Bone Disease Biology

Osteoclast-mediated bone resorption is balanced with osteoblast-mediated new bone formation.45 Any disruptions to this delicate balance favoring resorption can result in bone loss, weakened structural integrity and greater potential for bone complications known as skeletal related events, as previously defined.37,41,45 In multiple myeloma, due to interactions between the tumor cell and bone marrow stromal cells, the normal bone remodeling process becomes uncoupled on a cellular level that strongly favors bone resorption.15,40,46,47

Normal bone remodeling: bone resorption balanced by bone formation 40,48




Factors and Cellular Source

  • ↑ MIP-1α; MM cells;41
  • ↑ IL-6; BMSCs, endothelial cells, osteoclasts;41,49
  • ↑ RANKL; BMSCs, osteoblasts, osteocytes, MM cells;15,40,50
  • ↓ OPG; BMSCs, osteoblasts, osteocystes;15,40
  • ↑ IL-3; MM cells, T cells;51,52
  • ↑ Sclerostin; Osteocytes;40
  • ↑ DKK1; MM cells, osteocytes;40
  • ↑ sFRP-2; MM cells;40

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

What changes occur in the tumor microenvironment in multiple myeloma?

In the bone marrow, interaction of myeloma cells with 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 healthy bone remodeling. Increased osteoclast formation and activity results in excessive bone resorption and decreased osteoblast formation and activity results in markedly reduced bone formation in the vicinity of the myeloma cells. Excessive osteolysis near tumor cells may further promote myeloma cell growth, contributing to the cycle of tumor growth and bone destruction.40,41,46,47