TNFRSF11B encodes osteoprotegerin (OPG), a decoy receptor that acts as the primary negative regulator of osteoclastogenesis. OPG binds RANKL (TNFSF11), preventing its interaction with RANK and thereby inhibiting osteoclast differentiation and activation 1. This regulatory function is critical for bone homeostasis, as the local ratio between RANKL and OPG determines bone resorption rates 2. Beyond skeletal effects, OPG inhibits TRAIL-induced apoptosis and may prevent arterial calcification 3. Clinically, TNFRSF11B dysfunction causes juvenile Paget disease (JPD), a rare disorder characterized by mutations that reduce OPG function, resulting in severely accelerated bone turnover, progressive skeletal deformity, hearing loss, and vascular complications including arterial aneurysms 4. Loss-of-function mutations in TNFRSF11B cause generalized, extremely rapid bone remodeling that requires life-long anti-resorptive therapy 4. Conversely, TNFRSF11B polymorphisms that enhance OPG function show protective effects against fractures in older adults, with 13-37% risk reduction in postmenopausal women 56. RANKL inhibition via denosumab (anti-RANKL antibody) improves bone strength and additionally enhances muscle function and insulin sensitivity 7, suggesting pleiotropic therapeutic potential.