Comparison of Fc-osteoprotegerin and zoledronic acid activities suggests that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms JE Quinn 1 , LG Brown 1 , J Zhang 2 , ET Keller 2 , RL Vessella 1,3 & E Corey 1 * 1 Department of Urology, University of Washington, Seattle, Washington, USA; 2 Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA; and 3 Puget Sound VA Medical Center, Seattle, Washington, USA Zoledronic acid (ZA) has been shown to inhibit prostate tumor growth in vitro and have beneficial effects in patients with advanced prostate cancer (CaP). The aim of this study was to determine whether ZA exhibits direct anti-tumor effects on CaP cells in vivo. To distinguish the effects of inhibition of osteolysis and direct anti- tumor activity of ZA in vivo, we compared the results of treatment with ZA and osteoprotegerin (Fc-OPG), which inhibits osteolysis, but without significant direct anti-tumor effects. In vitro Fc-OPG had no significant effects on C4-2 proliferation, whereas ZA decreased proliferation. However, both agents decreased tumor growth in bone. Moreover, both increased bone volume and prevented the overall decreases in BMD associated with growth of C4-2 cells in bone. Our study provides novel and significant observations that the in vivo effects of ZA are consistent with indirect effects mediated by osteoclasts. Prostate Cancer and Prostatic Diseases (2005) 8, 253–259. doi:10.1038/sj.pcan.4500815; published online 5 July 2005 Keywords: osteoprotegerin; bisphosphonates; zoledronic acid; bone metastasis Introduction Advanced prostate cancer (CaP) is often accompanied by bone metastasis, which contributes significantly to the morbidity and mortality of the disease. The balance between osteoclastic bone resorption and osteoblastic bone formation is disrupted during tumor metastasis of many cancer types. In CaP, a large percentage of bone metastases have the radiographic appearance of osteo- blastic lesions, but elevated markers of bone lysis are also present in the serum of CaP patients with bone metastasis. 1 Inhibitors of bone resorption such as bi- sphosphonates (BPs), osteoprotegerin (OPG), and metal- loproteinase (MMP) inhibitors have been reported to decrease bone resorption associated with bone metastasis and decrease tumor burden in several animal models. 2–6 BPs are currently used to treat osteoporosis, reduce bone metabolic activity in Paget’s disease, and control metastatic breast cancer and associated osteolytic bone lesions, as well as metastatic CaP. In a clinical study Diel et al 7 reported that clodronate, a first-generation BP, decreased numbers of both bone and soft tissue meta- stases in breast cancer patients, suggesting potential direct effects of BPs on metastases in addition to decreased bone lysis in vivo. Zoledronic acid (ZA) has also been reported to inhibit visceral metastases in a breast cancer model in vivo. 8 ZA is a new-generation BP and a very potent inhibitor of bone lysis. 9 The value and potential of ZA in treatment of patients with cancer-related bone disease were recently reviewed. 10 In addition to inhibition of osteolysis, several studies have shown that BPs, including ZA, exhibit direct anti-tumor effects in vitro. 4,5,11–13 We and others have also shown that ZA inhibits growth of osteoblastic CaP tumors in animal models. 4,6 Unfortu- nately, no method has been found to distinguish the Received 17 February 2005; revised 26 May 2005; accepted 26 May 2005; published online 5 July 2005 *Correspondence: E Corey, Department of Urology, Mailstop 356510, University of Washington, Seattle, WA 98195, USA. E-mail: ecorey@u.washington.edu Prostate Cancer and Prostatic Diseases (2005) 8, 253–259 & 2005 Nature Publishing Group All rights reserved 1365-7852/05 $30.00 www.nature.com/pcan