Causes and mechanism of myeloma bone disease
The skeleton is a metabolically active organ that undergoes continuous bone remodelling throughout life.
Bone remodelling is the process whereby mineralised bone is broken down by specialised cells known as osteoclasts followed by the formation of new bone by other cells called osteoblasts. The process involves two distinct phases:
- Resorption – during which osteoclasts break down old bone
- Formation – when osteoblasts lay down new bone until the resorbed bone is completely replaced
The sustained equilibrium of bone formation and bone breakdown keeps bone in a state of constant renewal throughout life, serving to regulate the gain and loss of bone mineral density, adjusting bone architecture to meet changing mechanical needs and maintaining bone thickness, strength and health. Bone remodelling also plays an important role in maintaining plasma calcium homeostasis.
In myeloma, however, the balance of normal bone resorption and bone formation is disrupted leading to increased bone destruction with no compensatory bone formation. This causes widespread diffuse bone osteopenia (bone thinning) and the appearance of focal lytic lesions (Figure 1). These lesions are purely osteolytic – they do not heal while the disease is active and become prone to fracture. It is this process of bone destruction that is commonly referred to as myeloma bone disease.
(Left) A lesion in the shinbone (tibia); (Centre) Two lesions in the thighbone (femur) near the knee; (Right) A large lesion in the upper thighbone near the hip
Bone resorption
The whole process of myeloma bone disease results from the direct interaction of the myeloma cells with the bone marrow microenvironment. Myeloma cells produce cytokines and growth factors which stimulate osteoclast activity and at the same suppress osteoblast activity and function.
In addition, osteoclasts produce their own cytokines which help promote myeloma cell growth. This generates a vicious circle between bone destruction and tumour cell survival.
Three major groups of cytokines and growth factors have been identified as the main osteoclast activators in myeloma. These are:
- Receptor activator of nuclear factor (NF)κB ligand – RANKL
- The chemokines macrophage inflammatory protein (MIP)-1α and MIP-1β
- Stromal derived factor-1 (SDF-1)
Of these, RANKL is regarded as the most important mediator of osteoclast differentiation and activation. It forms part of the RANK-RANKL-osteoprotegerin (OPG) system and is produced mainly by osteoblasts and stromal cells. The receptor for RANKL, RANK, is found on the surface of osteoclasts. Binding of RANKL to RANK induces maturation and activation of the osteoclast and consequently the resorption of bone.
Under normal conditions, bone resorption is regulated by the presence of the protein, OPG. Secreted by osteoblasts, OPG acts as a decoy receptor antagonist for RANKL i.e. it binds to RANKL thereby preventing RANKL from binding to RANK and halting osteoclast activation. The RANKL/OPG ratio is therefore an important determinant of bone mass and integrity.
In myeloma, the RANKL/OPG ratio is unbalanced. Myeloma cells induce RANKL expression in stromal cells within the bone microenvironment through direct cell-cell contact. In addition, they decrease OPG levels by inhibiting their secretion in osteoblasts and stromal cells.
The overall result is an increased RANKL/OPG ratio in the bone marrow microenvironment that favours the maturation and activation of osteoclasts and bone resorption.
Bone formation
In contrast to bone metastases in other malignancies, myeloma causes bone destruction without sufficient osteoblastic response to repair. This leads to lytic lesions and suggests something is inhibiting bone formation. The canonical Wingless-type (Wnt) cell signalling pathway is recognised to play a central role in osteoblast function and bone development.
Wnt signalling and therefore bone formation is controlled by a number of proteins. In myeloma, the most significant protein is Dickkopf-1 (Dkk-1). Dkk-1 is a Wnt pathway inhibitor, and is secreted by myeloma cells and acts to inhibit the Wnt signalling pathway and therefore osteoblast differentiation. At the same time, Dkk-1 supresses OPG expression thereby increasing bone resorption.
Targeting the signalling pathways for both bone resorption and formation is a key area of clinical research. The two main classes of treatment for myeloma bone disease, bisphosphonates and denosumab, both work by inhibiting osteoclast activity.
Watch the following animation which describes what happens during normal bone metabolism, how it becomes disrupted in myeloma and what the possible consequences are:
Further reading
Roux et al. (2025) Tackling myeloma bone disease: From pathophysiology to cutting-edge therapies. Blood Reviews, https://doi.org/10.1016/j.blre.2025.101305