For many years, it was known that osteoblasts regulate the differentiation of the osteoclast precursors (OPG) and the activation of osteoclasts (OC). It was also recognised that inflammatory and infectious diseases affect the skeleton by means of inflammatory cytokines and produce localised bone lesions or generalised osteoporosis. However, the molecular mechanisms and the connection between the immune cells and bone cells that produce bone destruction were unknown. It has now been well established that osteoclasts are derived from the haematopoietic stem cells that also give rise to immune cells. In the 1980s, it was shown that the RANK/RANKL/OPG system plays a crucial role in the osteoclastogenesis. It was also demonstrated that calcitonin and some inflammatory mediators, such as PGE2 and interferon-γ inhibit the osteoclastic bone resorption. Osteoclasts are positively regulated by TRANCE-TRANCE-R signalling and negatively by OPG. Studies show that activated T-cells may induce osteoclastogenesis through expression of TRANCE (TNF-related activation cytokine, a member of the TNF family) (Fig. 96.1). But activated T-cells can also produce interferon-γ and, via this pathway, suppress osteoclastic activity. This suggests that activated T-cells may both positively and negatively regulate osteoclastic bone resorption. This balance may be influenced by local and systemic factors, including infections, nutrition, metabolism, mechanical factors, hormones and cytokines (TNFs and interleukins).