Emerging therapeutic opportunities for skeletal restoration View Full Text


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Article Info

DATE

2011-02-01

AUTHORS

Masanobu Kawai, Ulrike I. Mödder, Sundeep Khosla, Clifford J. Rosen

ABSTRACT

Key PointsThere have been major advances in our understanding of skeletal remodelling. Consequently, new therapeutic opportunities have the potential to not only prevent further bone loss but also to augment skeletal mass.Conventional therapies (for example, oestrogens, selective oestrogen receptor modulators, bisphosphonates and calcitonin) for osteoporosis are centred on inhibiting bone resorption, thereby slowing turnover and enhancing mineralization. Fracture-risk reduction is in the order of 30% for non-vertebral sites. The introduction of anabolic agents, such as parathyroid hormone administered intermittently, set the stage for newer approaches for treatment, which focus on bone formation.The emergence of the WNT–β-catenin pathway as a key regulatory network in the process of bone formation has led to novel targets for osteoporosis prevention and treatment.Sclerostin, a protein produced by osteocytes, has been shown to naturally inhibit WNT signalling by binding to the WNT family co-receptors lipoprotein receptor-related protein 5 (LRP5) and LRP6. A monoclonal antibody to sclerostin is in Phase II trials. Animal and Phase I clinical studies show tremendous promise for enhancing bone mineral density. However, the full context of adverse events with this agent or others that target this pathway has not yet been elucidated.This Review explores the rationale for drug discovery of novel osteoporosis therapies — with a background on limitations of current approaches, enumeration of potential new targets for drug development and the many roads to regulatory approval for these agents. More... »

PAGES

141-156

References to SciGraph publications

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    http://scigraph.springernature.com/pub.10.1038/nrd3299

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    37 schema:description Key PointsThere have been major advances in our understanding of skeletal remodelling. Consequently, new therapeutic opportunities have the potential to not only prevent further bone loss but also to augment skeletal mass.Conventional therapies (for example, oestrogens, selective oestrogen receptor modulators, bisphosphonates and calcitonin) for osteoporosis are centred on inhibiting bone resorption, thereby slowing turnover and enhancing mineralization. Fracture-risk reduction is in the order of 30% for non-vertebral sites. The introduction of anabolic agents, such as parathyroid hormone administered intermittently, set the stage for newer approaches for treatment, which focus on bone formation.The emergence of the WNT–β-catenin pathway as a key regulatory network in the process of bone formation has led to novel targets for osteoporosis prevention and treatment.Sclerostin, a protein produced by osteocytes, has been shown to naturally inhibit WNT signalling by binding to the WNT family co-receptors lipoprotein receptor-related protein 5 (LRP5) and LRP6. A monoclonal antibody to sclerostin is in Phase II trials. Animal and Phase I clinical studies show tremendous promise for enhancing bone mineral density. However, the full context of adverse events with this agent or others that target this pathway has not yet been elucidated.This Review explores the rationale for drug discovery of novel osteoporosis therapies — with a background on limitations of current approaches, enumeration of potential new targets for drug development and the many roads to regulatory approval for these agents.
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