Address for Correspondence
Dept of Pharmacology,
Osmania Medical College,
Osteoporosis is a clinical condition characterized by abnormal loss of bone predisposing to fractures. Whenever, the plasma calcium levels decreased bone calcium is mobilized by osteoclasts bone resorption activity which is stimulated by Para Thyroid hormone and Vitamin D. Currently calcium dietary supplements and Vitamin D, Sodium Fluoride, Calcitonin, Bisphosphonates, female sex hormones were used in Osteoporotic therapy.
Denosumab is a newer drug with different mode of action. It effectively controls bone loss in Osteoporosis. The present review considers recent knowledge of Denosumab, mechanism of action, therapeutic uses and adverse drug reactions.
Keywords :- Osteoporosis, Osteoclast, Bone mineral density, Rank L, Monoclonal antibody.
Osteoporosis is a disorder of impaired bone strength associated with skeletal fragility and fracture risk(1). It is a common and costly disorder associated with significant mortality and morbidity. Painful vertebral fractures are most common complications (2). Spine fractures, Hip fractures, Height loss, Kyphosis, back pain and impaired physical and psychological function occurs with Osteoporosis. Estrogen deficiency in females at menopause, Androgen deficiency in men, Vitamin D deficiency in both sexes are some important leading causative factors of Osteoporosis(3).
Low-bone mineral density (BMD) is an important risk factor for fractures associated with osteoporosis(4).
Denosumab is an investigational new drug with a novel mechanism of action that is being developed for use in the management of Post menopausal osteoporosis.
Denosumab is a fully human monoclonal antibody (IgG2 immunoglobulin isotype) with a high affinity and specifity for human receptor activator of nuclear factor – K B ligand (RANK.L) and blocks the binding of RANK-L to RAN K.RANK- is a 316 AA transmembrane protein expressed by osteoblasts, synovial fibro blasts and activated T.Cells. RANK-L bind to and activates its receptor RANK, a transmembrane protein receptor on the surface of osteoclast precussors and induces the differentiation, activation and enhanced survival of osteoclasts, leading to enhanced bone resorption(5).
Upon binding of RANK-L to RANK; TRAF-6 a member of a family of tumor. Necrosis factor signal transducers is recruited to carry signals down stream through several cascades including nuclear factor K-B and mitogen activated protein kinases Osteoprotegerin is a natural inhibitor of RANK-L preventing RANK-L from binding to its Osteoclast receptor.Denosumab by blocking the binding of RANK L to RANk inhibits the maturation of Osteoclast and the drug mimics the endogenous effects of Osteoprotegerin(6).
The Pharmaco Kinetics of Denosumab are nonlinear with dose. The absorption, distribution, bioavailability and elimination of Denosumab have not been well defined. It is given by subcutaneous route and probable bioavailability is in the range of 50-100%(7).It has long plasma half life, ranges from 26-32 days. Clearance is probably by the reticulo endothelial system and no significant circulating Denosumab appears to be filtered and excreted by the Kidneys.
Adverse drug reactions
Frozen bone, Immuno suppression, Osteonecrosis of jaw are very rare complications.Eczema, cellulites are the other minor side effects. Otherwise the drug is well tolerated and safe when compared with other existing drugs used in the treatment of Osteoporosis(8).
No evidence of drug interaction has been reported so far. It can be safely combined with Anabolic agents in the treatment of Osteoporosis which is not so with bisphosphonates.
Uses :- Post Menopausal osteoporosis Rheumatoid arthritis, Multiple Myeloma, Giant cell tumor of bone, Hip fractures, Vertebral and non vertebral fractures, Kyphosis due to osteoporosis, Prostatic Cancer, Non metastatic Breast Cancer, Periprosthetic Osteolysis(9).
In various Phase-II and Phase-III clinical trials it has been proved that Denosumab is potentially safe and has many advantages over the other drugs like bisphosphonates and osteoprotegerin in the treatment of osteoporosis by having less side effects, long plasma half life and it can be combined with anabolic agents safely.
Denosumab is an investigational fully human monoclonal antibody with high specifity and affinity to RANK-L which is the prinicipal mediator of osteoclastic bone resorption. It could be the Ist antibone resorbing agent to halt focal erosion and osteolysis. It is given subcutaneously in a dose 60 mg approximately for every 6 months for a minimum period of 3 years. It is a promising therapeutic agent for the management of post menopausal osteoporosis and other skeletal diseases associated with bone loss. Like other antibone resorptive agents the long term safety, efficacy and impact on other metabolic functions is lacking and there is a need to evaluate this aspect in future long term clinical trials.
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