A 55-year-old woman presents with a lytic lesion in the proximal femur with a 'soap bubble' appearance and cortical expansion. Biopsy shows large mononuclear stromal cells, abundant osteoclast-like giant cells, and haemosiderin deposits. She is commenced on denosumab. What is the mechanism of action of denosumab in this context?

• A Inhibits osteoclastogenesis by blocking M-CSF receptor (c-Fms) on osteoclast precursors
• B Monoclonal antibody against RANKL, preventing RANKL-RANK interaction on osteoclast precursors and mature osteoclasts, thereby reducing bone resorption ✓
• C Inhibits cathepsin K secretion by mature osteoclasts, preventing collagen degradation in the resorption lacuna
• D Blocks the Wnt signalling pathway to reduce sclerostin production, increasing bone formation

Explanation

Denosumab is a fully human monoclonal antibody (IgG2) targeting RANKL (Receptor Activator of NF-κB Ligand). In GCT, the stromal cells overexpress RANKL, which recruits and activates osteoclast-like giant cells responsible for bone destruction. Denosumab inhibits RANKL-RANK interaction, suppressing osteoclast differentiation and activity, reducing bone destruction. It is now used preoperatively to shrink GCT, convert inoperable to operable, reduce recurrence risk, and treat unresectable/metastatic GCT. Cathepsin K inhibitors (option C, e.g., odanacatib) are a different class; Wnt/sclerostin inhibition (option D) promotes bone formation.

Reference: Maheshwari Essential Orthopaedics, 6th ed.

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Written and medically reviewed by the StethoPrep medical team.