Parathyroid hormone (PTH) paradoxically increases both bone resorption (via osteoclasts) and bone formation (when given intermittently as teriparatide). Which cellular mechanism explains how PTH promotes osteoclast-mediated bone resorption, given that osteoclasts lack PTH receptors?

• A PTH activates calcitonin receptors on osteoblasts, which release cathepsin K to dissolve bone matrix
• B PTH increases urinary calcium loss, which signals osteoclasts to release calcium from bone
• C PTH binds osteoblasts → upregulates RANKL expression on osteoblast surface → RANKL binds RANK on osteoclast precursors → osteoclastogenesis and osteoclast activation ✓
• D PTH directly enters osteoclasts via transcytosis and activates intracellular PKA

Explanation

Osteoclasts lack PTH1R receptors. PTH acts indirectly: it binds osteoblasts and stromal cells via PTH1R (Gs-coupled) → cAMP → PKA → increases RANKL expression and decreases OPG (osteoprotegerin, the decoy receptor for RANKL). The net rise in RANKL/OPG ratio allows RANKL to bind RANK on osteoclast precursors and mature osteoclasts, driving osteoclastogenesis, osteoclast activation, and bone resorption. Bisphosphonates and denosumab (anti-RANKL antibody) exploit this pathway. Intermittent PTH (teriparatide) anabolically activates osteoblasts when signalling is transient rather than continuous.

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

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