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 via inhibiting RANK-mediated activation of osteoclasts. It is the first and currently the only RANKL inhibitor approved to prevent osteoclast-mediated bone loss.6 Chemically, it consists of 2 heavy and 2 light chains, with each light chain consisting of 215 amino acids and each heavy chain consisting of 448 amino acids with 4 intramolecular disulfides.5

Denosumab was approved by the FDA approved on June 2010 for the treatment of osteoporosis in postmenopausal women. It further received additional indication approval to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer and women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer in September 2011 and in men with osteoporosis at high risk for fracture in September 2012.5

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
References:
  1. NIH Inxight: denosumab [Link]
Download FASTA Format
Synonyms
  • Denosumab
External IDs
  • AMG-162

Pharmacology

Indication

Denosumab under the brand name Prolia is indicated as a treatment for osteoporosis in menopausal women or men and glucocorticoid-induced osteoporosis in men and women at high risk of fracture. It is also used to increase bone mass in men at high risk for fractures receiving androgen deprivation therapy for nonmetastatic prostate cancer or women at high risk for fractures receiving adjuvant aromatase inhibitor therapy for breast cancer.7

Denosumab under the brand name Xgeva is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors and to treat giant cell tumors of bone in adults and skeletally mature adolescents and hypercalcemia of malignancy refractory to bisphosphonate therapy.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofBone loss•••••••••••••••• •••• •• ••••••••• •••••••• •••••• •••••••••••••••••••••••
Management ofBone loss•••••••••••••••••• ••••••• •••• •••• •• •••••••••••••••••
Management ofOsteoporosis•••••••••••••••••••••••••••••• •••• •• •••••••••••••••••
Management ofOsteoporosis•••••••••••••••• •••• •• ••••••••• ••••••• •• ••••• ••••••• ••• •••••••••••••••••••••
Management ofOsteoporosis caused by glucocorticoid treatment•••••••••••••••• •••• •• •••••••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

In clinical studies, treatment with 60 mg of denosumab resulted in a reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of denosumab on bone remodelling.7

These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab treatment. 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 [P1NP]) were observed starting 1 month after the first dose of denosumab. After discontinuation of denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months.7

In patients with breast cancer and bone metastases, the median reduction in urinary N-terminal telopeptide corrected for creatinine (uNTx/Cr) was 82% within 1 week following initiation of denosumab 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 denosumab-treated patients.8

In a phase 3 study of patients with newly diagnosed multiple myeloma who received subcutaneous doses of denosumab 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing.8

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.7

TargetActionsOrganism
ATumor necrosis factor ligand superfamily member 11
antibody
Humans
Absorption

In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (Cmax) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (Tmax) was 10 days (range: 3 to 21 days). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg⋅day/mL (SD = 101 mcg⋅day/mL.7

No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months.7

Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) Cmax values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81.9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) Tmax values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in the seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21.1 (± 36.5) ng/mL across all subjects (n = 12).7

In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach a steady state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19.0 (± 24.1), 31.6 (± 27.3), 36.4 (± 20.6) mcg/mL, respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23.4 (± 12.1) mcg/mL.8

Volume of distribution

The central volume of distribution and volume of distribution at steady-state were calculated to be 2.49 L/66 kg and 3.5-7 L respectively.3

Protein binding

No information is available on the protein binding of denosumab.

Metabolism

No information is available on the metabolism of denosumab.

Route of elimination

As an antibody, denosumab is likely cleared by the reticuloendothelial system with minimal renal filtration and excretion.4

Half-life

After Cmax, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46).7

Clearance

No information is available on the clearance of denosumab.

Adverse Effects
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Toxicity

Denosumab is contraindicated for use in pregnant women because it may cause harm to a fetus. There are insufficient data with denosumab use in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth.7

In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfect treated with denosumab products, including Prolia. Some cases required hospitalization and were complicated by acute renal injury. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years.7

The carcinogenic and genotoxic potential of denosumab has not been evaluated in long-term animal studies. Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg).7

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.
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
ProliaInjection, solution60 mg/mlSubcutaneousAmgen Europe B.V.2021-01-27Not applicableEU flag
ProliaInjection60 mg/1mLSubcutaneousAMGEN INC2010-06-05Not applicableUS flag
ProliaInjection, solution60 mg/mlSubcutaneousAmgen Europe B.V.2021-01-27Not applicableEU flag
ProliaSolution60 mg / mLSubcutaneousAmgenNot applicableNot applicableCanada flag
ProliaInjection, solution60 mg/mlSubcutaneousAmgen Europe B.V.2021-01-27Not 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. Stefania S, Rotondo C, Mele A, Trotta A, Cantatore FP, Corrado A: Role of denosumab in bone erosions in rheumatoid arthritis. Postgrad Med J. 2023 Aug 22;99(1175):976-984. doi: 10.1093/postmj/qgad013. [Article]
  3. Sutjandra L, Rodriguez RD, Doshi S, Ma M, Peterson MC, Jang GR, Chow AT, Perez-Ruixo JJ: Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011 Dec 1;50(12):793-807. doi: 10.2165/11594240-000000000-00000. [Article]
  4. Narayanan P: Denosumab: A comprehensive review. South Asian J Cancer. 2013 Oct;2(4):272-7. doi: 10.4103/2278-330X.119895. [Article]
  5. Zaheer S, LeBoff M, Lewiecki EM: Denosumab for the treatment of osteoporosis. Expert Opin Drug Metab Toxicol. 2015 Mar;11(3):461-70. doi: 10.1517/17425255.2015.1000860. Epub 2015 Jan 22. [Article]
  6. Kendler DL, Cosman F, Stad RK, Ferrari S: Denosumab in the Treatment of Osteoporosis: 10 Years Later: A Narrative Review. Adv Ther. 2022 Jan;39(1):58-74. doi: 10.1007/s12325-021-01936-y. Epub 2021 Nov 11. [Article]
  7. FDA Approved Drug Products: Prolia® (denosumab) Injection, for subcutaneous use (Jan 2024) [Link]
  8. FDA Approved Drug Products: Xgeva (denosumab) injection, for subcutaneous use [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 RecruitingPreventionBariatric Surgery Candidates / Bone Loss1
4Active Not RecruitingTreatmentOsteoporosis / Postmenopausal Osteoporosis1
4Active Not RecruitingTreatmentOsteoporosis / Sarcopenia1
4Active Not RecruitingTreatmentPostmenopausal Osteoporosis1
4CompletedDiagnosticPostmenopausal Osteoporosis / Type 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionSubcutaneous60 mg/1mL
Injection, solutionParenteral; Subcutaneous60 MG/ML
SolutionSubcutaneous60 mg / mL
SolutionSubcutaneous60.000 mg
Injection, solutionSubcutaneous60 mg/ml
SolutionSubcutaneous60 mg
InjectionSubcutaneous
InjectionSubcutaneous120 mg/1.7mL
Injection, solutionParenteral; Subcutaneous120 MG
SolutionSubcutaneous120 mg / 1.7 mL
SolutionSubcutaneous120.000 mg
Injection, solutionSubcutaneous
SolutionSubcutaneous
Injection, solutionSubcutaneous120 mg
SolutionSubcutaneous120 mg
SolutionSubcutaneous12000000 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]
  3. FDA Approved Drug Products: Prolia® (denosumab) Injection, for subcutaneous use (Jan 2024) [Link]

Drug created at March 19, 2008 16:43 / Updated at February 16, 2024 07:35