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.

TargetActionsOrganism
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.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Denosumab is combined with Abatacept.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Denosumab.
AdalimumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Adalimumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Denosumab.
AducanumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Aducanumab.
AldesleukinThe risk or severity of adverse effects can be increased when Denosumab is combined with Aldesleukin.
AlefaceptThe risk or severity of adverse effects can be increased when Denosumab is combined with Alefacept.
AlemtuzumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Alemtuzumab.
AlirocumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Alirocumab.
Allogeneic processed thymus tissueThe 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
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ProliaSolution60 mg / mLSubcutaneousAmgenNot applicableNot applicableCanada flag
ProliaInjection, solution60 mg/mlSubcutaneousAmgen Europe B.V.2021-01-27Not applicableEU flag
ProliaSolution60 mg / mLSubcutaneousAmgen2010-08-12Not applicableCanada flag
ProliaInjection, solution60 mg/mlSubcutaneousAmgen Europe B.V.2021-01-27Not applicableEU flag
ProliaInjection, solution60 mg/mlSubcutaneousAmgen Europe B.V.2021-01-27Not applicableEU flag
ProliaInjection60 mg/1mLSubcutaneousAMGEN INC2010-06-05Not applicableUS flag
XgevaInjection120 mg/1.7mLSubcutaneousAMGEN INC2010-11-18Not applicableUS flag
XgevaInjection, solution120 mgSubcutaneousAmgen Europe B.V.2016-09-08Not applicableEU flag
XgevaInjection, solution120 mgSubcutaneousAmgen Europe B.V.2016-09-08Not applicableEU flag
XgevaInjection, solution120 mgSubcutaneousAmgen Europe B.V.2016-09-08Not applicableEU flag

Categories

ATC Codes
M05BX04 — Denosumab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
4EQZ6YO2HI
CAS number
615258-40-7

References

General References
  1. 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]
  2. Link [Link]
  3. Link [Link]
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
PhaseStatusPurposeConditionsCount
4Active Not RecruitingSupportive CareBone Giant Cell Tumor1
4Active Not RecruitingTreatmentOsteoporosis / Osteoporosis Fracture / Postmenopausal Osteoporosis1
4Active Not RecruitingTreatmentOsteoporosis / Postmenopausal Osteoporosis1
4CompletedDiagnosticPostmenopausal Osteoporosis / Type 2 Diabetes Mellitus1
4CompletedOtherPostmenopausal Osteoporosis1
4CompletedPreventionOsteoarthritis in the Hip Joint1
4CompletedPreventionResorption, Bone1
4CompletedTreatmentBreast Cancer / Metastatic Cancer / Prostate Cancer1
4CompletedTreatmentDenosumab Allergy / Zoledronic Acid Allergy1
4CompletedTreatmentMetabolic Bone Disorder1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionSubcutaneous60 mg/1mL
Injection, solutionParenteral; Subcutaneous60 MG/ML
SolutionSubcutaneous60 mg / mL
Injection, solutionSubcutaneous60 mg/ml
SolutionSubcutaneous60 mg
InjectionSubcutaneous
InjectionSubcutaneous120 mg/1.7mL
Injection, solutionParenteral; Subcutaneous120 MG
SolutionSubcutaneous120 mg / 1.7 mL
SolutionSubcutaneous120 mg
Injection, solutionSubcutaneous
SolutionSubcutaneous
Injection, solutionSubcutaneous120 mg
Injection, solution120 mg/1.7ml
Injection, solution60 mg/1ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2257247No2012-09-112018-04-15Canada flag
CA2274987No2012-01-242017-12-22Canada flag
CA2285746No2010-09-282018-04-15Canada flag
CA2400929No2011-05-312021-02-23Canada flag
CA2328140No2012-03-132019-05-13Canada flag

Properties

State
Solid
Experimental Properties
Not Available

Targets

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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
  1. 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]
  2. 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