Dasatinib (SPRYCEL, Bristol-Myers Squibb, New York) is a small-molecule tyrosine kinase inhibitor with activity against several signaling proteins [96]. Dasatinib is now being evaluated in phase-I and II trials in

a variety of tumor types, including prostate and lung cancers [97] and [98]. AZD-0530 is an another dual Src/Abl inhibitor that has been shown to inhibit the formation and activity of human osteoclasts, as PLX3397 in vitro well as to suppress tumor growth and metastasis [89]. Specific inhibitors of ET-1 signaling (antagonists of the endothelin-A receptor [ETAR]) have beneficial effects on bone metastatic lesions arising from prostate cancer [99]. Selective ETAR antagonists may block the proliferative effects of exogenous ET-1 on both prostate cancer cells and osteoblasts. More specifically, Src inhibitor Atrasentan (ABT-627), an antagonist of ETARs, may inhibit tumor growth in bone both by direct effects on the tumor cells and by destroying important bone/tumor interactions

[100], [101] and [102]. ZD4054, a specific ETA antagonist, is being examined currently in phase-II studies on prostate cancer, little data on its efficacy has been reported, but an improvement was seen in overall survival [103]. Radionuclide therapy is a useful and cost-effective means of alleviating bone pain in metastatic disease and may be more effective when combined with chemotherapy, bisphosphonates, and radiation therapy [104] and [105]. Due to the chemical similarity between strontium and calcium, 89Sr (Metastron®) is preferentially retained in the skeleton, especially in areas of rapid osteoblastic activity

and bone formation associated with tumor-mediated bone remodeling by a factor of about 10 versus its retention in healthy bone [104]. 153Sm-EDTMP (Quadramet®) is most widely used in the United States to relieve pain from bone metastasis, with palliation occurring in Aldehyde dehydrogenase 65–80% of patients with better overall response rates at higher doses in early phase-I and -II studies [105]. 153Sm is administered with a large excess of a bone targeting phosphonate-chelating agent [lexidronam or ethylenediaminetetramethylenephosphonate (EDTMP)] to enable delivery of the injected 153Sm to areas of bone formation. The absorption of this radiopharmaceutical is 17 times faster in lesions than in normal bone, and due to its rapid renal clearance, nonosseous radioactive exposure is low [106]. Osteoclastogenesis and angiogenesis is the most fundamental step leading to tumor-induced bone destruction. Based on the accumulating data in vitro and the phenotypic change observed in the CCN2 KO mice, CCN2 is now believed to be such a central modulator of extracellular signaling and molecular architecture in the endochondral ossification process. Final stage of endochondral ossification is the most fundamental step for osteoclast activation and angiogenesis from bone marrow.