Pathogenesis and Treatment of Myeloma-Related Bone Disease

Abstract

Multiple myeloma is a hematologic malignancy of plasma cells that causes bone-destructive lesions and associated skeletal-related events (SREs). The pathogenesis of myeloma-related bone disease (MBD) is the imbalance of the bone-remodeling process, which results from osteoclast activation, osteoblast suppression, and the immunosuppressed bone marrow microenvironment. Many important signaling cascades, including the RANKL/RANK/OPG axis, Notch signaling, the Wnt/β-Catenin signaling pathways, and signaling molecules, such as DKK-1, sclerostin, osteopontin, activin A, chemokines, and interleukins are involved and play critical roles in MBD. Currently, bisphosphonate and denosumab are the gold standard for MBD prevention and treatment. As the molecular mechanisms of MBD become increasingly well understood, novel agents are being thoroughly explored in both preclinical and clinical settings. Herein, we will provide an updated overview of the pathogenesis of MBD, summarize the clinical management and guidelines, and discuss novel bone-modifying therapies for further management of MBD.

Effects of Bisphosphonate on Osteocyte Proliferation and Bone Formation in Patients with Diabetic Osteoporosis

“…Bisphosphonates combined with calcium crystals are first-line drugs for the treatment of osteoporosis. According to some authors [ 26 , 27 ], bisphosphonates can have direct positive effects on osteoblasts, bone formation, and mineralization. Bisphosphonates reduce bone resorption and increase bone mineral density by inhibiting osteoclast function [ 28 ].…”

“…Even in the absence of underlying diabetes, men and women experience bone loss of approximately 1% per year starting at age 30. This increase in bone resorption demonstrates the importance of timely intervention with potent antiresorptive drugs, such as bisphosphonates [24][25][26]. Bisphosphonates combined with calcium crystals are first-line drugs for the…”

Targeted therapy for multiple myeloma: an overview on CD138-based strategies

“…Similarly, Activin A is a pleiotropic cytokine that belongs to the TGF-β superfamily and can trigger the NF-kB signaling pathway by inducing RANK expression to support OCs differentiation ( 132 ). Overall, RANKL and its antagonist OPG are two important molecules to understand the features of myeloma bone disease (MBD) as they are closely associated with the clinical outcome of the disease ( 133 ). Finally, CD138 in synergy with HPSE has been shown to promote MM bone disease by activating the HGF-Met-IL-11-RANKL signaling axis, resulting in inhibition of bone formation and promotion of bone resorption ( 134 ).…”

Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma

“…Numerous factors have been recognized to block osteoblast formation, comprising dickkopf-1 (DKK1). Different experiments have displayed that DKK1 can inhibit osteoblasts and augment the function of osteoclasts, provoking an alteration in bone metabolism [ 119 ].…”