![]() Thereby, a clear connection between the skeletal and the immune system has been established which, in the last two decades, was further complemented by the pioneering work on the role of T-helper 17 (Th17) cells in osteoimmunology (Sato et al., 2006 Tsukasaki and Takayanagi, 2019). Amongst these are proinflammatory cytokines such as interleukin 1 (IL-1), and tumour necrosis factor (TNF), which already in the 1980s have been demonstrated to stimulate bone resorption (Bertolini et al., 1986 Gowen et al., 1983). The role of RANKL as a key regulator of bone homeostasis is strengthened by the fact that many other cytokines known to influence bone resorption do so by indirectly manipulating RANKL signaling. ![]() In addition to osteoblasts and bone marrow stromal cells, RANKL is expressed also by osteocytes and by various extraskeletal cells and tissues including cells of lymphoid tissues (Leibbrandt and Penninger, 2008 Nakashima et al., 2011). RANKL was initially found to be expressed by osteoblasts and its progenitors and, together with macrophage colony-stimulating factor (M-CSF), is regarded as a master regulator of osteoclast survival, activation, and differentiation from hematopoetic linage cells (Boyce and Xing, 2008). A major step forward in understanding this “coupling” process was the discovery of receptor activator of nuclear factor-kB (RANK), its ligand RANKL and its decoy receptor osteoprotegerin (OPG). In particular remodeling depends on a fine tuned crosstalk between these protagonists to ensure that the amount of bone resorbed by osteoclasts equals the amount of bone formed by osteoblasts and thereby, to ensure the maintenance of bone mass. Key cellular components in bone modeling and remodeling are three types of bone cells: bone resorbing osteoclasts, bone forming osteoblasts, and osteocytes, former osteoblasts that have become trapped in the bone matrix (Figure 1 (Fig. The crucial role of remodeling in overall bone homeostasis is highlighted by the fact that impaired remodeling favoring bone resorption over bone formation is a fundamental pathophysiological mechanism leading to bone pathologies such as osteoporosis. Additionally, remodeling processes maintain calcium and phosphate homeostasis by targeted release and incorporation from and into the bone matrix. Remodeling, in contrast, is a highly coordinated process of concomitant resorption and formation at a distinct site and is responsible for the maintenance of skeletal integrity by renewing old and damaged bone. Thereby, changes in dimensions and shape of bone during growth and adaption of bone to altering mechanical demands are facilitated. During modeling either bone formation or bone resorption occur independently at distinct sites. In order to perform its diverse functions, bone undergoes continuous cycles of modeling and remodeling. Accordingly, it is now well accepted that bone, in addition to its classical roles in locomotion, protection of internal organs, and regulation of mineral homeostasis, contributes to the regulation of glucose metabolism and energy expenditure and influences male fertility and cognitive functions through the secretion of osteocalcin by osteoblasts (Ponzetti and Rucci, 2019 Wei and Karsenty, 2015). Research over the years has evidenced the central role of bone as an organ that is in constant exchange with and regulates several other tissues. Based upon our personal expertise, a special focus will be given to osteoimmunology. This article is intended to contribute to this goal in reviewing disease mechanisms, the current and potential future treatment options for osteoporosis. With the aging of our societies, it is very likely that the number of patients suffering from osteoporosis will increase dramatically thus, intensive further research to identify novel therapeutic targets urgently is needed. In contrast to other musculoskeletal diseases such as osteoarthritis or sarcopenia, for osteoporosis effective treatment options that interfere with the underlying disease processes are available nevertheless, in clinical reality only a relatively small fraction of patients is treated adequately. Although osteoporosis can occur at any age and in both genders, it typically is an age related disease that more frequently affects women than men. Furthermore, bone strength is defined to “primarily reflect the integration of bone density and bone quality” (NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001). Osteoporosis, the most frequent form of metabolic bone diseases, is defined as a ”skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture”.
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