Denosumab Overview

Introduction of Denosumab

Denosumab is a novel, fully human IgG2 monoclonal antibody specific to receptor activator of nuclear factor kappa-B ligand (RANKL, also known as tumor necrosis factor ligand superfamily member 11, TNFSF11), suppresses bone resorption markers in patients with a variety of metastatic tumors. It was developed by Amgen for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone. On June 1, 2010, denosumab was approved by the US Food and Drug Administration (FDA) for use in postmenopausal women with risk of osteoporosis under the trade name Prolia, and in November 2010, as Xgeva, for the prevention of skeleton-related events in patients with bone metastases from solid tumors. Denosumab is the first RANKL inhibitor to be approved by the FDA. In addition, the drug was approved for marketing by the European Commission on May 28, 2010. At present, denosumab is an efficacious and safe osteoporosis treatment option, with current data up to 8 years of continued use showing continued improvement in bone density with sustained fracture risk reduction. Safety profiles overall are similar to placebo, with no new safety concerns in extension trials, though a theoretical increased risk of infection exists with RANKL inhibition.

Mechanism of Action of Denosumab

Osteoporosis is a systemic skeletal disease that increases with age and is common among postmenopausal women. Characterized by reduced bone mineral density (BMD) and weakened bone structure, osteoporosis decreases bone resistance to low-energy trauma and increases bone fragility and fracture risk. A complex mechanism controls bone remodeling in human. This mechanism includes the receptor activator of nuclear factor kappa B ligand (RANKL), its natural receptor (RANK) and osteoprotegerin (OPG). The RANK/RANKL pathway is a key that promotes osteoclast formation and activation and prolongs osteoclast survival. OPG acts as a decoy receptor for RANKL and prevents its interaction with RANK thereby inhibiting osteoclast formation, function and survival. Alteration of the RANK/RANKL/OPG system in favor of increased osteoclastic activity and enhanced osteoblastic dysfunction is proposed as an important mechanism in the etiology of osteoporosis. Denosumab is a antiresorptive agent, with a novel mechanism of action. Briefly, denosumab is a fully human monoclonal antibody that inhibits RANKL and helps regulate turnover in healthy bone. Denosumab binds with high specificity and affinity to the cytokine RANKL, inhibiting its action; as a result, osteoclast recruitment, maturation and action are inhibited, and bone resorption slows. Denosumab is indicated for postmenopausal women with osteoporosis at high risk of fracture, or for patients who have failed or are intolerant to other available osteoporosis therapies.

Fig 1. Mechanism of Action of Denosumab

Table 1. Clinical Projects of Denosumab*

Table 2. Approved Drugs of Denosumab**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Prolia	Postmenopausal Women with Osteoporosis at High Risk for Fracture	Injection	60MG/ML / vial	Subcutaneous use	Amgen	June 1, 2010
Xgeva	Bone Metastasis from Solid Tumors	Injection	70MG/ML / vial	Subcutaneous use	Amgen	November 1, 2010
Prolia	Bone Resorption, Osteoporosis, Postmenopausal	Solution for injection	60MG/ML / vial	Subcutaneous use	Amgen Europe	May 26, 2010
Xgeva	Fractures, Bone, Neoplasm Metastasis	Solution for injection	70MG/ML / vial	Subcutaneous use	Amgen Europe	July 13, 2011
Prolia	Osteoporosis, Bone loss	Solution for injection	60MG/ML / vial	Subcutaneous use	Amgen Australia	July 6, 2011
Xgeva	Bone Metastasis, Bone Lesions, Giant Cell Tumour of Bone	Solution for injection	70MG/ML / vial	Subcutaneous use	Amgen Australia	August 9, 2011

What We Provide

Therapeutic Antibody

Denosumab

We provide high-quality Denosumab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

Reference
*The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?term=Denosumab

**Information presented in the table were collected from the following website:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125320

For research use only. Not intended for any clinical use.