Bone is a common site for metastasis in breast cancer; approximately 75% of women with advanced breast cancer will develop bone metastases.1-3 Bone metastases associated with breast cancer are predominately osteolytic4; complications include hypercalcemia, increased fracture risk, need for surgery or radiotherapy, and spinal cord compression.1,5 Bone metastases in breast cancer are also characterized by elevated bone turnover markers such as the urinary-N-telopeptide/creatinine ratio (uNTx/Cr); patients with elevated levels of uNTx/Cr are at increased risk for skeletal complications, disease progression, and death.6-8
Receptor activator of nuclear factor-κB ligand (RANKL) is a key mediator in the vicious cycle of bone destruction in metastatic cancer. Within the bone microenvironment, factors secreted by tumor cells stimulate stromal cells and osteoblasts to express and secrete RANKL, which binds to RANK on the surface of precursor and mature osteoclasts. RANKL is a critical mediator of osteoclast differentiation, function, and survival.9-11 Osteoclast-mediated bone resorption releases growth factors that further stimulate tumor growth, resulting in a pattern of bone destruction and tumor cell proliferation.12 RANKL has recently been shown to promote migration of RANK-expressing tumor cells to bone.13