Single Dosing of Zoledronic Acid in Cancer Therapy Induced Bone Loss (CTIBL)

Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. Skeletal complications due to metastatic disease include (severe) bone pain, spinal cord compromise, pathological fractures, and hypercalcemia. Zoledronic acid is a member of a class of compounds known as bisphosphonates. Bisphosphonates are effective inhibitors of osteoclastic bone resorption and have demonstrated therapeutic efficacy in the treatments of hypercalcemia of malignancy, lytic bone disease associated with multiple myeloma, and mixed lytic and blastic bone metastases associated with breast cancer. The precise mechanism by which bisphosphonates inhibit osteoclast function is not fully understood, but may include a direct toxic effect on mature osteoclasts, an inhibition of osteoclast production from precursor cells, and an impairment of osteoclast chemotaxis to sites of active bone resorption. Osteoclasts are specialized bone cells which erode mineralized bone by secreting acids and lysosomal enzymes. In normal bone remodeling, osteoclastic bone resorption is coupled to and is in equilibrium with osteoblastic bone formation. The lytic bone destruction associated with malignant bone metastases develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The osteoclastic activating factors released by tumor cells include parathyroid hormone-related peptide (PTHrP), growth factors, and cytokines. The malignant activation of osteoclasts results in a disruption of normal bone remodeling wherein the equilibrium between bone resorption and bone formation is shifted toward increased bone resorption. This relative increase in osteoclastic bone resorption results in a net loss of bone. Thus, the predominant role of the osteoclast in the pathogenesis of bone destruction and the inhibitory effects of bisphosphonates on osteoclast function have formed the rationale for the use of bisphosphonates in the treatment of osteolytic bone metastases. The common role, regardless of tumor type, of the osteoclast as the mediator of bone destruction in metastatic skeletal disease is indicated by the inhibitory effects of bisphosphonates on tumor-induced osteolysis in animal models utilizing various malignant cell lines and the effectiveness of bisphosphonates in the therapy of tumor-induced hypercalcemia arising from any type of cancer. Moreover, recent studies have specifically shown that therapy with the bisphosphonate pamidronate (Aredia) combined with antineoplastic therapy significantly reduces the proportion of patients having skeletal complications due to the lytic bone disease associated with multiple myeloma and breast cancer compared to antineoplastic therapy alone.