Endocrine Abstracts

Osteoclasts are derived from macrophagic/monocytic lineage cells and represent differentiated, multinucleated cells specialized in resorbing bone. An increased number and activity of osteoclasts is the hallmark of various bone diseases, including osteoporosis, rheumatoid arthritis, and skeletal metastases. Recently, receptor activator of nuclear factor-κB ligand (RANKL) has been identified as the stem cell factor for osteoclasts. RANKL promotes osteoclast formation, function, and survival. The discovery and characterization of RANKL, its receptor RANK, and its decoy receptor osteoprotegerin (OPG) has led to a molecular understanding of bone cell biology. In addition, this progress has created a translational novel approach of treating a wide spectrum of bone diseases in which RANKL becomes up-regulated and causes severe bone loss. This includes, amongst others, glucocorticoid-induced osteoporosis, bone loss following estrogen or androgen withdrawal, and myeloma bone disease. Several strategies have been developed to specifically inhibit RANKL actions on bone. Initially, OPG fusion protein was used in preclinical animal models of various forms of osteoporosis, inflammatory and malignant bone disease metastases and proved the concept that RANKL inhibition is able to inhibit osteoclasts and to prevent bone loss in these conditions. More recently, denosumab a fully human monoclonal antibody that neutralizes RANKL was developed. The major advantages of denosumab over OPG fusion proteins include a higher affinity and specificity for RANKL, improved pharmacokinetics, and lower immunogenicity. Randomized controlled trials employing denosumab have been conducted in postmenopausal women with low bone mass and men on androgen-ablation therapy for prostate cancer. Denosumab induces a rapid, profound and sustained suppression of bone resorption and bone turnover, increases bone mineral density at all sites, and reduced the vertebral fractures by 62% (osteoporosis following androgen-ablation) and 68% (postmenopausal osteoporosis), respectively. In conclusion, RANKL inhibition by denosumab has emerged as a novel treatment principle across a wide spectrum of bone diseases.