In multiple myeloma, the cytokine primarily responsible for osteoclast activation and bone resorption, leading to lytic lesions without blastic activity, is secreted by myeloma cells and bone marrow stromal cells. Which molecule is now recognized as the key osteoclast-activating factor targeted by denosumab?

• A Receptor activator of NF-kappaB ligand (RANKL) ✓
• B Interleukin-6 (IL-6)
• C Macrophage inflammatory protein-1 alpha (MIP-1α)
• D Dickkopf-1 (DKK1)

Explanation

Myeloma cells stimulate osteoblasts and stromal cells to secrete RANKL, which binds RANK on osteoclast precursors, driving osteoclastogenesis and bone resorption. Simultaneously, myeloma cells suppress osteoprotegerin (OPG), the decoy receptor for RANKL. Denosumab is a monoclonal antibody against RANKL, used in myeloma bone disease. IL-6 is the main growth factor for myeloma cells. MIP-1α also promotes osteoclast activity. DKK1 inhibits osteoblast differentiation, explaining the absence of blastic response.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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