The RANK-RANKL-OPG axis regulates osteoclast development. Osteoblasts express RANKL which binds RANK on osteoclast precursors, driving osteoclastogenesis. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL. Denosumab is a monoclonal antibody that inhibits bone resorption. What is its exact mechanism?

• A Denosumab inhibits RANK on osteoclast precursors, preventing RANKL binding and subsequent osteoclast differentiation
• B Denosumab binds and neutralizes RANKL, preventing its interaction with RANK on osteoclast precursors and mature osteoclasts, thereby reducing osteoclastogenesis and osteoclast activity ✓
• C Denosumab is a bisphosphonate that incorporates into hydroxyapatite and is ingested by osteoclasts, inducing osteoclast apoptosis
• D Denosumab activates the OPG receptor on osteoblasts to increase endogenous OPG production in a positive feedback loop

Explanation

Denosumab is a fully human IgG2 monoclonal antibody that binds RANKL (receptor activator of nuclear factor kappa-B ligand) with high affinity and specificity, preventing RANKL from interacting with RANK on osteoclast precursors and mature osteoclasts. This mimics the action of endogenous OPG but with greater potency and duration. By blocking RANK-RANKL signaling, denosumab inhibits osteoclast differentiation, activation, and survival, reducing bone resorption. It is approved for osteoporosis, bone metastases, and giant cell tumor of bone. Unlike bisphosphonates, denosumab's effects are fully reversible upon discontinuation (but rebound hypercalcemia can occur).

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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