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.

Mechanism of Action of Denosumab

Fig 1. Mechanism of Action of Denosumab

Table 1. Clinical Projects of Denosumab*

NCT ID Status Conditions Lead Sponsor Update Time
NCT03620019 Recruiting Melanoma Stage Iii, Melanoma Stage Iv, Melanoma, Melanoma (Skin), Cutaneous Melanoma UNC Lineberger Comprehensive Cancer Center August 8, 2018
NCT03620149 Not yet recruiting Bone Giant Cell Tumor European Organisation for Research and Treatment of Cancer - EORTC August 8, 2018
NCT03605199 Recruiting Aneurysmal Bone Cysts, Giant Cell Granuloma, Osteoblastoma, Chondroblastoma, Chondromyxoid Fibroma Leiden University Medical Center July 30, 2018
NCT03270020 Recruiting Langerhans Cell Histiocytosis Hellenic Society for the Study of Bone Metabolism September 1, 2017
NCT03358212 Not yet recruiting Giant Cell Tumor of Bone Peking University People's Hospital November 30, 2017
NCT03691311 Recruiting Breast Neoplasm Female, Stage I Breast Cancer, Stage II Breast Cancer, Hormone Receptor Negative Neoplasm, Hormone Receptor Positive Tumor Institut Català d'Oncologia October 1, 2018
NCT02613416 Recruiting Breast Cancer Stony Brook University November 24, 2015
NCT03029442 Recruiting Secondary Osteoporosis, Spinal Cord Injury James J. Peters Veterans Affairs Medical Center January 24, 2017
NCT03839459 Not yet recruiting Smoldering Multiple Myeloma University of Rochester February 15, 2019
NCT02491515 Recruiting Osteoporosis Tomidahama Hospital July 8, 2015
NCT03259152 Recruiting Giant Cell Tumor of Bone Hebei Medical University Third Hospital August 23, 2017
NCT03532087 Not yet recruiting Breast Neoplasms Borstkanker Onderzoek Groep May 22, 2018
NCT03301857 Active, not recruiting Giant Cell Tumor of Bone Amgen October 4, 2017
NCT03280667 Recruiting Renal Cell Carcinoma, Clear Cell, Metastatic Kidney Cancer Australian and New Zealand Urogenital and Prostate Cancer Trials Group September 12, 2017
NCT02418273 Not yet recruiting Osteoporosis, Juvenile Rheumatoid Arthritis, Dermatomyositis, Polyarthritis, Systemic Lupus Erythematosis, Vasculitis, Glucocorticoid-induced Osteoporosis Indiana University April 16, 2015
NCT02900469 Recruiting Breast Cancer New York University School of Medicine September 14, 2016
NCT01983475 Recruiting Osteoporosis, Spinal Cord Injury James J. Peters Veterans Affairs Medical Center November 14, 2013
NCT02049866 Active, not recruiting Adult Idiopathic Generalized Osteoporosis Elizabeth Shane January 30, 2014
NCT01358669 Recruiting Revision Surgery of Total Hip Arthroplasty Sheffield Teaching Hospitals NHS Foundation Trust May 24, 2011
NCT03457818 Recruiting Diabetes Mellitus, Type 2, Osteoporosis Mishaela Rubin March 8, 2018
NCT02444585 Recruiting Arthroplasty, Replacement, Hip University of Southern California May 14, 2015
NCT02632916 Active, not recruiting Osteoporosis Children's Hospital of Eastern Ontario December 17, 2015
NCT03030196 Recruiting Infertility, Male Martin Blomberg Jensen January 24, 2017
NCT03040765 Recruiting Thalassemia Majors (Beta-Thalassemia Major), Osteoporosis Hamad Medical Corporation February 2, 2017
NCT01952054 Active, not recruiting Breast Cancer M.D. Anderson Cancer Center September 27, 2013
NCT02129699 Active, not recruiting Lung Cancer Non-Small Cell Stage IV European Thoracic Oncology Platform May 2, 2014
NCT02299817 Active, not recruiting Osteolysis Olof Skoldenberg November 24, 2014
NCT02903446 Recruiting Gout University of Alabama at Birmingham September 16, 2016
NCT03324932 Recruiting Breast Cancer Kyoto Prefectural University of Medicine October 30, 2017
NCT03869762 Recruiting Castration-resistant Prostate Cancer, Metastatic Cancer, Bone Metastases Cancer Trials Ireland March 11, 2019
NCT02470091 Active, not recruiting Childhood Osteosarcoma, Metastatic Osteosarcoma, Recurrent Osteosarcoma, Stage IV Osteosarcoma AJCC v7, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7 Children's Oncology Group June 12, 2015
NCT02051218 Recruiting Metastatic Breast Cancer, Metastatic Prostate Cancer, Bone Metastases Swiss Group for Clinical Cancer Research January 31, 2014
NCT03623633 Recruiting Osteoporosis, Postmenopausal, Osteoporosis Massachusetts General Hospital August 9, 2018
NCT03164928 Recruiting Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects with Glucocorticoid-induced Osteoporosis Amgen May 24, 2017
NCT03401060 Recruiting Osteoporosis, Systemic Mastocytosis Assistance Publique - Hôpitaux de Paris January 17, 2018
NCT03732495 Not yet recruiting Thyroid Cancer Metastatic Centre Leon Berard November 6, 2018
NCT02833610 Recruiting Multiple Myeloma Massachusetts General Hospital July 14, 2016
NCT01545648 Active, not recruiting Early Stage Breast Cancer Hope Rugo, MD March 7, 2012
NCT03005678 Recruiting Osteoporosis Tuen Mun Hospital December 29, 2016
NCT03293108 Recruiting Osteoporosis AryoGen Pharmed Co. September 26, 2017
NCT02352753 Active, not recruiting Osteogenesis Imperfecta Amgen February 2, 2015
NCT03669523 Recruiting Carcinoma, Non-Small-Cell Lung, Bone Metastases Centre Hospitalier de la Région d'Annecy September 13, 2018
NCT03868033 Recruiting Osteoporosis National Taiwan University Hospital March 8, 2019
NCT03292146 Recruiting Bone Density, Bone Loss, Anorexia Nervosa, Eating Disorder, Atypical Anorexia Nervosa Massachusetts General Hospital September 25, 2017
NCT03382574 Not yet recruiting BRCA1 Gene Mutation, BRCA2 Gene Mutation, Fallopian Tube Carcinoma, Ovarian Carcinoma, Premenopausal National Cancer Institute (NCI) December 26, 2017
NCT03638128 Recruiting Osteogenesis Imperfecta (OI) Amgen August 20, 2018
NCT02366130 Active, not recruiting Breast Cancer M.D. Anderson Cancer Center February 19, 2015
NCT03792763 Not yet recruiting Multiple Myeloma Arbeitsgemeinschaft medikamentoese Tumortherapie January 3, 2019
NCT03520231 Recruiting Urothelial Carcinoma, Kidney Cancer, Ureter Cancer, Bladder Cancer University Health Network, Toronto May 9, 2018
NCT03161756 Recruiting Melanoma Stage Iv, Melanoma Stage Iii, Melanoma Australia and New Zealand Melanoma Trials Group May 22, 2017
NCT03571191 Enrolling by invitation Bone Diseases, Pain National Institute of Dental and Craniofacial Research (NIDCR) June 27, 2018
NCT01345019 Active, not recruiting Cancer, Hematologic Malignancies, Multiple Myeloma, Oncology, Bone Metastases Amgen April 29, 2011
NCT03174366 Active, not recruiting Multiple Myeloma Bone Lesions Western University of Health Sciences June 2, 2017
NCT03651947 Recruiting Charcot Joint of Foot Qilu Pharmaceutical Co., Ltd. August 29, 2018
NCT03239080 Active, not recruiting Healthy People Chinese University of Hong Kong August 3, 2017
NCT03027557 Active, not recruiting Rheumatoid Arthritis Peter Vestergaard January 23, 2017
NCT02422108 Active, not recruiting Primary Hyperparathyroidism, Parathyroid Adenoma, Parathyroid Hyperplasia Martin Blomberg Jensen April 21, 2015
NCT01624766 Active, not recruiting Testis, Infertility, Sperm M.D. Anderson Cancer Center June 21, 2012
NCT02176382 Active, not recruiting Advanced Malignant Neoplasm, Metastatic Malignant Neoplasm, Recurrent Malignant Neoplasm, Refractory Malignant Neoplasm Massachusetts General Hospital June 27, 2014
NCT02130973 Active, not recruiting Postmenopausal Osteoporosis Health Research, Inc. May 6, 2014
NCT00556374 Active, not recruiting Osteoporosis Amgen November 12, 2007
NCT02156960 Recruiting Breast Cancer Shinshu University June 5, 2014
NCT02771860 Recruiting Osteoporosis, Hand Osteoarthritis University Hospital, Ghent May 13, 2016
NCT03629717 Recruiting Breast Cancer Prevention, Mammographic Density Washington University School of Medicine August 14, 2018
NCT02520362 Active, not recruiting Post-Menopausal Osteoperosis, Male Osteoperosis Amgen August 11, 2015
NCT02753283 Recruiting Osteoporosis, Postmenopausal, Osteoporosis, Osteoporotic Fractures Susan L. Greenspan April 27, 2016
NCT03087851 Active, not recruiting Osteoporosis Aarhus University Hospital March 23, 2017
NCT01967160 Active, not recruiting Osteonecrosis of the Jaw, Infection Leading to Hospitalization Amgen October 22, 2013
NCT03812367 Recruiting Osteoporosis, Postmenopausal University of California, Davis January 23, 2019
NCT03427853 Recruiting Healthy Adults Luye Pharma Group Ltd. February 9, 2018
NCT03702140 Recruiting Osteoporosis Shinshu University October 10, 2018
NCT03408652 Recruiting Metastatic Renal Cell Carcinoma Centre Leon Berard January 24, 2018
NCT03755193 Recruiting Osteoporosis Shinshu University November 27, 2018
NCT03396315 Recruiting IOP, Osteoporosis Columbia University January 10, 2018
NCT03472846 Recruiting Postmenopausal Osteoporosis, Diabetes Type 2 Medical University of Vienna March 21, 2018
NCT02274623 Active, not recruiting Breast Cancer, Prostate Cancer, Bone Neoplasms, Hypocalcemia, Hyperparathyroidism, Secondary OPKO Ireland Global Holdings Ltd. October 24, 2014
NCT03811509 Recruiting Osteoporosis, Osteoporosis Fracture, Arthralgia Generalized Parc de Salut Mar January 21, 2019
NCT03217513 Not yet recruiting Osteoporosis, Knee Osteoarthritis Edward Fox July 14, 2017
NCT02721433 Active, not recruiting Breast Cancer, Prostate Cancer, Metastasis Ottawa Hospital Research Institute March 29, 2016
NCT01847976 Active, not recruiting Pain Ottawa Hospital Research Institute May 7, 2013
NCT02932501 Recruiting Medication-related Osteonecrosis of the Jaw, Bisphosphonate-Associated Osteonecrosis of the Jaw AO Clinical Investigation and Documentation October 13, 2016
NCT02521844 Recruiting Solid Tumors D3 (Drug Discovery and Development), A*STAR Research Entities August 13, 2015
NCT02150850 Recruiting Atypical Femur Fracture McGill University May 30, 2014
NCT02855775 Recruiting Breast Cancer Centre Hospitalier Universitaire de Besancon August 4, 2016
NCT02839291 Recruiting Tumor with Bone Metastasis Centre Hospitalier Universitaire de Besancon July 20, 2016
NCT03390777 Not yet recruiting Osteonecrosis Due to Drugs, Jaw University of Roma La Sapienza January 4, 2018
NCT02239523 Recruiting Osteoporotic Fracture Shaare Zedek Medical Center September 12, 2014
NCT03696407 Recruiting Advanced Renal Cell Carcinoma Ipsen October 4, 2018
NCT02398526 Active, not recruiting Castration-Resistant Prostatic Cancer Bayer March 25, 2015

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 Denosumab Overview
Xgeva Bone Metastasis from Solid Tumors Injection 70MG/ML / vial Subcutaneous use Amgen November 1, 2010 Denosumab Overview
Prolia Bone Resorption, Osteoporosis, Postmenopausal Solution for injection 60MG/ML / vial Subcutaneous use Amgen Europe May 26, 2010 Denosumab Overview
Xgeva Fractures, Bone, Neoplasm Metastasis Solution for injection 70MG/ML / vial Subcutaneous use Amgen Europe July 13, 2011 Denosumab Overview
Prolia Osteoporosis, Bone loss Solution for injection 60MG/ML / vial Subcutaneous use Amgen Australia July 6, 2011 Denosumab Overview
Xgeva Bone Metastasis, Bone Lesions, Giant Cell Tumour of Bone Solution for injection 70MG/ML / vial Subcutaneous use Amgen Australia August 9, 2011 Denosumab Overview

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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

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