Sclerostin: from bench to bedside
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REVIEW ARTICLE
Sclerostin: from bench to bedside Sakae Tanaka1 · Toshio Matsumoto2 Received: 17 August 2020 / Accepted: 26 October 2020 © The Japanese Society Bone and Mineral Research 2020
Abstract Skeletal integrity is maintained by a meticulous balance between bone resorption and bone formation, and recent studies have revealed the essential role of canonical Wnt signaling pathways in maintaining skeletal homeostasis. The SOST gene, which encodes sclerostin, a member of Dan family glycoproteins, was originally identified as the gene responsible for two sclerosing bone dysplasias, sclerosteosis and van Buchem disease. Sclerostin is highly expressed by osteocytes, negatively regulates canonical Wnt signaling pathways by binding to low-density lipoprotein receptor-related protein (LRP) 5/6, and suppresses osteoblast differentiation and/or function. Romosozumab, a specific anti-sclerostin antibody, inhibits sclerostinLRP5/6 interactions and indirectly activates canonical Wnt signaling pathways and bone formation. This review focuses on the mechanism of action of sclerostin and summarizes clinical studies that demonstrated the efficacy of romosozumab to increase bone mineral density and reduce osteoporotic fractures, as well as its cardiovascular safety. Keywords Osteoporosis · Fracture · Remodeling · Sclerostin · Romosozumab
Introduction Osteoporosis is a serious health concern, particularly in aging societies. The burden of osteoporosis, in particular, the morbidity and mortality caused by osteoporosis-related fragility fractures, has become a critical socioeconomic problem. The US National Institutes of Health (NIH) consensus statement defines osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture [1]. Skeletal integrity is maintained by a balance between bone resorption and bone formation, a process called bone remodeling, which continues throughout life. Bone remodeling is triggered by osteoclasts (“activation” phase defined as the conversion of the bone surface from the quiescent to active state) followed by the differentiation of osteoclast precursors into mature osteoclasts (“resorption” phase). In the “reversal” phase,
* Sakae Tanaka tanakas‑[email protected]‑tokyo.ac.jp 1
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7‑3‑1 Hongo, Bunkyo‑ku, Tokyo 113‑0033, Japan
Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
2
osteoclasts complete the resorption process and generate signals that directly or indirectly initiate bone formation, and in the “formation” phase, mesenchymal cells differentiate into functional osteoblasts to form a bone matrix, and the bone surface returns to the quiescent state [2–4]. The duration of the resorption phase is relatively short (2–4 weeks) compared with the formation phase (4–6 months), and the life span of osteoclasts is much shorter than that of osteoblasts. Therefore, increased bone remodeling n
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