Potential sites of estrogen antagonism of zoledronic acid function. Bone-bound zoledronic acid (ZA) poisons osteoclasts and inhibits liberation of matrix-bound cytokines. Cytokines induced by stroma or macrophages are also inhibited by ZA but can be upregulated by estrogen. Estrogen also increases numbers of endosteal osteoblasts that can support disseminated tumor cells. Tumor cell migration to extra-osseous sites could be suppressed by anti-angiogenic and anti-migratory effects of ZA, while estrogen support of angiogenesis could promote cancer cell proliferation and dissemination. At extra-osseous sites, estrogen and ZA are proposed to have opposing effects on macrophage polarization and natural killer (NK) activity as described in the text. ZA up to 1 mM intra-osseous and 1 μM extra-osseous concentrations. DTC, quiescent disseminated tumor cell; E2, estrogen; FGF, fibroblast growth factor; IGF, insulin-like growth factor; M1 or M2, macrophages polarized to M1 or M2, respectively; MMP1, matrix metalloproteinase-1; PDGF, platelet-derived growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.