Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies

Abstract

Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients' quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the mainstay to prevent skeletal-related events in MM for almost two decades. Excitingly, the most recent approval of the receptor activator of NF-kappa B ligand (RANKL) inhibitor, denosumab, expanded treatment options for MBD, for patients with compromised renal function, in particular. In addition, several other bone-targeting agents, including bone anabolic drugs, are currently in preclinical and early clinical assessment. This review summarizes our up-to-date knowledge on the pathogenesis of MBD and discusses novel state-of-the-art treatment strategies that are likely to enter clinical practice in the near future.

Keywords: Wnt inhibitors; bisphosphonates; denosumab; multiple myeloma; osteolytic bone disease.

Figure 1

Schematic representations of the main signaling pathways involved in the pathogenesis of myeloma bone disease and their inhibitors. Malignant plasma cells modify their microenvironment by directly secreting and, indirectly, by stimulating the release of cytokines, which regulate osteoclastogenesis and osteoblastogenesis. Osteoclast-activating cytokines include RANKL, IL-3, IL-6, IL-17, CCL3, and CLL20. OB inhibition is mediated by MM-derived DKK1 and CCL3, as well as by BMSC-derived activin A and osteocyte-derived sclerostin. Importantly, MM cells also increase the RANKL/OPG ratio by stimulating osteocyte secretion of RANKL and inhibiting BMSC release of OPG. As a result of these complex interactions, the bone remodeling balance is disrupted and osteolytic lesions develop