The backbone of progress--preclinical studies and innovations with zoledronic acid.

Bisphosphonates (BPs) are antiresorptive agents that block pathologic bone resorption by inhibiting osteoclast function and later inducing osteoclast apoptosis. These agents localize to bone and break the vicious cycle of bone resorption that results from cross-stimulation between cancer cells and the bone remodeling cells, thereby reducing cancer-induced osteolysis and the tumor burden in bone. Thus nitrogen-containing BPs (N-BPs) have well established clinical benefits in the treatment of bone metastases from solid tumors and bone lesions from multiple myeloma. Preclinical data indicate that N-BPs, especially zoledronic acid (ZOL), can exert antimyeloma activity both in vitro and in vivo. Studies show that N-BPs can inhibit multiple intracellular processes essential for cancer cell proliferation and invasion and induce apoptosis. Furthermore, clinically relevant doses of N-BPs inhibit tumor-associated angiogenesis and can modulate macrophage phenotype in vivo, which is likely to contribute to anticancer effects.