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With the increasing life expectancy of patients with cystic fibrosis (CF), prevalence of late complications such as CF-related bone disease (CFBD) has increased. It was initially described in 24% of the adult population with CF and has also been reported in the pediatric population. CFBD is multifactorial and progresses in different steps. Both decreased bone formation and increased bone resorption (in different amounts) are observed. CFBD is likely primitive (directly related to the CFTR defect itself), but is also worsened by acquired secondary factors such as lung infections, chronic inflammation, denutrition, vitamin deficiency, and decreased physical activity. CFBD may be clinically apparent (i.e., mainly vertebral and costal fractures), or clinically asymptomatic (therefore corresponding to abnormalities in bone density and architecture). CFBD management mainly aims to prevent the occurrence of fractures. Prevention and regular monitoring of bone disease as early as 8 years of age is of the utmost importance, as is the control of possible secondary deleterious CFBD factors. New radiological tools, such as high-resolution peripheral quantitative computed tomography, allow an accurate evaluation of cortical and trabecular bone micro-architecture in addition to compartmental density; as such, they will likely improve the assessment of the bone fracture threat in CF patients in the near future., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A better knowledge of physiopathologic phenomena responsible for vascular mineralization leads to emerging biological markers of vascular calcifications. In calcified arteries, the presence of bone matrix as well as osteoblast cells suggest that vascular calcification is an active and highly regulated process. The OPG/RANK/RANKL system is clearly of central significance in controlling vascular calcifications as in bone metabolism. Converging results suggest that circulating OPG determination should be a relevant marker of calcifications. The OPG/RANK/RANKL pathway also represents a potential therapeutic target in diseases associated with high bone resorption.

Bone homeostasis is maintained by the remodelling of bone which depends on a balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Malignant bone lesions are very common in patients with cancer; whether they result from a tumor in bone (giant cell tumour of bone, osteosarcoma, multiple myeloma...) or they are bony metastases from advanced cancers of which the most osteotropic are breast and prostate cancer. Malignant cells within the bone disrupt the normal bone remodelling process, leading to increased bone destruction and occurence of pathological fractures. Receptor activator of NF-kB (RANK) and its ligand (RANKL) play a pivotal role in the regulation of bone remodelling; by binding to RANK, RANKL stimulates osteoclastogenesis and bone resorption, whereas its cognate decoy receptor osteoprotegerin (OPG) blocks this process by interacting with RANKL. Tumour cells produce different factors that manipulate the RANK/RANKL/OPG pathway in order to stimulate bone destruction. Furthermore, pending on the tumour type, RANKL plays a role in the migration, invasion and proliferation of malignant cells within the bone, while OPG increases survival of tumour cells. Inhibition of RANK/RANKL system may therefore offer new therapeutic perspectives for the treatment of primitive and secondary bone cancers.

Study of dysregulations of the immune system resulting in abnormal bone homeostasis has led to the emergence of the field of osteoimmunology. Among the interactions between the immune system and bone, several signaling molecules and pathways previously identified in immune cells have been shown to be key players in the osteoclast, the bone resorbing cell. Osteoclast differentiation requires two signaling pathways: the RANK/RANKL pathway and the signal initiated by the ITAM-harboring adaptor proteins DAP12 and FcRgamma. Until recently, it was unclear how RANK and ITAM signals merge to cooperatively stimulate activation of NFATc1, the master transcription factor in osteoclastogenesis. A recent study from H. Takayanagi's group has shown that the tyrosine kinases Btk and Tec form a multiprotein complex with adaptor molecules such as BLNK, that is able to integrate these two signaling pathways and thus stimulate osteoclastogenesis. Taken together, these new data open novel clinical perspectives especially for osteoarticular inflammatory diseases.

Bone tissue undergoes permanent remodeling based on the coupled activity of osteoclasts resorbing old bone and osteoblasts forming a new matrix. The latter are considered as the main target of remodeling control pathways. Indeed, they have the full control of osteoclastogenesis through RANK-L / osteoprotegerin, the most critical pathway in the balance between bone formation and resorption. They also are under the effects of numerous transcription factors, especially members of the AP1 complex as well as the canonic Wnt - betacatenin pathway. Most bone tissue pathologies are mediated by alterations of these remodeling control pathways. Therefore, lots of efforts are made to modulate these factors which are very interesting potential therapeutic targets.

Given the increasing risk of fractures with aging in western countries, there is a need for the development of safe and efficient anti-osteoporotic drugs for the prevention and treatment of osteoporosis. Recent studies have provided evidence for an essential role of RANKL (Receptor Activator of Nuclear Factor-kappa B Ligand) and its decoy receptor osteoprotegerin in the control of osteoclast differentiation and survival. Post-menopausal osteoporosis results from an imbalance between resorption and formation associated with decreased OPG/RANKL. Targeting the OPG/RANKL system may therefore have a beneficial impact in osteoporosis. Accordingly, the development of novel strategies targeting OPG/RANKL using anti-RANKL or therapeutic intervention proved to be efficient to reduce bone resorption and to prevent bone loss in postmenopausal osteoporosis. This opens the way for novel therapeutic strategies for correcting bone metabolism in various pathologic disorders characterized by increased bone remodelling and bone loss.