Bone remodeling is a cyclic and continuous physiological process, which ensures the conservation and renewal of the bone matrix. Osteosynthesis of the bone matrix is achieved by osteoblasts and coordinated within this complex machinery of bone remodeling with resorption of extracellular bone matrix performed by osteoclasts. The mismatch between the activities of osteoblasts and osteoclasts has immunopathologic implications associated with either a decrease or increase of bone mass mineral density. The balance of the trimolecular control factor complex composed of osteoprotegerin (OPG), RANKL (osteoprotegerin ligand) and RANK maintains physiologic bone remodeling. This trimolecular complex functions as receptors and ligands and belongs to the superfamily of tumor necrosis factor (TNF). This mini review highlights the complex interplay of the RANKL-RANK/OPG axis and their immunopathologic implications in clinical medicine.