Clinical calcium最新文献

In bone tissues, there are various kinds of cell types, such as osteoclasts, osteoblasts, monocytes, granulocyte, lymphocytes, mesenchymal cells and hematopoietic stem cells. They form a network with each other, and play critical roles in our life activities. The recent development of intravital two-photon imaging has enabled us to visualize the in vivo behavior of bone marrow cells in living bone tissues. This technique facilitates investigation of cellular dynamics in the physiology and pathogenesis of bone disorders in vivo, and would thus be useful for evaluating the efficacy of novel drugs. In this review, we summarize the basis of intravital bone imaging, and also discuss its further application.

Bone tissue consist of a wide variety of cells such as osteoclasts, osteoblasts and osteocytes which are involved in bone metabolism, hematopoietic cells which can differentiate and mature in the bone marrow, other mesenchymal cells and nerve cells. Recent advances in "fluorescent imaging technology" have made it possible to observe bone tissue alive. And intravital imaging enable us not only to examine the "morphology" but also to analyze the "dynamics" of the cells. We have improved "two-photon microscope" which can observe deep tissue with minimally invasive manner and have established an imaging method to observe the movement of cells in living bone tissue in real time. In this review, we summarize the methodology of intravital imaging, such as the principle of two-photon excitation microscope, method of in vivo imaging of bone, and analysis of acquired imaging data.

Fluorescent molecules are widely used as a tool to directly visualize target biomolecules in vivo. Fluorescent probes have the advantage that desired function can be rendered based on rational design. For bone-imaging fluorescent probes in vivo, they should be delivered to bone tissue upon administration. Recently, a fluorescent probe for detecting osteoclast activity was developed. The fluorescent probe has acid-sensitive fluorescence property, specific delivery to bone tissue, and durability against laser irradiation, which enabled real-time intravital imaging of bone-resorbing osteoclasts for a long period of time.

As of February 2018, 5 originator TNF inhibitors(infliximab, etanercept, adalimumab, golimumab and certolizumab pegol)and biosimilar agents of infliximab and etanercept are available for rheumatoid arthritis(RA)in Japan. The effectiveness of TNF inhibitors considerably improves with concomitant methotrexate regardless of their immunogenicity. The Japan College of Rheumatology guideline for TNF inhibitor use in RA has been updated in March 2017 according to recent evidences. During the remission induction phase, maintenance of drug trough level above effective blood concentration is paramount, while the tapering and withdrawal of TNF inhibitors may be considered after achieving sustained remission.

Osteoarthritis(OA)of the knee is a joint disease that is primarily affected by articular cartilage and also affected by subchondral bone and meniscus, leading to walking pain and impairing moving ability and as a result, disability. Knee OA is diagnosed by plain radiograph, however, it is not sensitive enough to detect the association between the pathophysiology and symptom of the disease. Treatment target of knee OA is to improve symptom, mainly pain. A conservative treatment is the principle of knee OA treatment, in which the combination of non-pharmacological and pharmacological treatment is primarily recommended. When the conservative treatment is ineffective, surgical treatment could be selected. It is estimated that there are 25 million people with radiographic knee OA in Japan. Recent researches using MRI and biomarkers, in addition to radiograph, have been revealed the precise mechanisms of pathophysiology of knee OA. Recently, it has been suggested that the pathophysiologies associated with pain in knee OA are altered depending upon the severity of disease. It has been expected that the pathophysiology of early stage knee OA will also be clarified.

It is well known that the rise of FSH is a hallmark of menopause associated with osteoporosis and visceral adiposity. Recent days, Zahidi's group reported that blocking FSH signals prevents bone loss in ovariectomized mice by inhibiting bone resorption and stimulating bone synthesis. The same research group also showed that blocking FSH action reduces body fat volume by promoting beige fat thermogenesis. These findings open new doors for novel and complementary treatments addressing post-menopausal osteoporosis and metabolic diseases.

Diabetes is associated with increased fracture risk, involving a variety of factors. Besides poor glycemic control itself, some glucose-lowering agents are also associated with increased fracture risk. Thiazolidinediones increase fracture risk probably through inhibition of bone formation as well as increased resorption leading to decreased BMD. Sodium-glucose cotransporter(SGLT)-2 inhibitors have been reported to decrease BMD and increase fracture risk. However, the class effect of SGLT-2 inhibitors on bone metabolism remains to be established. In diabetic patients, especially in those with high fracture risk such as postmenopausal women, careful selection of glucose-lowering agents as well as appropriate and timely intervention for osteoporosis is necessary.

Recently, it has been found that systemic metabolic disorders are associated with the onset and progression of various joint diseases. Although osteoarthritis(OA)is mainly a degradative condition of the articular cartilage induced by mechanical stress, there is a growing body of data demonstrating the involvement of metabolic factors including fat metabolism. Recent studies have revealed that adipokines including adiponectin and leptin are associated with inflammation of rheumatoid arthritis. A better understanding of these relationships may lead to new strategies to treat or prevent joint disease such as OA.

Calcimimetics are widely used for severe secondary hyperparathyroidism in hemodialysis patients. Two clinical studies showed that cinacalcet, one of calcimimetics, has possibility to reduce the risk of fracture in hemodialysis patients. Although the mechanism in which calcimimetics reduce the risk of fracture in hemodialysis patients remains unclear, improvement of severe secondary hyperparathyroidism may cause the reduction of fracture risk. However, the optimal intact PTH levels for reducing the risk of fracture in hemodialysis patients is not known. In addition, since calcium-sensing receptor also exists in bone, calcimimetics may have direct effects on bone.

The bones are the most common organ where estrogen-receptor positive breast cancer tends to metastasize. Thus, it is important to treat and prevent bone metastases by studying pathogenesis of developing metastasis to the bones. As advancing treatments have significantly improved the quality of life in patients with bone metastases of breast cancer. Among them, bone-modifying agents have been playing the most crucial roles by reducing the rate of skeletal related events and also having a possibility of favorable effects on prognosis. Zoledronic-acid and denosumab are currently available and denosmab seems to be superior to zoledronic-acid in inhibiting osteoclastic activity. Although both of these are safe drugs, several rare but serious adverse events need to be cautious like osteonecrosis of the jaw, hypocalcemia, renal dysfunction and atypical fracture.