Cancer Therapy: Preclinical Zoledronic Acid Inhibits Both the Osteolytic and Osteoblastic Components of Osteosarcoma Lesions in a Mouse Model

Purpose: 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. Experimental Design: 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 μg/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. Osteogenic sarcoma, commonly referred to as osteosarcoma (OS), is the most frequent primary malignancy of the skeleton, developing mainly before the age of 30 years (1, 2). Metastatic spread, preferentially to the lungs, is seen in 20% of presenting patients and is correlated with poor survival statistics (3–5). Bone lesions caused by OS are characterized based on their radiologic appearance and appear as either osteolytic, osteoblastic (osteosclerotic), or mixed (6). Osteolysis is a common manifestation associated with OS, even within predominantly osteoblastic lesions, and is mediated primarily by osteoclasts and their bone-resorbing activity (7, 8). Factors released from the bone are believed to stimulate tumor growth and tumor cells are in turn able to produce factors that stimulate osteoclast differentiation and activity. This results in the establishment of a host-tumor relationship, often termed “the vicious cycle” due to its progressively destructive nature (9). By mechanisms that are not well understood, tumor cells associated with osteoblastic lesions can stimulate osteogenesis (10, 11). Bisphosphonates (BP) are commonly used for the prevention and treatment of various bone diseases associated with enhanced bone resorption, such as Paget's disease and osteoporosis (12, 13). In addition to their antiresorptive activity, there is growing evidence supporting the direct effects of BPs on cancer cells themselves, at least in vitro. In this respect, zoledronic acid (ZOL) exhibits the highest potency of its class. The antitumor activity of BPs has been shown in awide variety of tumor cell types, including leukemia (14), breast cancer (15), prostate cancer (16), and OS (17, 18). These in vitro studies have shown that BPs can dose dependently inhibit proliferation and induce apoptosis in tumor cells. A reduction by BPs in tumor cell adhesion, invasion, and angiogenesis has also been reported, making BPs potentially attractive agents in the treatment of metastatic cancers (19). Preclinical animal models of metastatic cancer have shown a reduction in tumor-induced osteolysis with ZOL treatment (20–22). Reports of animal models of prostate cancer have all shown reduced osteolysis with ZOL treatment, with conflicting Authors' Affiliations: Discipline of Orthopaedics and Trauma, University of Adelaide, The Royal Adelaide Hospital and The Hanson Institute, Adelaide, South Australia, Australia and Department of Neurology, Memorial SloanKettering Cancer Center, New York, New York Received 6/24/08; revised 1/9/09; accepted 2/19/09; published OnlineFirst