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Zoledronic acid has differential anti-tumour activity in the pre-and post-menopausal bone microenvironment in vivo.


PURPOSE: Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumor cells. Here, we report a differential antitumor effect of zoledronic acid (ZOL) in these two settings. EXPERIMENTAL DESIGN: Twleve-week-old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumor cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and postmenopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100 mug/kg ZOL weekly. Tumor growth was assessed by in vivo imaging and effects on bone by real-time PCR, micro-CT, histomorphometry, and measurements of bone markers. Disseminated tumor cells were detected by two-photon microscopy. RESULTS: OVX increased bone resorption and induced growth of disseminated tumor cells in bone. Tumors were detected in 83% of animals following OVX (postmenopausal model) compared with 17% following sham operation (premenopausal model). OVX had no effect on tumors outside of bone. OVX-induced tumor growth was completely prevented by ZOL, despite the presence of disseminated tumor cells. ZOL did not affect tumor growth in bone in the sham-operated animals. ZOL increased bone volume in both groups. CONCLUSIONS: This is the first demonstration that tumor growth is driven by osteoclast-mediated mechanisms in models that mimic post- but not premenopausal bone, providing a biologic rationale for the differential antitumor effects of ZOL reported in these settings. Clin Cancer Res; 20(11); 2922-32. (c)2014 AACR.

Type Journal
Authors Ottewell, P.D.; Wang, N.; Brown, H.K.; Reeves, K.; Fowles, A.; Croucher, P.; Eaton, C.; Holen, I.
Published Date 2014-06-01
Published Volume 20
Published Issue 11
Published Pages 2922-32
Status Published in-print
DOI 10.1158/1078-0432.CCR-13-1246
URL link to publisher's version
OpenAccess link to author's accepted manuscript version