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Romosozumab is a bone-forming agent with a dual effect of increasing bone formation and decreasing bone resorption by inhibiting sclerostin. In the pivotal Fracture study in postmenopausal women with osteroposis(FRAME)and the extension trial, 12 months of romosozumab led to persistent fracture, especially new vertebral fracture, reduction benefit and ongoing BMD(bone mineral density)gains when follow 24 months of denosumab. The sequence therapy of romosozumab followed by denosumab may be a promising regimen for the treatment of osteoporosis.

Zoledronic acid is a bisphosphonate with the most potent anti-bone resorbing activity. Several previous studies demonstrated that zoledronic acid once a year significantly reduced the risk of vertebral, non-vertebral, and hip fractures in postmenopausal women. In a phase Ⅲ 2-year placebo-controlled, randomized, double-blind comparative study in Japan(ZONE study)demonstrated that once-yearly infusion of zoledronic acid 5 mg increased lumbar spine and proximal femoral BMD, and reduced the incidence of vertebral and non-vertebral fractures in Japanese patients with primary osteoporosis compared to placebo.

In osteoporosis, the risk of fracture is influenced by decrease of bone mineral density and deterioration of bone quality. The latter includes deterioration of the material and structural properties of bone. These changes arise from the influence of changes in hormonal balance, aging, changes in mechanical stress, lifestyle-related diseases, etc. on bone absorption and bone formation as the coupled functions of osteoclasts and osteoblasts. Deterioration of bone quality occurs at various levels ranging from the molecular to the tissue level, or even at the individual level, and leads to an increased fracture risk. In this chapter, bone quality evaluation using quantitative computed tomography is discussed among evaluation methods of various fracture risk.

Rheumatoid arthritis (RA) is an autoimmune diseases characterized by inflammation and destruction of bone and cartilage. Osteoclastogenesis induced by inflammatory cytokines contributes to focal and systemic bone and cartilage destruction including secondary osteoporosis. Recent progress in treatment enables us to prevent disease activity. Not only anti-inflammatory management but also therapies directly targeting bone metabolism can further prevent bone destruction in RA.

The importance of receptor activator of nuclear factor-κB ligand(RANKL)during osteoclastogenesis was discovered in 1998. After that Nfatc1, downstream gene of RANKL-RANK signaling, was identified as a master regulator of osteoclastogenesis by transcriptome analysis. In recent years, with the advancement of epigenetic analysis method and big data analysis technology, epigenetic analysis about osteoclastogenesis gradually progresses. Some papers using H3K4me3 and H3K27me3 histone modification change data, DNase-seq data and formaldehyde-assisted isolation of regulatory elements(FAIRE)-seq data during osteoclastogenesis were published recently. It will probably contribute to elucidate the crosstalk between osteoclasts and osteoblasts, osteocytes or chondrocytes in the future.

Joint cartilage is under exposure to repetitive mechanical stress. It is well known fact that the mechanical stress is a major cause of joint disorders such as osteoarthritis. However the molecular mechanisms of cartilage under mechanical stress remain unclear. In recent years, some notable mechanosensor or signal cascades relating to mechanotransduction had been identified, which might be promising targets for treatment of joint disorders.

Significant advancement in pharmacological treatment including biological agents has gradually changed the role and content of surgical treatments for patients with rheumatoid arthritis. The number of joint replacements in the large joints of lower limbs has decreased, while the number of surgeries in the small joints of hand and feet has increased. Favorable disease control by pharmacological treatment has changed the needs of patients for surgeries and expanded the options of operative procedures for surgeons. The changing needs of patients demanding the higher level of quality of life may seek a change in the surgical treatments.

RANKL (receptor activator of nuclear factor-κB ligand) critically regulates the differentiation, activation, and survival of the osteoclast, and the hyperactivation of the RANKL-RANK signaling pathway leads to osteoporosis. Denosumab is a complete human monoclonal antibody against human RANKL, and suppresses bone resorption by inhibiting the interaction between RANKL and RANK. Accumulating evidence has demonstrated the clinical usefulness of denosumab on postmenopausal osteoporosis. Although the effectiveness of denosumab on disease activity of rheumatoid arthritis has not been clarified yet, previous studies reported that denosumab significantly increased the bone density of lumbar spine and proximal femur of rheumatoid arthritis patients.

The population of elderly individuals who need nursing care is rapidly increasing in Japan. Locomotive syndrome involves a decrease in mobility due to locomotive organ dysfunction, and increases risk for dependency on nursing care service. Because gait speed and chair stand time are correlated with such risks, patients with locomotive syndrome are assessed using brief methods such as the two-step test, which involves dividing the maximum stride length by the height of the patient, and the stand-up test, which involves standing on one or both legs at different heights. One leg standing and squatting are recommended as beneficial locomotive home exercises. Locomotive syndrome has been recognized widely in Japan, and included in the National Health Promotion Movement (2013-2022).

Osteoporosis is a disorder of bone formation and resorption balance. Advances in our knowledge of the molecular mechanisms of bone formation and resorption led to promising therapeutic targets for osteoporosis. In the novel biological drugs, denosumab, a monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL) has been clinically applied by positive effect on bone mineral density, negative effect on bone resorption, preventive effect on fragility fractures and safety. Odanacatib, a cathepsin K inhibitor is drawing attention as an antiresorptive drug which has lower bone resorption potency than bisphosphoneate. On the other hand, BHQ-880, an anti-Dickkopf-1 (Dkk-1) antibody and romosozumab (AMG-785) , an anti-sclerostin antibody which activate Wnt/β-catenin signaling pathway are drawing attention as bone formation accelerators with no bone resorption acceleration. Clinical studies of these drugs are now ongoing and their clinical applications are expected.

The aim of osteoporosis treatment is to reduce fracture risk. Many kinds of anti-osteoporosis drugs are available in these days, and most of them increase bone mineral density and reduce the risk of fractures. Japanese 2011 guidelines for prevention and treatment of osteoporosis documents the recommendation level of each osteoporosis drugs. It is important to select drugs appropriate for each osteoporosis patient considering the mechanisms of drug action and their clinical efficiency.

Endochondral ossification is an essential process for skeletal development, in which chondrocyte undergoes apoptosis and induces mineralization after terminal differentiation. The apoptosis of chondrocyte is accompanied by marked accumulation of extracellular phosphate ions, which up-regulates the concentration of intra-cellular phosphate ions and leads to the activation of pro-apoptotic factors. The mineralization of chondrocyte is regulated by the orchestrated process mediated by intra-vesicular phosphate ion production by PHOSPHO1, phosphate ion influx into matrix vesicles through Pit-1, and the functions of TNAP and NPP1 that controls pyrophosphate to phosphate ratio in the extra-vesicular progression of mineralization. The apoptosis and mineralization of chondrocyte are related to not only skeletal development but also pathological conditions such as rickets/osteomalacia and osteoarthritis.

Osteoporosis and osteoporosis-related fractures tend to increase year by year around the world including Japan. Denosumab, a fully human monoclonal antibody to receptor activator of NF-κB ligand (RANKL) , a cytokine member of the TNF family essential for osteoclast differentiation has recently been approved in Japan, Europe and the US for the treatment of postomenopausal osteoporosis as well as bone metastasis. In some large clinical trials, denosumab significantly decreased bone resorption, increased bone mineral density (BMD) , and reduced the risk of vertebral, nonvertebral and hip fractures in postmenopausal women. However, the mechanism of adverse events of denosumab, such as hypocalcemia and osteonecrosis of the jaws, has not been completely explained. Therefore, further knowledge should be accumulated by additional basic researches and clinical studies on denosumab.

In rheumatoid arthritis (RA) , the osteoclast pathway is activated by abnormal immune conditions accompanied by chronic inflammation resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors lead to systemic osteoporosis, including reduced physical activity and pharmacotherapies such as steroids. These conditions cause decreased bone mineral density and bone quality, and expose patients to an increased risk of fracture. When treating patients with RA osteoporosis, it is important to improve systemic osteoporosis using anti-osteoporotic agents, and to suppress fracture risk by controlling inflammation (which is associated with periarticular osteoporosis and bone destruction) with a combination of disease-modifying anti-rheumatic drugs or biological agents.

In rheumatoid arthritis (RA) , the osteoclast pathway is activated by abnormal immune conditions accompanied by chronic inflammation, resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors, including reduced physical activity and pharmacotherapies such as steroids, lead to systemic osteoporosis. These conditions cause decreasing bone mineral density and deterioration of bone quality, and expose patients to increased risk of fracture. Understanding the bone structures of RA and evaluating fracture risk are central to the treatment of RA.

In rheumatoid arthritis (RA) , the osteoclast pathway is activated by an abnormal immune condition accompanied by chronic inflammation, resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors including pharmacotherapies such as steroids, and reduced physical activity, lead to systemic osteoporosis. These conditions expose patients to increased fracture risk. In RA treatment, it is important to achieve suppression of fracture risk by controlling inflammation, which is associated with periarticular osteoporosis and bone destruction, using disease-modifying anti-rheumatic drugs or biologic agents and by improving systemic osteoporosis using anti-osteoporotic agents.

In osteoporosis, the risk of fracture is influenced by decrease of bone mineral density and deterioration of bone quality. The latter includes deterioration of the material and structural properties of bone. These changes arise from the influence of changes in hormonal balance, aging, changes in mechanical stress, lifestyle-related diseases, etc. on bone absorption and bone formation as the coupled functions of osteoclasts and osteoblasts. Deterioration of bone quality occurs at various levels ranging from the molecular to the tissue level, or even at the individual level, and leads to an increased fracture risk. Evaluating fracture risk on the basis of a sound understanding of the various etiologies of osteoporosis is important when treating osteoporosis.

Osteoclasts are multinuclear fusion cells derived from monocyte and macropharge lineage cells, which are differentiated in the presence of M-CSF and RANKL. Some transcription factors, such as NFATc1, are known to be associated with osteoclastogenesis however, the epigenetic regulation is not uncovered. Recently it was revealed that the activation and the repression of gene in the ES cells were strictly regulated by the histone modification, such as H3K4/H3K27 trimethylation mark. In this section we review the epigenetic regulation by histone modification and the role in osteoclastogenesis.

Patients with rheumatoid arthritis (RA) often have progression of bone destruction owing to chronic inflammation. Treatment for bone destruction is still insufficient in these patients although goal of treatment has become remission since biologics have been used widely. It is shown that collagen cross-linked C-peptide (CTX- I ) and tartrate-resistant acid phosphatase (TRACP) have correlated with bone destruction in patients with RA, in addition, evidence of new biomarker such as hepatocyte growth factor and macrophage inhibitory factor have been accumulated recently. These biomarkers may help evaluation of bone quality clinically.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is induced by abundant inflammatory cytokines releasing from synovial fibroblasts and T lymphocytes. These cytokines differentiate monocyte-macrophage lineage cells to mature osteoclasts, which cause bone resorption and then joint destruction. RANKL is involved in the development of osteoclasts, cooperating with another key molecule, M-CSF. Indeed, RANKL is over-expressed in the synovium of RA. We summarize RANKL/RANK signaling in RA, including recent therapeutic topics.

The collagen-induced arthritis (collagen-induced arthritis, CIA) is an autoimmune arthritis that resembles rheumatoid arthritis (RA) in many ways, therefore it has been used most commonly as a model of RA. CIA is induced by immunization with an emulsion of complete Freund's adjuvant (CFA) and type II collagen (C II ) . Collagen antibody-induced arthritis (CAIA) is induced by the administration of a cocktail of monoclonal antibodies recognizing conserved epitopes located within the CB11 fragment. CAIA offers several advantages over CIA, including rapid disease onset, high uptake rate, and the capacity to use genetically modified mice, such as transgenics and knockouts.

Bone homeostasis is maintained by delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. Bisphosphonates are widely used nowadays by suppressing bone resorption to treat patients with osteoporosis, which results from high bone turnover, causing excessive bone resorption phase. While bisphosphonates increase bone mineral density and improve back pain due to spinal compression fracture, they may have some problems such as osteonecrosis of jaw and excessive suppression of bone turnover. Cathepsin K inhibitor, which has a new mechanism in addition to function of suppressing bone resorption, is recently focused. Cathepsin K is a protease which specifically expresses in osteoclasts and plays an important role in resolution of bone collagen. Cathepsin K inhibitor has a potential of inhibiting bone resorption without suppressing bone formation and could be an attractive therapeutic target of osteoporosis.

It is now widely recognized that the RANKL-RANK-OPG signaling system plays an important role in the differentiation, activation and cell death of osteoclasts. Recently, several genetic disorders involving the RANKL-RANK-OPG system have been discovered. In this article, we would like to show a brief review on a genetic disorder familial expansile osteolysis (FEO) , in which RANK gene mutation was identified, and other genetic disorders of the RANKL-RANK-OPG system.

Osteoporosis is a disease in which the density and quality of bone is reduced, leading to an increase in fragility fractures. Osteoporosis is a major health threat affecting more than 10 million people in Japan. Emerging evidence has shown that anti-resorptive drugs such as bisphosphonates and raloxifene efficiently increase bone mass and prevent osteoporotic fractures by maintaining bone homeostasis. In addition, anabolic drugs such as parathyroid hormone and novel anti-resorptive drugs such as anti-RANKL drugs and cathepsin K inhibitors, which directly target osteoclasts are under development. In this review, we would like to summarize the current status of the development of anti-osteoporotic drugs.

We should consider not only controlling disease activity using DMARDs and biologics as a matter of course, but also preventing against joint destruction, in the treatment for rheumatoid arthritis. Although we can indirectly regulate bone erosion via controlling disease activity, the osteoclast-targeting therapy might be more effective to stop joint destruction. We are waiting for new drugs directly targeting osteoclasts, such as OPG which is the natural inhibitor of RANKL, or cathepsin K inhibitor which reduces degeneration of bone matrix.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized progressive joint destruction. Recent studies have revealed an essential role of receptor activator of NF-kappaB ligand (RANKL) in bone destruction in RA, and therapeutics targeting RANKL has been attracting a great deal of attention.

The majority of current therapeutics for osteoporosis is targeting bone resorption by osteoclasts. Bisphosphonates, potent and specific inhibitors of bone resorption, are widely used for postmenopausal osteoporosis on the basis of large scale clinical trials which proved their ability to reduce fracture risk. Estrogen, which had been widely used in the US, lost its position of standard drug therapy for osteoporosis because of the recent evidence of increasing adverse events. On the other hand, the market share of selective estrogen-receptor modulators (SERMs), which utilize valuable functions of estrogen and have less adverse effects, has been climbing. Other novel therapeutic agents which aim at signal transduction of osteoclast differentiation and activation are promising as specific inhibitors of bone resorption.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone destruction, in which proinflammatory cytokines such as tumor necrosis factor-alpha play essential roles. Recent studies have revealed an important involvement of osteoclasts in bone destruction of RA. In this review, I would like to explain the molecular mechanism of osteoclast development in RA, and propose the possibility of anti-osteoclast therapy to the disease.

Purpose: To report recurrent fungal endophthalmitis which developed after endogenous fungal endophthalmitis. The patient was suspected to be suffering from Munchausen syndrome., Case: A 44-year-old woman contracted endogenous fungal endophthalmitis in her right eye in October 2000. After the endophthalmitis was healed by vitrectomy, corneal ulcer and endophthalmitis repeatedly occurred in the eye from an unknown cause. The patient finally lost the sight of her right eye. The corneal ulcer and endophthalmitis resulted from self-injury for which we found material evidence in the course of the treatment. Munchausen's syndrome was suspected but the patient persistently refused to see a psychiatrist., Conclusion: We must be prepared to provide mental and psychiatric care in addition to ophthalmological treatment for such a case.

A therapeutic vaccine approach, targeting RANKL, can be used to inhibit bone destruction in pathological bone loss conditions such as osteoporosis, rheumatoid arthritis and bone metastasis. Compared to other therapeutic recombinant protein against pathological antigen such as monoclonal antibodies, soluble receptor or other antagonists, a vaccine needs small doses of protein to induce its affect. Once the immune response is established by vaccination, it is maintained by boosting with the vaccine. This RANKL vaccination would be a novel approach to any kind of pathological bone

Rheumatoid arthritis (RA) is characterized by the presence of inflammatory synovitis accompanied by cartilage and bone destruction. Histological examination of RA pannus shows a number of osteoclasts on the surface of the destructed bone. RA synovial tissues produce a variety of proinflammatory cytokines and growth factors that may increase osteoclast formation, activity, and/or survival. Synovial fibroblasts from RA patients express high levels of RANKL, which is essential for the differentiation of osteoclasts, and therefore, RANKL can be a good therapeutic target of joint destruction in RA.

The vaccination method is used to induce antibody response against disease-related proteins by immunization with modified pathological antigen as preventive therapy to acquire disease resistance. A RANKL vaccine was developed by modifying the soluble TNF-like domain of murine RANKL to incorporate a promiscuous Th epitope. Immunization with RANKL vaccine prevented pathological bone resorption in arthritic mice or ovariactomized mice.

Osteopetrosis is a genetic disorder characterized by increased bone mass due to the reduced bone resorption. It is also characterized by the discrepancy between bone mass and bone strength. In this review, I would like to introduce the up-to-date of the research and treatment of osteopetrosis.

Injury to the articular cartilage occurs under various pathological conditions such as trauma, inflammation and aging and is followed by osteoarthritic changes of the affected joints. Recently, some studies have revealed that enough chondrogenic proliferation was required using some factors such as TGF-beta and BMPs. We, also, have reported that synovial tissues include multipotent mesenchymal stem cells, which can differentiate into chondrocytes. These results suggest that not only are synovial cells a good therapeutic target of inflammatory joint diseases, but also can be utilized for tissue engineering of cartilage.

RANKL is a membrane-bound cytokine, which plays an important role in osteoclast differentiation and activation. We established a novel therapeutic approach against pathological bone resorption using RANKL vaccine. Administration of RANKL vaccine induced a rapid anti-RANKL antibody induction in mice, and efficiently suppressed bone destruction in arthritis model mice, and bone loss in ovariectomized mice.