Patients with multiple myeloma (MM) experience pathologic fractures, bone pain, 
hypercalcemia, neurologic symptoms, and renal insufficiency with substantial 
morbidity and mortality. Bisphosphonates have been used successfully for the 
management of MM-related bone disease. Increased incidence of osteonecrosis of 
the jaw has been observed in patients with cancer receiving bisphosphonate 
therapy. Recent advances in the pathobiology of MM-related bone disease and 
other cancer-related bone metastases have led to the identification of novel 
therapeutic targets, such as receptor activator of nuclear factor-kappaB (RANK); 
its ligand (RANKL); and a decoy receptor, osteoprotegerin, for the development 
of potential targeted agents. Initials studies have demonstrated that targeting 
RANK/ RANKL signaling with the fully human monoclonal antibody denosumab 
prevented skeletal complications in patients with MM and other cancers with bone 
metastases. Ongoing studies evaluating the clinical utility of denosumab in 
cancer- related bone destruction have been discussed. In addition, several 
potential targets, such as macrophage inflammatory protein-1alpha, chemokine 
receptors 1 and 5, interleukin-3, and Wnt signaling, are b riefly described.