Bone Disease

Bone disease is a key feature of multiple myeloma.27 Almost 80% of patients have abnormalities in bone radiographs at diagnosis.28 This bone disease is characterized by lytic lesions commonly found in the vertebrae, ribs, skull, shoulders, pelvis, and long bones.29 Osteolytic lesions develop as a result of uncoupled bone remodeling and are observed in up to 90% of patients during the disease course.27,29,30 Bone disease can lead to severe bone pain, hypercalcemia, and skeletal related events (SREs) defined as spinal cord compression, pathological fracture, radiation to bone, and surgery to bone.6,31

Factors and Cellular Source

  • ↑ MIP-1α; MM cells;31
  • ↑ IL-6; BMSCs, endothelial cells, osteoclasts;31,33
  • ↑ RANKL; BMSCs, osteoblasts, osteocytes, MM cells;15,30,34
  • ↓ OPG; BMSCs, osteoblasts, osteocystes;15,30
  • ↑ IL-3; MM cells, T cells;35,36
  • ↑ Sclerostin; Osteocytes;30
  • ↑ DKK1; MM cells, osteocytes;30
  • ↑ sFRP-2; MM cells;30

Abbreviations

BMSC
Bone marrow stromal cell
DKK1
Dickkopf homolog 1
IL-3
Interleukin-3
IL-6
Interleukin-6
OPG
Osteoprotegerin
MIP-1α
Macrophage inflammatory protein 1 alpha
RANKL
Receptor activator of nuclear factor kappa-B ligand
MIP-1α
Macrophage inflammatory protein 1 alpha
sFRP-2
Secreted frizzled related protein-2

Binding of multiple myeloma cells to bone marrow stromal cells induces secretion of cytokines and growth factors that play various roles in disease pathogenesis. In addition to increasing anti-apoptotic signaling and expression in myeloma cells, these factors contribute to the uncoupling of bone remodeling. Bone remodeling is a coordinated process of bone resorption by osteoclasts and formation by osteoblasts that renews the skeleton while maintaining structural integrity.32,37 In multiple myeloma, these interactions become uncoupled with an increase in osteoclast activity and reduced or absent osteoblast activity.38 As a result of this imbalance favoring bone resorption, bone lesions form.15,39