Zoledronic acid inhibits both the osteolytic and osteoblastic components of osteosarcoma lesions in a mouse model.
OBJECTIVE
To evaluate the efficacy of zoledronic acid (ZOL) against osteosarcoma (OS) growth, progression, and metastatic spread using an animal model of human OS that closely resembles the human disease.


METHODS
Human K-HOS or KRIB OS cells, tagged or untagged with a luciferase reporter construct, were transplanted directly into the tibial cavity of nude mice. ZOL was given as weekly, or a single dose of 100 microg/kg body weight, equivalent to the 4 mg i.v. dose used clinically. Tumor growth at the primary site and as pulmonary metastases was monitored by bioluminescence imaging and histology, and OS-induced bone destruction was measured using high-resolution micro-computed tomography.


RESULTS
Mice transplanted with OS cells exhibited aberrant bone remodeling in the area of cancer cell transplantation, with areas of osteolysis mixed with extensive new bone formation extending from the cortex. ZOL administration prevented osteolysis and significantly reduced the amount of OS-induced bone formation. However, ZOL had no effect on tumor burden at the primary site. Importantly, ZOL failed to reduce lung metastasis and in some cases was associated with larger and more numerous metastatic lesions.


CONCLUSIONS
Our data show that clinically relevant doses of ZOL, while protecting the bone from OS-induced bone destruction, do not inhibit primary tumor growth. Moreover, lung metastases were not reduced and may even have been promoted by this treatment, indicating that caution is required when the clinical application of the bisphosphonate class of antiresorptives is considered in OS.
Labrinidis
Agatha
A
Discipline of Orthopaedics and Trauma, University of Adelaide, The Royal Adelaide Hospital and The Hanson Institute, Adelaide, South Australia, Australia.
Hay
Shelley
S
Liapis
Vasilios
V
Ponomarev
Vladimir
V
Findlay
David M
DM
Evdokiou
Andreas
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010006:Osteoblasts / Q000187:drug effects* / Q000473:pathology; D010014:Osteolysis / Q000473:pathology / Q000517:prevention & control*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D000077211:Zoledronic Acid; D008156:Luciferases