title: Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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. ©2014 AACR.
authors.affiliation: Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia P.D.Ottewell@sheffield.ac.uk.
authors.forename: Penelope D
authors.initials: PD
authors.lastname: Ottewell
authors.affiliation: Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Brown
authors.affiliation: Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Reeves
authors.affiliation: Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia.
authors.forename: C Anne
authors.initials: CA
authors.lastname: Fowles
authors.affiliation: Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Croucher
authors.affiliation: Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia.
authors.forename: Colby L
authors.initials: CL
authors.lastname: Eaton
authors.affiliation: Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D060833:Cellular Microenvironment; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D017698:Postmenopause / Q000187:drug effects / Q000378:metabolism; D017697:Premenopause / Q000187:drug effects / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid