Zoledronic Acid Has Differential Antitumor Activity in the Pre- and Postmenopausal Bone Microenvironment In Vivo

• Published in: Clinical cancer research Vol. 20; no. 11; pp. 2922 - 2932
• Main Authors: OTTEWELL, Penelope D, NING WANG, BROWN, Hannah K, REEVES, Kimberly J, FOWLES, C. Anne, CROUCHED, Peter I, EATON, Colby L, HOLEN, Ingunn
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-06-2014
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Bone and Bones - drug effects; Bone Density Conservation Agents - pharmacology; Bone Neoplasms - secondary; Breast Neoplasms - pathology; Cell Line, Tumor; Cellular Microenvironment; Diphosphonates - pharmacology; Disease Models, Animal; Female; Humans; Imidazoles - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Confocal; Osteoclasts - drug effects; Osteoclasts - metabolism; Ovariectomy; Pharmacology. Drug treatments; Postmenopause - drug effects; Postmenopause - metabolism; Premenopause - drug effects; Premenopause - metabolism; Real-Time Polymerase Chain Reaction; X-Ray Microtomography; Xenograft Model Antitumor Assays; Zoledronic Acid; Antineoplastic agent; Antiosteoporotic; Menopause; Antiresorptive agent; Diphosphonic acid derivatives; Microenvironment; Bisphosphonates; Biological activity; Osteoarticular system; In vivo; Zoledronic acid; Postmenopause; Bone
• DOI: 10.1158/1078-0432.CCR-13-1246
• EISSN: 1557-3265
• ISSN: 1078-0432

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.
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 μg/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.
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.
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. ©2014 AACR.