Abstract

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.

Links

Publisher Full Text

Authors

Dempster DW, Lambing CL, Kostenuik PJ, Grauer A

Institution

Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York 10993, USA. ddempster9@aol.com

Source

Clinical therapeutics 34:3 2012 Mar pg 521-36

MeSH

Animals
Antibodies, Monoclonal
Bone Density
Bone Remodeling
Bone and Bones
Clinical Trials as Topic
Disease Models, Animal
Drug Evaluation, Preclinical
Estrogens
Female
Humans
Osteoporosis
Osteoporosis, Postmenopausal
RANK Ligand
Testosterone
Treatment Outcome

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

22440513