Biology and management of myeloma-related bone disease

Bone disease is one of the most common complications of multiple myeloma. It is the result of increased osteoclast activity which is not compensated by osteoblast activity and leads to osteolytic lesions characterized by bone pain and increased risk for pathological fracture, spinal cord compression and need for radiotherapy or surgery to the bone. Recent studies have revealed novel pathways and molecules that are involved in the biology of myeloma bone disease including the receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, the Wnt signaling inhibitors dickkopf-1 and sclerostin, macrophage inflammatory proteins, activin A, and others. A thorough study of these pathways have provided novel agents that may play a critical role in the management of myeloma related bone disease in the near future, such as denosumab (anti-RANKL), sotatercept (activin A antagonist), romosozumab (anti-sclerostin) or BHQ-880 (anti-dickkopf 1). Currently, bisphosphonates are the cornerstone in the treatment of myeloma related bone disease. Zoledronic acid and pamidronate are used in this setting with very good results in reducing skeletal-related events, but they cannot be used in patients with severe renal impairment. Furthermore, they have some rare but serious adverse events including osteonecrosis of the jaw and acute renal insufficiency. This review paper focuses on the latest advances in the pathophysiology of myeloma bone disease and in the current and future treatment options for its management.