A 70-year-old man has serum protein electrophoresis showing an M-spike at 4.2 g/dL (IgG kappa). Bone marrow biopsy reveals 35% plasma cells. He has lytic skull lesions and serum calcium of 11.8 mg/dL. Which cytokine produced by myeloma plasma cells most directly mediates osteoclast activation and lytic bone disease?

• A IL-6 acting directly on osteoclast precursors
• B RANKL (receptor activator of NF-kB ligand) upregulation and OPG downregulation ✓
• C PTHrP secreted by plasma cells
• D TNF-alpha causing cortical bone resorption

Explanation

Multiple myeloma plasma cells and the bone marrow microenvironment upregulate RANKL (also via MIP-1alpha, IL-3, and direct cell contact with osteoblasts) while simultaneously downregulating OPG (osteoprotegerin, the RANKL decoy receptor). The resulting increase in RANKL:OPG ratio activates RANK on osteoclast precursors, promoting osteoclastogenesis and lytic bone destruction. IL-6 supports myeloma cell survival but is not the primary osteoclast activator. PTHrP is a paraneoplastic mediator in solid tumors with hypercalcemia of malignancy.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.