Inflammatory bone loss: pathogenesis and therapeutic intervention

Bone homeostasis is dependent on the concerted actions of bone-building osteoblasts and bone-degrading osteoclasts — a process called bone remodelling.Two of the major factors that induce osteoblast differentiation and activation are: the signalling mediated by bone morphogenetic proteins via runt-related transcription factor 2; and the WNT–Frizzled–β-catenin pathway. Conversely, Dickkopf-related protein 1 (DKK1) and sclerostin inhibit osteoblast activation.Major molecules involved in osteoclast differentiation and activation include macrophage colony-stimulating factor and receptor activator of nuclear factor-κB (RANK) as well as its ligand (RANKL).Inflammation is associated with the overproduction of various cytokines, such as tumour necrosis factor, interleukin-1 (IL-1), IL-6 or IL-17. Their upregulation in the course of inflammation leads to excessive bone degradation mainly due to hyperactivation of osteoclasts, although some cytokines can also impair osteoblast function.Many diseases lead to inflammatory bone loss, including inflammatory bowel disease, chronic obstructive lung disease, cystic fibrosis, periodontitis, rheumatoid arthritis and other inflammatory diseases.Inflammatory bone loss is always systemic, and in some diseases — such as rheumatoid arthritis or periodontitis — it can also involve local bone.Therapies interfering with inflammation also affect systemic inflammatory bone loss, primarily by reducing the effects of cytokines on osteoclast activation; however, many of these treatments will not fully control inflammation. Owing to this ongoing inflammatory activity (even at low levels), bone loss will continue to accrue and therefore also requires specific targeting of bone cells.Bisphosphonates and denosumab are among the bone-targeting therapies that have been shown to be effective in treating inflammatory bone loss, but it is assumed that blockers of DKK1 and sclerostin — which are upregulated by cytokines and inhibit osteoblast repair mechanisms — are also likely to be effective.