Denosumab

Identification

Summary

Denosumab is a RANK ligand (RANKL) inhibitor used for the management of osteoporosis in patients at high risk for bone fractures.

Brand Names

Prolia, Xgeva

Generic Name

Denosumab

DrugBank Accession Number

DB06643

Background

Denosumab is a novel, fully human IgG2 monoclonal antibody specific to receptor activator of nuclear factor kappa-B ligand (RANKL), suppresses bone resorption markers in patients with a variety of metastatic tumors and is being investigated in multiple clinical trials for the prevention and treatment of bone metastases. Chemically, it consists of 2 heavy and 2 light chains. Each light chain consists of 215 amino acids. Each heavy chain consists of 448 amino acids with 4 intramolecular disulfides. FDA approved on June 1, 2010.

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

Protein Chemical Formula: C₆₄₀₄H₉₉₁₂N₁₇₂₄O₂₀₀₄S₅₀
Protein Average Weight: 144700.0 Da

Sequences

> Denosumab αOPGL-1 heavy chain sequence
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGITGSGGSTYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDPGTTVIMSWFDPWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

> Denosumab αOPGL-1 light chain sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVRGRYLAWYQQKPGQAPRLLIYGASSRATGIP
DRFSGSGSGTDFTLTISRLEPEDFAVFYCQQYGSSPRTFGQGTKVEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Download FASTA Format

Synonyms

Denosumab

External IDs

AMG-162

Pharmacology

Indication

Prolia is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture. It reduces the incidence of vertebral, nonvertebral, and hip fractures. Prolia is also indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. It can also be used in men with osteoporosis at high risk for fracture or in men receiving androgen deprivation therapy for nonmetastatic prostate cancer to increase bone mass. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

In clinical studies, treatment with 60 mg of Prolia resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e. osteocalcin and procollagen type 1 N-terminal peptide [PlNP]) were observed starting 1 month after the first dose of Prolia.

Mechanism of action

Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

Target	Actions	Organism
ATumor necrosis factor ligand superfamily member 11	antibody	Humans

Absorption

When 60 mg of denosumab was subcutaneously administered to healthy subjects after fasting for 12 hours, the pharmacokinetic parameters are as follows: Cmax = 6.75 mcg/mL; Tmax= 10 days (range of 3 to 21 days); AUC (0-16 weeks) = 316 mcg•day/mL. Denosumab does not accumulate following multiple doses once every 6 months. The pharmacokinetics of denosumab were not affected by the formation of antibodies.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Not Available

Route of elimination

Not Available

Half-life

25.4 days

Clearance

Not Available

Adverse Effects

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Toxicity

In patients with postmenopausal osteoporosis, the most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials. In male patients with osteoporosis, the most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis. In patients experiencing bone loss due to hormone ablation for cancer, the most common adverse reactions (≥ 10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abatacept	The risk or severity of adverse effects can be increased when Denosumab is combined with Abatacept.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Denosumab.
Adalimumab	The risk or severity of adverse effects can be increased when Denosumab is combined with Adalimumab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Denosumab.
Aducanumab	The risk or severity of adverse effects can be increased when Denosumab is combined with Aducanumab.
Aldesleukin	The risk or severity of adverse effects can be increased when Denosumab is combined with Aldesleukin.
Alefacept	The risk or severity of adverse effects can be increased when Denosumab is combined with Alefacept.
Alemtuzumab	The risk or severity of adverse effects can be increased when Denosumab is combined with Alemtuzumab.
Alirocumab	The risk or severity of adverse effects can be increased when Denosumab is combined with Alirocumab.
Allogeneic processed thymus tissue	The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Denosumab.

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Food Interactions

Administer calcium supplement. Calcium supplements should be used as necessary to prevent hypocalcemia.
Administer vitamin supplements. Vitamin D should be administered as necessary to complement calcium in preventing hypocalcemia.

Products

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International/Other Brands

Ranmark (Daiichi Sankyo)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Prolia	Solution	60 mg / mL	Subcutaneous	Amgen	Not applicable	Not applicable
Prolia	Injection, solution	60 mg/ml	Subcutaneous	Amgen Europe B.V.	2021-01-27	Not applicable
Prolia	Solution	60 mg / mL	Subcutaneous	Amgen	2010-08-12	Not applicable
Prolia	Injection, solution	60 mg/ml	Subcutaneous	Amgen Europe B.V.	2021-01-27	Not applicable
Prolia	Injection	60 mg/1mL	Subcutaneous	AMGEN INC	2010-06-05	Not applicable
Prolia	Injection, solution	60 mg/ml	Subcutaneous	Amgen Europe B.V.	2021-01-27	Not applicable
Xgeva	Injection, solution	120 mg	Subcutaneous	Amgen Europe B.V.	2016-09-08	Not applicable
Xgeva	Injection	120 mg/1.7mL	Subcutaneous	AMGEN INC	2010-11-18	Not applicable
Xgeva	Injection, solution	120 mg	Subcutaneous	Amgen Europe B.V.	2016-09-08	Not applicable
Xgeva	Injection, solution	120 mg	Subcutaneous	Amgen Europe B.V.	2016-09-08	Not applicable

Chemical Identifiers

UNII: 4EQZ6YO2HI
CAS number: 615258-40-7

References

General References

Malan J, Ettinger K, Naumann E, Beirne OR: The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Dec;114(6):671-6. doi: 10.1016/j.oooo.2012.08.439. [Article]
Link [Link]
Link [Link]

External Links

KEGG Drug: D03684
PubChem Substance: 347910354
RxNav: 993449
ChEMBL: CHEMBL1237023
PharmGKB: PA166048634
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Denosumab

FDA label

Download (226 KB)

MSDS

Download (97.5 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Supportive Care	Bone Giant Cell Tumor	1
4	Active Not Recruiting	Treatment	Osteoporosis / Osteoporosis Fracture / Postmenopausal Osteoporosis	1
4	Active Not Recruiting	Treatment	Osteoporosis / Postmenopausal Osteoporosis	1
4	Completed	Diagnostic	Postmenopausal Osteoporosis / Type 2 Diabetes Mellitus	1
4	Completed	Other	Postmenopausal Osteoporosis	1
4	Completed	Prevention	Osteoarthritis in the Hip Joint	1
4	Completed	Prevention	Resorption, Bone	1
4	Completed	Treatment	Breast Cancer / Metastatic Cancer / Prostate Cancer	1
4	Completed	Treatment	Denosumab Allergy / Zoledronic Acid Allergy	1
4	Completed	Treatment	Metabolic Bone Disorder	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Subcutaneous	60 mg/1mL
Injection, solution	Parenteral; Subcutaneous	60 MG/ML
Solution	Subcutaneous	60 mg / mL
Injection, solution	Subcutaneous	60 mg/ml
Solution	Subcutaneous	60 mg
Injection	Subcutaneous
Injection	Subcutaneous	120 mg/1.7mL
Injection, solution	Parenteral; Subcutaneous	120 MG
Solution	Subcutaneous	120 mg / 1.7 mL
Solution	Subcutaneous	120 mg
Injection, solution	Subcutaneous
Solution	Subcutaneous
Injection, solution	Subcutaneous	120 mg
Injection, solution		120 mg/1.7ml
Injection, solution		60 mg/1ml

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
CA2257247	No	2012-09-11	2018-04-15
CA2274987	No	2012-01-24	2017-12-22
CA2285746	No	2010-09-28	2018-04-15
CA2400929	No	2011-05-31	2021-02-23
CA2328140	No	2012-03-13	2019-05-13

Properties

State: Solid
Experimental Properties: Not Available

Targets

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Details1. Tumor necrosis factor ligand superfamily member 11

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antibody

General Function: Tumor necrosis factor receptor superfamily binding
Specific Function: Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be...
Gene Name: TNFSF11
Uniprot ID: O14788
Uniprot Name: Tumor necrosis factor ligand superfamily member 11
Molecular Weight: 35477.81 Da

References

Lipton A, Jun S: RANKL inhibition in the treatment of bone metastases. Curr Opin Support Palliat Care. 2008 Sep;2(3):197-203. doi: 10.1097/SPC.0b013e32830baac2. [Article]
Westenfeld R, Ketteler M, Brandenburg VM: Anti-RANKL therapy--implications for the bone-vascular-axis in CKD? Denosumab in post-menopausal women with low bone mineral density. Nephrol Dial Transplant. 2006 Aug;21(8):2075-7. Epub 2006 May 15. [Article]

Drug created at March 19, 2008 16:43 / Updated at March 24, 2023 20:20

Denosumab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References