Role of RANKL inhibition in osteoporosis

Abstract

When the rate of bone resorption exceeds that of bone formation, destruction of bone tissue occurs, resulting in a fragile skeleton. The clinical consequences, namely osteoporosis and fragility fractures, are common and costly problems. Treatments that normalize the balance of bone turnover by inhibiting bone resorption preserve bone mass and reduce fracture risk. The discovery of receptor activator of nuclear factor-κB ligand (RANKL) as a pivotal regulator of osteoclast activity provides a new therapeutic target. Early studies have demonstrated that denosumab, an investigational, highly specific anti-RANKL antibody, rapidly and substantially reduces bone resorption. Pharmacokinetics of the antibody allow dosing by subcutaneous injection at an interval of 6 months. Inhibiting RANKL appears to be a promising new treatment for osteoporosis and related disorders. More information about the effectiveness of denosumab in reducing fracture risk, its tolerability and safety, and the response to discontinuing therapy will be provided by ongoing clinical studies.

Osteoporosis and inflammation

“…Denosumab is a fully human monoclonal anti-RANKL antibody. This medication blocks the binding of RANKL to RANK (46). Clinical trials with AR patients demonstrated that compared with placebo markers of bone resorption (serum CTX-I and procollagen type 1 intact N-terminal propeptide [P1NP]) and cartilage loss (urine CTX-II) were significantly decreased (47), and BMDs in the lumbar spine, total hip, and trochanter were significantly increased (48) on denosumab therapy.…”

The contribution of cortical and trabecular tissues to bone strength: insights from denosumab studies

“…Several pathways, involving cytokines, hormones and growth factors, affect bone loss; among them an important role is played by RANK/RANKL/OPG interaction (11). Discovery and characterization of a new pathway involving the receptor activator of nuclear factor-kB (RANK) ligand (RANKL), its receptor RANK, and its soluble decoy receptor osteoprotegerin (OPG) has been a crucial step towards the understanding of bone biology, disclosing an innovative way to develop a targeted treatment for bone diseases characterized by unbalanced osteoclastic activity (12)(13)(14)(15)(16). RANKL, by binding to osteoclast surface receptor RANK is a key factor for maturation, proliferation and fusion of pre-osteoclasts, furthermore it is crucial to osteoclast activation and survival.…”

The relationship between bone mineral density and levels of RANKL, osteoprotegerin and cathepsin-K in patients with rheumatoid arthritis

“…3 It is important to find out new determiners which show bone cycles such as OPG/RANK/RANKL in order to cure bone diseases and detect new therapeutic agents. 4,5,6 It was shown that OPG/RANK/RANKL have a role in not only focal and generalized bone lost but also joint inflammation pathophysiology in Rheumatoid Arthritis. 7,8 It was shown in the studies that active T cells are important resources of RANKL in inflame synovium, synovial fibroblast and synovial tissue.…”