assessed in a study of patients with multiple myeloma (N=94) who were randomized to receive standard anti-cancer therapy with or without a conventional (4mg monthly) dose of zoledronic acid [18]. Patients who received zoledronic acid had significantly improved progression free survival (PFS) (20% versus 48%; p<0.01), event-free survival (80% versus 52%; p<0.01), and overall survival (OS) (80% versus 46%; p<0.01) compared with patients who received only anticancer therapy, as well as a reduction in the incidence of skeletal-related events [18]. Since all patients received the same anti-cancer treatment in the same setting, the improved clinical results of zoledronic acid-containing regimen were attributed to the anti-tumor activity of zoledronic acid. Preliminary clinical data regarding the anti-tumor activity of conventional setting of zoledronic acid are encouraging, but further analyses are required to confirm the optimal treatment setting.