Zoledronic acid effectiveness against breast cancer metastases - a role for estrogen in the microenvironment?

Abstract

Zoledronic acid (ZA) is an imidazole-containing bisphosphonate that has been extensively studied as an osteoclast inhibitor. ZA decreases bone turnover and has been effective in limiting osteolysis in metastatic cancers, including breast cancer. Recent clinical trials that demonstrated enhancement of disease-free survival by bisphosphonates have prompted interest in bisphosphonates as anti-cancer agents. ZA, for example, increased disease-free survival in postmenopausal and in premenopausal, hormone-suppressed breast cancer patients. Intriguingly, however, there was a lack of an anti-cancer effect of ZA in premenopausal women without ovarian suppression. These observations have prompted the conjecture that anti-cancer effects of ZA are limited to estrogen-poor environments. This review explores possible mechanisms compatible with differences in ZA activity in premenopausal women compared with postmenopausal (or hormone-suppressed) women.

Figure 1

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.