ChEMBL

On June 2nd, the FDA approved Denosumab (previously known as AMG-162), a human monoclonal antibody against RANK-ligand, for the treatment of postmenopausal osteoporosis (PMO). The ATCC code is M05BX04

Osteoporosis is characterized by reduced bone mineral density and a degradation of the small-scale bone structure, leading to increased risk of bone fracture. Osteoporosis is a common disease, affecting primarily women aged 50 and above and are at high risk of fracturing their lumbar vertebrae, hips, wrists and ribs. Osteoporosis is estimated to cause 2 million fractures annually in the US.

Bones undergo constant remodeling that can be understood as a process of simultaneous deconstruction of bone material by osteoclasts (these are big, mobile cells which derive from a common lineage with macrophages) and formation of mineral bone by osteoblasts. Both processes are in a dynamic equilibrium, and this equilibrium keeps the bone mineral density at a stable level. Reduced levels of estrogen, as encountered in women after entering the menopause, increase the number of osteoclasts and promote their activity of resorbing mineral bone. The resulting loss of mineral bone eventually causes osteoporosis.

The bone remodeling equilibrium is regulated by a network of cytokine signalling molecules in which the RANK-ligand (RANKL, O14788) molecule plays a key role, mediating osteoclast activation through binding of the membrane protein receptor activator of nuclear Factor κB (RANK, Q9Y6Q6).  RANKL is a member of the tumor necrosis factor (TNF) family of proteins.

Denosumab exerts its effect through binding to RANKL, and is functionally similar to an endogenous protein, osteoprotegerin, a membrane protein that binds RANKL but does not promote any activating effect.

Denosumab is administered as a subcutaneous (s.c.) injection of 60mg once every 6 months. The half-life of Denosumab in blood serum is 24.5 days. Side effects of Denosumab usage are listed as hypocalcemia, serious infections of the skin, abdomen, urinary tract and ear, dermatologic adverse reactions and osteonecrosis of the jaw.

Denusomab is marketed by Amgen under the name Prolia. The full prescribing information can be found here.