Wikipedia

Denosumab

Denosumab,sold under the brand namesProliaandXgevaamong others, is a humanmonoclonal antibodyused for the treatment ofosteoporosis,treatment-induced bone loss,metastasesto bone, andgiant cell tumor of bone.[11][12]

Denosumab
Denosumab injection
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetRANK ligand
Clinical data
Trade namesProlia, Xgeva, others
Other namesAMG-162
Biosimilarsdenosumab-bbdz, Jubbonti,[1][2]Wyost[3]
AHFS/DrugsMonograph
MedlinePlusa610023
License data
Pregnancy
category
  • AU:D
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokineticdata
BioavailabilityN/A
MetabolismProteolysis
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6404H9912N1724O2004S50
Molar mass144722.80g·mol−1
☒NcheckY(what is this?)(verify)

Denosumab is contraindicated in people withlow blood calcium levels.The most common side effects arejointandmuscle painin the arms or legs.[13]

Denosumab is aninhibitor of RANKL (receptor activator of nuclear factor kappa-Β ligand),[11]which works by decreasing the development ofosteoclasts,which are cells thatbreak down bone.It was developed by the biotechnology companyAmgen.[14]

Medical uses

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Denosumab is used for those withosteoporosisat high risk forfractures,bone loss due to certain medications, and in those withbone metastases.[15]

Cancer

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A 2012 meta-analysis found that denosumab was better than placebo,zoledronic acid,andpamidronate,in reducing the risk of fractures in those with cancer.[16]

Osteoporosis

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In those with postmenopausal osteoporosis denosumab decreases the risk of fractures but increases the risk of infection.[17]A 2013 review concluded that it is a reasonable treatment for postmenopausal osteoporosis.[18]A 2017 review did not find benefit in males.[19]

Mechanism of action

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Bone remodelingis the process by which the body continuously removes old bone tissue and replaces it with new bone. It is driven by various types of cells, most notablyosteoblasts(which secrete new bone) andosteoclasts(which break down bone);osteocytesare also present in bone.

Precursors to osteoclasts, called pre-osteoclasts, express surface receptors calledRANK(receptor activator ofnuclear factor-kappa B). RANK is a member of thetumor necrosis factor receptor(TNFR) superfamily. RANK is activated by RANKL (the RANK-Ligand), which exists as cell surface molecules on osteoblasts. Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. Denosumab mimics the natural action ofosteoprotegerin,an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreasedeffectiveness) in people with osteoporosis. This protects bone from degradation, and helps to counter the progression of the disease.[12]

Contraindications and interactions

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It is contraindicated in people withhypocalcemia;sufficient calcium andvitamin Dlevels must be reached before starting on denosumab therapy.[20]Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.[20]

Denosumab works by lowering the hormonal message that leads to excessive osteoclast-driven bone removal and is active in the body for only six months. Similarly tobisphosphonates,denosumab appears to be implicated in increasing the risk ofosteonecrosis of the jaw(ONJ) following extraction of teeth or oral surgical procedures but, unlike bisphosphonate, the risk declines to zero approximately 6 months after injection.[21]Invasive dental procedures should be avoided during this time.

Adverse effects

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The most common side effects arejointandmuscle painin the arms or legs.[13]There is an increased risk ofinfectionssuch ascellulitis,hypocalcemia(low blood calcium), hypersensitivity allergy reactions,osteonecrosis of the jaw,and atypicalfemur fractures.[13][20]Another trial showed significantly increased rates ofeczemaandhospitalizationdue to infections of the skin.[22]It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in theimmune system.[23]RANKL is expressed byT helper cells,and is thought to be involved indendritic cellmaturation.[24]

Use of Prolia can increase the risk of severehypocalcemiaamong those with advanced kidney disease, especially those on dialysis.[25]

Discontinuation of denosumab is associated with a rebound increase in bone turnover. In rare cases this has led to severe hypercalcemia, but is common in children.[26]Vertebral compression fractures have also occurred in some people after discontinuing treatment.[26]

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United States

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In August 2009, a meeting was held between Amgen and the Advisory Committee for Reproductive Health Drugs (ACRHD) of the U.S.Food and Drug Administration(FDA) to review the potential uses of denosumab.[27]

In October 2009, the FDA delayed approval of denosumab, stating that it needed more information.[28]

In June 2010, denosumab was approved by the FDA for use in postmenopausal women with risk of osteoporosis[29]under the brand name Prolia,[30]and in November 2010 as Xgeva for the prevention of skeleton-related events in people withbone metastasesfrom solidtumors.[31]Denosumab is the firstRANKL inhibitorto be approved by the FDA.[29]

In June 2013, the FDA approved denosumab for treatment of adults and skeletally mature adolescents withgiant cell tumor of bonethat is unresectable or where resection would result in significant morbidity.[32]

In January 2024, the FDA added ablack box warningto Prolia because of the risk of severe hypocalcemia in those with advanced kidney disease. An FDA review found that Prolia had resulted in "hospitalization, life-threatening events, and death" in that population.[33]

In March 2024, the FDA approved applications fromSandozfor Jubbonti (denosumab-bbdz), abiosimilarto Prolia; and Wyost (denosumab-bbdz), a biosimilar to Xgeva.[34][35]

European Union

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In December 2009, theCommittee for Medicinal Products for Human Use(CHMP) of theEuropean Medicines Agencyissued a positive opinion for denosumab for the treatment of postmenopausal osteoporosis in women and for the treatment of bone loss in men withhormone ablation therapy for prostate cancer.[13]Denosumab, as Prolia, was approved for medical use in the European Union in May 2010,[9][36]and as Xgeva in July 2011.[10][37]

In March 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Jubbonti, intended for the treatment of osteoporosis in women who have been through menopause and in men at increased risk of fractures whose bone loss is linked to hormone ablation or long-term treatment with systemic glucocorticoid.[2][38]The applicant for this medicinal product is Sandoz GmbH.[2]In March 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Wyost, intended for the prevention of bone complications in adults with advanced cancer involving bone and for the treatment of adults and skeletally mature adolescents with giant cell tumour of bone.[39]The applicant for this medicinal product is Sandoz GmbH.[39]Denosumab, as Wyost,a biosimilar, was approved for medical use in the European Union in May 2024 for all indications of denosumab treated by Xgeva..[40]Denosumab, as Jubbonti, a biosimilar, was approved for medical use in the European Union in May 2024 for all indications of denosumab treated by Prolia.[40]

In November 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Obodence, intended for the treatment of osteoporosis in women who have been through menopause, treatment of bone loss linked to hormone ablation in men at increased risk of fractures, or treatment of bone loss associated with long-term treatment with systemic glucocorticoid.[41]The applicant for this medicinal product is Samsung Bioepis NL B.V.[41]Obodence is a biosimilar medicinal product that is highly similar to the reference product Prolia (denosumab), which was authorized in the EU in May 2010.[41][42]

In November 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Xbryk, intended for the prevention of bone complications in adults with advanced cancer involving bone and for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone.[43]The applicant for this medicinal product is Samsung Bioepis NL B.V.[43]Xbryk is a biosimilar medicinal product that is highly similar to the reference product Xgeva (denosumab), which was authorized in the EU in July 2011.[43][42]

Canada

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Health Canadaapproved Jubbonti, a biosimilar to Prolia, in February 2024;[1]and approved Wyost, a biosimilar to Xgeva, in March 2024.[3]

References

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  18. ^Josse R, Khan A, Ngui D, Shapiro M (March 2013). "Denosumab, a new pharmacotherapy option for postmenopausal osteoporosis".Current Medical Research and Opinion.29(3): 205–16.doi:10.1185/03007995.2013.763779.PMID23297819.S2CID206967103.
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  24. ^EntrezGene8600TNFSF11 tumor necrosis factor (ligand) superfamily, member 11; Homo sapiens

    also known asRANKL.This protein was shown to be a dentritic cell survival factor and is involved in the regulation of T cell-dependent immune response.
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  34. ^"Jubbonti BLA #761362"(PDF).U.S.Food and Drug Administration(FDA).Archived(PDF)from the original on 6 March 2024.Retrieved5 March2024.
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  39. ^ab"Wyost EPAR".European Medicines Agency.21 March 2024.Archivedfrom the original on 23 March 2024.Retrieved23 March2024.Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  40. ^ab"Sandoz receives European Commission approval for Wyost® and Jubbonti®, the first and only biosimilars of denosumab in Europe".Yahoo Finance(in German). 22 May 2024.Retrieved23 May2024.
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  42. ^ab"Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 11-14 November 2024".European Medicines Agency(EMA)(Press release). 15 November 2024.Retrieved16 November2024.
  43. ^abc"Xbryk".European Medicines Agency (EMA).14 November 2024.Retrieved16 November2024.Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Further reading

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  • Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, et al. (May 2012). "Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab".Nature Reviews. Drug Discovery.11(5): 401–19.doi:10.1038/nrd3705.PMID22543469.S2CID7875371.
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