Document Detail


Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: a review of preclinical and clinical data.
MedLine Citation:
PMID:  22440513     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Postmenopausal osteoporosis results from bone loss and decreased bone strength mediated by an increased rate of bone remodeling secondary to reduced estrogen levels. Remodeling cycles are initiated by osteoclasts, the formation, function, and survival of which depend on RANK ligand (RANKL). RANKL inhibition therefore represents a novel strategy for reducing remodeling and its effects on fracture risk.
OBJECTIVES: The goal of this study was to review the preclinical and clinical evidence supporting the value of RANKL inhibition in conditions of bone loss and to provide the rationale for the use of the fully human antibody denosumab, a RANKL inhibitor, in such conditions.
METHODS: We searched PubMed from January 2005 to May 2011 using the following terms: RANK Ligand, RANKL, denosumab, and NOT cancer, metastatic bone, or rheumatoid in the title.
RESULTS: The search method retrieved 111 articles. Preclinical evidence from several bone disease models suggests that RANKL inhibition leads to increased bone volume, density, and strength. Denosumab prevents RANKL from binding to its receptor, decreasing osteoclast activity and thereby reducing bone resorption and increasing cortical and trabecular bone mass and strength. It has consistently been reported to reduce bone turnover, increase bone density, and reduce the risk of fracture in clinical studies of postmenopausal women. Phase III head-to-head trials comparing denosumab with the bisphosphonate alendronate reported that denosumab was associated with significantly greater increases in bone density. Eczema as an adverse event and cellulitis as a serious adverse event were more common with denosumab than with placebo.
CONCLUSIONS: Preclinical studies defined the role of RANKL in bone remodeling and provided evidence for the therapeutic potential of RANKL inhibition in conditions of bone loss. Clinical studies evaluating RANKL inhibition with denosumab in postmenopausal women have reported significant reductions in vertebral, nonvertebral, and hip fractures, providing evidence compatible with the use of denosumab in postmenopausal women with osteoporosis.
Authors:
David W Dempster; Cheryl L Lambing; Paul J Kostenuik; Andreas Grauer
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Clinical therapeutics     Volume:  34     ISSN:  1879-114X     ISO Abbreviation:  Clin Ther     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-23     Completed Date:  2012-07-16     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  7706726     Medline TA:  Clin Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  521-36     Citation Subset:  IM    
Copyright Information:
Copyright © 2012. Published by EM Inc USA.
Affiliation:
Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York 10993, USA. ddempster9@aol.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Monoclonal / pharmacokinetics,  pharmacology,  therapeutic use*
Antibodies, Monoclonal, Humanized
Bone Density / drug effects
Bone Remodeling / drug effects
Bone and Bones / drug effects*,  metabolism,  pathology
Clinical Trials as Topic
Disease Models, Animal
Drug Evaluation, Preclinical
Estrogens / deficiency
Female
Humans
Osteoporosis / drug therapy*,  immunology,  metabolism,  pathology
Osteoporosis, Postmenopausal / drug therapy,  immunology,  metabolism,  pathology
RANK Ligand / antagonists & inhibitors*
Testosterone / deficiency
Treatment Outcome
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Estrogens; 0/RANK Ligand; 4EQZ6YO2HI/denosumab; 58-22-0/Testosterone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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