RANKL as a target for the treatment of osteoporosis
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INVITED REVIEW
RANKL as a target for the treatment of osteoporosis Toshio Matsumoto1 · Itsuro Endo2 Received: 9 August 2020 / Accepted: 23 August 2020 © The Japanese Society Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2020
Abstract Osteoporosis is characterized by compromised bone strength, predisposing to an increased risk of fracture. Because bone is constantly remodeled, and bone mass and structure are determined by the balance between bone resorption and bone formation, it is important to maintain normal bone turnover. Therefore, therapies that reduce bone resorption have been the mainstream of osteoporosis treatment. Receptor activator of nuclear factor-kappa B ligand (RANKL)-RANK signaling was found to play a pivotal role in the regulation of osteoclastic bone resorption, and inhibition of RANKL-RANK system has become an important therapeutic target for the treatment of osteoporosis. Denosumab, a fully human monoclonal antiRANKL neutralizing antibody, is developed as a drug for the treatment of osteoporosis. This review summarized pharmacokinetic and pharmacodynamic properties of denosumab, clinical studies including phase 2 dose-ranging and its extension study, phase 3 fracture prevention study (FREEDOM) with extension up to 10 years, studies on male osteoporosis (ADAMO study), and on glucocorticoid-induced osteoporosis, along with relevant clinical studies in Japan. In addition, mechanism of denosumab action that can explain its long-term sustained effects, combination and sequential treatment as well as the problems in discontinuation of denosumab, and finally safety of denosumab therapy is discussed. Keywords Denosumab · Bone resorption · Bone turnover marker (BTM) · Bone mineral density (BMD) · Fracture
Introduction The risk of fracture increases with age due to an increase in bone fragility by osteoporosis. With the aging of society in the world including Japan, the risk of osteoporotic fractures increases. Therefore, there is an urgent need for treatment of osteoporosis. Osteoporosis is characterized by compromised bone strength, predisposing to an increased risk of fractures. Bone strength is composed of bone mineral density (BMD) and bone quality. Bone quality is deteriorated by a damage in bone microarchitecture such as loss of trabecular connectivity and cortical porosity or in material properties such as microcracks, derangement of collagen crosslinks
* Toshio Matsumoto toshio.matsumoto@tokushima‑u.ac.jp 1
Fujii Memorial Institute of Medical Sciences, Tokushima University, 3‑18‑15 Kuramoto‑cho, Tokushima‑shi, Tokushima 770‑8503, Japan
Department of Bioregulatory Sciences, Tokushima University Graduate School of Medical Sciences, Tokushima, Japan
2
and abnormal mineralization. Because bone is constantly remodeled, and bone mass and structure are determined by the balance between bone resorption and bone formation, it is important to maintain normal bone turnover. Therefore, therapies that reduce bone resorption have long been the mainstream of osteoporosi
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