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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
Download FASTA FormatReferences:
- NIH Inxight: denosumab [Link]
- 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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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Bone loss •••••••••••• •••• •••• •• ••••••••• •••••••• •••••• •••••••••••••• ••••••••• Management of Bone loss •••••••••••• •••••• ••••••• •••• •••• •• •••••••• ••••••••• Management of Osteoporosis •••••••••••• •••••••••••••• •••• •••• •• •••••••• ••••••••• Management of Osteoporosis •••••••••••• •••• •••• •• ••••••••• ••••••• •• ••••• ••••••• ••• •••••••••••• ••••••••• Management of Osteoporosis caused by glucocorticoid treatment •••••••••••• •••• •••• •• •••••••• ••••••••• - Associated Therapies
- Contraindications & Blackbox Warnings
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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
Target Actions Organism ATumor necrosis factor ligand superfamily member 11 antibodyHumans - 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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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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept 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. - 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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Ranmark (Daiichi Sankyo)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Jubbonti Solution 60 mg / mL Subcutaneous Sandoz Canada Incorporated 2024-07-25 Not applicable Canada 
Jubbonti Injection, solution 60 mg/ml Subcutaneous Sandoz 2024-07-10 Not applicable EU 
Prolia Injection 60 mg/1mL Subcutaneous AMGEN INC 2010-06-05 Not applicable US 
Prolia Injection, solution 60 mg/ml Subcutaneous Amgen Europe B.V. 2021-01-27 Not applicable EU Prolia Solution 60 mg / mL Subcutaneous Amgen Not applicable Not applicable Canada
Categories
- ATC Codes
- M05BX04 — Denosumab
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Antibodies
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Blood Proteins
- Bone Density Conservation Agents
- Cancer immunotherapy
- Drugs Affecting Bone Structure and Mineralization
- Drugs for Treatment of Bone Diseases
- Globulins
- Immunoglobulins
- Immunoproteins
- Immunosuppressive Agents
- Immunotherapy
- Musculo-Skeletal System
- Proteins
- RANK Ligand Blocking Activity
- RANK Ligand Inhibitor
- Serum Globulins
- 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
- 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]
- 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]
- 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]
- Narayanan P: Denosumab: A comprehensive review. South Asian J Cancer. 2013 Oct;2(4):272-7. doi: 10.4103/2278-330X.119895. [Article]
- 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]
- 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]
- FDA Approved Drug Products: Prolia® (denosumab) Injection, for subcutaneous use (Jan 2024) [Link]
- FDA Approved Drug Products: Xgeva (denosumab) injection, for subcutaneous use [Link]
- External Links
- KEGG Drug
- D03684
- PubChem Substance
- 347910354
- 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
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Osteoporosis 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Non-Small Cell Lung Carcinoma 1 somestatus stop reason just information to hide 4 Active Not Recruiting Prevention Bariatric Surgery Candidates / Bone Loss 1 somestatus stop reason just information to hide 4 Active Not Recruiting Prevention Osteoporosis / Spinal Cord Injuries 1 somestatus stop reason just information to hide 4 Active Not Recruiting Treatment Breast Cancer / Castration Resistant Prostate Cancer 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection Subcutaneous 60 MG/ML Injection Subcutaneous 60 mg/1mL Injection, solution Parenteral; Subcutaneous 60 MG/ML Solution Subcutaneous 60 mg / mL Solution Subcutaneous 60.000 mg Injection, solution Subcutaneous 60 mg/ml Solution Subcutaneous 60 mg/ml Solution Subcutaneous 60 mg Injection Subcutaneous Injection Subcutaneous 120 mg/1.7mL Injection Subcutaneous 70 MG/ML Injection, solution Parenteral; Subcutaneous 120 MG Solution Subcutaneous 120 mg / 1.7 mL Solution Subcutaneous 120.000 mg Injection, solution Subcutaneous Injection, solution Subcutaneous 120 mg Solution Subcutaneous 120 mg Solution Subcutaneous 12000000 mg Injection, solution 120 mg/1.7ml Injection, solution 60 mg/1ml - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region CA2257247 No 2012-09-11 2018-04-15 Canada CA2274987 No 2012-01-24 2017-12-22 Canada CA2285746 No 2010-09-28 2018-04-15 Canada CA2400929 No 2011-05-31 2021-02-23 Canada CA2328140 No 2012-03-13 2019-05-13 Canada
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antibody
- General 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 an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy (PubMed:22664871). Induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca (2+) resulting in the activation of NFATC1, which translocates to the nucleus and induces osteoclast-specific gene transcription to allow differentiation of osteoclasts. During osteoclast differentiation, in a TMEM64 and ATP2A2-dependent manner induces activation of CREB1 and mitochondrial ROS generation necessary for proper osteoclast generation (By similarity)
- Specific Function
- Cytokine activity
- 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]
- 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