Denosumab targets which pathway?
Denosumab fully human IgG2 mAb 147 kDa XenoMouse transgenic targeting RANKL trimeric TNF superfamily 35 kDa type II membrane expressed osteoblasts stromal activated T lymphocytes secreting soluble form cleaved MMPs. RANKL binds RANK TNFRSF11a osteoclast precursors monocyte macrophage lineage activating adaptor TRAF6 leading NF-kB p52 RelB MAPK c-Fos calcium oscillations calcineurin dephosphorylating NFATc1 driving transcription fusion genes DC-STAMP Atp6v0d2 differentiation multinucleated osteoclasts bone-resorbing forming sealing zone actin ring secreting HCl via V-ATPase acidifying Howship lacuna pH 4.5 dissolving hydroxyapatite cathepsin K degrading type I collagen releasing N-telopeptide crosslinks. OPG secreted decoy normally neutralizes RANKL preventing excessive resorption. Denosumab mimics OPG sequestering RANKL affinity 3 pM preventing engagement inhibiting formation function survival reducing turnover urinary N-telopeptide 80 percent within 3 days increasing BMD spine 9 percent hip 6 percent 3 years. Administration subcutaneous 60 mg every 6 months osteoporosis 120 mg monthly oncology bone metastases providing reversible antiresorptive without incorporation bone matrix unlike bisphosphonates allowing cessation reversal recovery turnover.
Ref: FDA Prolia Xgeva Denosumab RANKL MOA Label; Lancet Denosumab Osteoporosis Trial 2009 Cummings; Alberts Bone Remodeling RANKL Pathway Chapter 22.