Circulating Osteoprotegerin and Receptor Activator for Nuclear Factor KappaB Ligand: Clinical Utility in Metabolic Bone Disease Assessment

Context: The discovery of the receptor activator for nuclear factor kappaB (RANK) ligand (RANKL)/RANK signaling pathway has marked a major advance in our understanding of the mechanisms controlling osteoclastogenesis. RANKL, expressed by preosteoblasts and stromal cells, binds to RANK, expressed by cells of the osteoclast lineage, inducing a signaling cascade leading to the differentiation and fusion of osteoclast precursor cells and stimulating the activity of the mature osteoclast. The effects of RANKL are counteracted by osteoprotegerin (OPG), a soluble neutralizing decoy receptor.

Evidence: This paper reviews the literature surrounding the use of circulating OPG and soluble RANKL (sRANKL) measurements and assesses their potential as markers of bone disease. Original clinical and basic research articles and reviews were identified using a Pubmed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and cover the time period up until January 2005. Search terms osteoprotegerin, OPG, RANK, RANKL, and RANK ligand were used alone and in combination with bone, osteoporosis, and disease.

Evidence Synthesis: Assays for detecting OPG and sRANKL in the circulation in humans have been developed, and differences in the circulating concentrations of OPG and sRANKL have been observed in different disease states. There are, however, some inconsistencies in study outcome. These may relate to differences in study design, methodology, and other unknown factors influencing the variability of these measurements.

Conclusions: The clinical utility of serum OPG and sRANKL measurements as markers of disease activity requires additional investigation. In particular, rigorous testing of assays and identification of the sources of measurement variability are required.