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Revision as of 12:03, 15 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,074 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL', 'CAS_number').← Previous edit		Latest revision as of 05:10, 17 December 2024 edit undoWhywhenwhohow (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers49,324 edits initial name
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			{{Short description|Human monoclonal antibody}}
	{{Copy edit|date=April 2011}}
			{{Use dmy dates|date=October 2024}}
	{{Drugbox
			{{cs1 config |name-list-style=vanc |display-authors=6}}
			{{Infobox drug
	| Verifiedfields = changed		| Verifiedfields = changed
			| Watchedfields = changed
	| verifiedrevid = 414623374
			| verifiedrevid = 460765534
	<!--Monoclonal antibody data-->
	| type = mab		| type = mab
			| image = Denosumab.jpg
			| alt =
			| caption = Denosumab injection
			<!-- Monoclonal antibody data -->
	| mab_type = mab		| mab_type = mab
	| source = u		| source = u
	| target = ]		| target = ]
	<!--Clinical data-->		<!-- Clinical data -->
	| tradename =		| pronounce =
			| tradename = Prolia, others
	| Drugs.com = {{drugs.com|monograph|denosumab}}		| Drugs.com = {{drugs.com|monograph|denosumab}}
	| MedlinePlus = a610023		| MedlinePlus = a610023
	| licence_US = Denosumab		| DailyMedID = Denosumab
	| pregnancy_US = C		| pregnancy_AU = D
			| pregnancy_AU_comment =
			| pregnancy_category =
			| routes_of_administration = ]
			| class =
			| ATC_prefix = M05
			| ATC_suffix = BX04
			| ATC_supplemental =
			| biosimilars = denosumab-bbdz, Jubbonti,<ref name="Jubbonti CA" /><ref name="Jubbonti EPAR" /> Wyost<ref name="Wyost CA" />
			<!-- Legal status -->
			| legal_AU = S4
			| legal_AU_comment = <ref>{{cite web | title=Jubbonti (Sandoz Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=13 September 2024 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/jubbonti-sandoz-pty-ltd | access-date=15 September 2024}}</ref>
			| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
			| legal_BR_comment =
			| legal_CA = Rx-only
			| legal_CA_comment = /{{nbsp}}Schedule D<ref name="Wyost CA">{{cite web | title=Regulatory Decision Summary for Wyost | website=Drug and Health Products Portal | date=1 March 2024 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1710769045419 | access-date=1 April 2024 | archive-date=1 April 2024 | archive-url=https://web.archive.org/web/20240401064821/https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1710769045419 | url-status=live }}</ref><ref name="Jubbonti CA">{{cite web | title=Regulatory Decision Summary for Jubbonti | website=Drug and Health Products Portal | date=16 February 2024 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1710165579186 | access-date=1 April 2024 | archive-date=1 April 2024 | archive-url=https://web.archive.org/web/20240401064821/https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1710165579186 | url-status=live }}</ref><ref>{{cite web | title=Summary Basis of Decision for Wyost | website=Drug and Health Products Portal | date=1 September 2012 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1729522137894 | access-date=13 November 2024}}</ref><ref>{{cite web | title=Summary Basis of Decision for Jubbonti | website=Drug and Health Products Portal | date=1 September 2012 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1729523262756 | access-date=13 November 2024}}</ref>
			| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
			| legal_DE_comment =
			| legal_NZ = <!-- Class A, B, C -->
			| legal_NZ_comment =
			| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
			| legal_UK_comment =
	| legal_US = Rx-only		| legal_US = Rx-only
			| legal_US_comment = <ref>{{cite web | title=Prolia- denosumab injection | website=DailyMed | date=24 January 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=49e5afe9-a0c7-40c4-af9f-f287a80c5c88 | access-date=6 March 2024 | archive-date=7 June 2023 | archive-url=https://web.archive.org/web/20230607092644/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=49e5afe9-a0c7-40c4-af9f-f287a80c5c88 | url-status=live }}</ref><ref>{{cite web | title=Xgeva- denosumab injection | website=DailyMed | date=9 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=628f0998-1206-4001-aeee-18133aa9f3bf | access-date=6 March 2024 | archive-date=13 April 2023 | archive-url=https://web.archive.org/web/20230413084426/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=628f0998-1206-4001-aeee-18133aa9f3bf | url-status=live }}</ref>
	| routes_of_administration = ] injection, every six months
			| legal_EU = Rx-only
			| legal_EU_comment = <ref name="Prolia EPAR" /><ref name="Xgeva EPAR" /><ref name="Jubbonti EPAR" />
			| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
			| legal_UN_comment =
			| legal_status = <!-- For countries not listed above -->
	<!--Pharmacokinetic data-->		<!-- Pharmacokinetic data -->
	| bioavailability = N/A		| bioavailability = N/A
			| protein_bound =
	| metabolism = ]
			| metabolism = ]
			| metabolites =
			| onset =
			| elimination_half-life =
			| duration_of_action =
			| excretion =
	<!--Identifiers-->		<!-- Identifiers -->
	| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}		| CAS_number_Ref = {{cascite|changed|??}}
			| CAS_number = 615258-40-7
	| ChemSpiderID = NA
			| CAS_supplemental =
	| CAS_number_Ref = {{cascite|correct|??}}
			| PubChem =
	| CAS_number = <!-- blanked - oldvalue: 615258-40-7 -->
	| ATC_prefix = M05		| IUPHAR_ligand =
	| ATC_suffix = BX04
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
			| DrugBank = DB06643
	| UNII_Ref = {{fdacite|changed|FDA}}
			| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
			| ChemSpiderID = none
			| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = 4EQZ6YO2HI		| UNII = 4EQZ6YO2HI
	| KEGG_Ref = {{keggcite|correct|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = D03684		| KEGG = D03684
			| ChEBI =
	| ChEMBL_Ref = {{ebicite|changed|EBI}}		| ChEMBL_Ref = {{ebicite|changed|EBI}}
	| ChEMBL = <!-- blanked - oldvalue: 1237023 -->		| ChEMBL = 1237023
			| NIAID_ChemDB =
	| C=6404 | H=9912 | N=1724 | O=2004 | S=50
			| PDB_ligand =
	| molecular_weight = 144.7 ]
	| synonyms = AMG 162		| synonyms = AMG-162
			<!-- Chemical and physical data -->
			| C=6404 | H=9912 | N=1724 | O=2004 | S=50
	}}		}}
	'''Denosumab'''<ref>{{cite journal|last=Pageau|first=Steven C.|title=Denosumab|journal=mAbs|year=2009|volume=1|issue=3|pages=210–215|doi=10.4161/mabs.1.3.8592|url=http://www.landesbioscience.com/journals/17/article/8592/|pmid=20065634|pmc=2726593}}</ref> is a fully human ] for the treatment of ], treatment induced bone loss, bone metastases, ], ] and ].<ref name="pmid16495394">{{cite journal | last1 = McClung | first1 = MR | last2 = Lewiecki | first2 = EM | last3 = Cohen | first3 = SB | last4 = Bolognese | first4 = MA | last5 = Woodson | first5 = GC | last6 = Moffett | first6 = AH | last7 = Peacock | first7 = M | last8 = Miller | first8 = PD | last9 = Lederman | first9 = SN | title = Denosumab in postmenopausal women with low bone mineral density | journal = ] | volume = 354 | issue = 8 | pages = 821–31 | year = 2006 | month = February | pmid = 16495394 | doi = 10.1056/NEJMoa044459 | url = http://www.nejm.org/doi/pdf/10.1056/NEJMoa044459 | format = PDF }}</ref><ref name="pmid18725648">{{cite journal | last1 = Ellis | first1 = GK | last2 = Bone | first2 = HG | last3 = Chlebowski | first3 = R | last4 = Paul | first4 = D | last5 = Spadafora | first5 = S | last6 = Smith | first6 = J | last7 = Fan | first7 = M | last8 = Jun | first8 = S | title = Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer | journal = ] | volume = 26 | issue = 30 | pages = 4875–82 | year = 2008 | month = October | pmid = 18725648 | doi = 10.1200/JCO.2008.16.3832 | url = http://jco.ascopubs.org/content/26/30/4875.full.pdf }}</ref> It was developed by the company ].<ref> from Amgen.</ref>
			'''Denosumab''', sold under the brand names '''Prolia''' among others, is a human ] used for the treatment of ], treatment-induced bone loss, ] to bone, and ].<ref name="pmid_20065634">{{cite journal | vauthors = Pageau SC | title = Denosumab | journal = mAbs | volume = 1 | issue = 3 | pages = 210–5 | year = 2009 | pmid = 20065634 | pmc = 2726593 | doi = 10.4161/mabs.1.3.8592 | url = http://www.landesbioscience.com/journals/17/article/8592/ | access-date = 27 March 2011 | archive-date = 8 March 2012 | archive-url = https://web.archive.org/web/20120308113034/http://www.landesbioscience.com/journals/17/article/8592/ | url-status = live }}</ref><ref name="pmid16495394">{{cite journal | vauthors = McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ | title = Denosumab in postmenopausal women with low bone mineral density | journal = The New England Journal of Medicine | volume = 354 | issue = 8 | pages = 821–31 | date = February 2006 | pmid = 16495394 | doi = 10.1056/NEJMoa044459 | author17 = AMG 162 Bone Loss Study Group | doi-access = free }}</ref>
	Denosumab is designed to target ] (] ligand), a protein that acts as the primary signal to promote bone removal. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction.
			The most common side effects are ] and ] in the arms or legs.<ref name="EMEA" />
	It was approved by ] (FDA) for use in postmenopausal women with risk of osteoporosis in June 2010, under the trade name '''Prolia''',<ref>{{cite web |url=http://www.biosciencetechnology.com/News/FeedsAP/2010/06/fda-clears-amgens-bone-strengthening-drug-prolia/ |title=FDA clears Amgen's bone-strengthening drug Prolia |author=Matthew Perrone |publisher=BioScience Technology |date=June 2, 2010}}</ref> and for the prevention of skeletal-related events in patients with ] from solid tumors in November 2010, as '''Xgeva''',<ref name=Nov2010 /> making it the first ] to be approved by the FDA.<ref name=FDA-deno>{{cite news |url=http://www.medpagetoday.com/Endocrinology/Osteoporosis/20432 |title=FDA Approves Denosumab for Osteoporosis |date=2 June 2010 }}</ref> In the summer of 2011 ]s were investigating giant cell tumors, multiple myeloma with bone metastases, dosing, safety, and hypercalcemia of malignancy.<ref>{{cite journal | author = Russell S. Crawford, BPharm; Morgane C. Diven, PharmD; Laura Yarbro, PharmD | title = Denosumab: A Review of Its Pharmacology and Clinical Implications | journal = Contemporary Oncology | volume = 3 | issue = 1 | year = 2011 | url = http://www.onclive.com/publications/contemporary-oncology/2011/summer-2011/Denosumab-A-Review-of-Its-Pharmacology-and-Clinical-Implications }}</ref>
			Denosumab is an ],<ref name="pmid_20065634"/> which works by decreasing the development of ]s, which are cells that ]. Denosumab is a human monoclonal IgG2 antibody that targets the protein RANKL, which is essential for the formation, function and survival of osteoclasts, the cell type responsible for bone resorption.<ref name="Osenvelt EPAR" /> Denosumab binds to RANKL with high affinity and specificity, preventing the interaction between RANKL and RANK.<ref name="Osenvelt EPAR" /> Increased osteoclast activity stimulated by RANKL is a key mediator of bone destruction in metastatic bone disease.<ref name="Osenvelt EPAR" /> This leads to a reduction in osteoclast numbers and function, and a decrease in bone resorption, cancer-induced bone destruction.<ref name="Osenvelt EPAR" /> It also leads to a decrease in bone resorption in cortical and trabecular bones.<ref name="Stoboclo EPAR" /> It was developed by the biotechnology company ].<ref>{{cite web|url=http://www.amgen.com/medpro/products_prolia.html|publisher=Amgen|access-date=6 May 2012|title=Prolia (denosumab)|website=Products|archive-date=29 September 2015|archive-url=https://web.archive.org/web/20150929025841/http://www.amgen.com/medpro/products_prolia.html|url-status=dead}}</ref>
	== Mechanism of action ==
	] is the process which continuously removes old material from the bone and adds new bone. It is driven by various types of cells, most notably ]s, which secrete new bone, and ]s, which break bone down. The role of ]s is not well understood.
			==Medical uses==
	Osteoblasts express a protein called ''receptor activator of ] ligand'' (RANKL). RANKL binds to its receptor RANK, a member of the ] superfamily. RANK is expressed by pre-osteoclasts, and induces their conversion into mature osteoclasts. Denosumab inhibits the maturation of osteoclasts by binding to RANKL, protecting the bone from degradation and thus from osteoporosis.<ref name="pmid16495394" /> The drug therefore mimics the ] effects of ], another protein produced by osteoblasts which acts as an alternate receptor for RANKL, modulating the RANK/RANKL induced osteoclast activity.
			Denosumab is used for those with ] at high risk for ]s, bone loss due to certain medications, and in those with ].<ref name=AHFS2014>{{cite web|title=Denosumab|url=https://www.drugs.com/monograph/denosumab.html|publisher=The American Society of Health-System Pharmacists|access-date=16 March 2015|archive-date=30 April 2021|archive-url=https://web.archive.org/web/20210430164801/https://www.drugs.com/monograph/denosumab.html|url-status=live}}</ref>
	== Effectiveness ==		===Cancer===
			A 2012 meta-analysis found that denosumab was better than placebo, ], and ], in reducing the risk of fractures in those with cancer.<ref>{{cite journal | vauthors = Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, Richardson GE, Siena S, Maroto P, Clemens M, Bilynskyy B, Charu V, Beuzeboc P, Rader M, Viniegra M, Saad F, Ke C, Braun A, Jun S | title = Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials | journal = European Journal of Cancer | volume = 48 | issue = 16 | pages = 3082–92 | date = November 2012 | pmid = 22975218 | doi = 10.1016/j.ejca.2012.08.002 }}</ref>
	Amgen has reported on two clinical trials designed and funded by the company:<ref name="LAT-12Aug09">{{cite news |work=] |url=http://www.latimes.com/features/health/la-sci-bone-drug12-2009aug12,0,1313143.story |title=New osteoporosis drug shown to reduce spinal fractures |author=Thomas H. Maugh II |date=August 12, 2009}}</ref>
			===Osteoporosis===
	*In a ] ('FREEDOM') involving 7,808 women, aged 60 to 90, there were significant improvements in the subset of women with more severe disease at the beginning of the study (two or more prevalent vertebral fractures and/or one or more prevalent vertebral fractures with moderate or severe deformity). Researchers reported a 35% risk reduction with denosumab compared with placebo (17% vs. 49%), with new vertebral fractures in this subset of only 31% for those taking denosumab, versus 71% receiving the placebo.<ref>{{cite web |date=September 16, 2009 |title=Denosumab: Fracture risk reduced in high-risk subset in FREEDOM |url=http://www.endocrinetoday.com/view.aspx?rid=43797 |work=Endocrine Today |author=Donald A. Bergman}}</ref><ref name="Cummings">{{cite journal | last1 = Cummings | first1 = SR | last2 = San Martin | first2 = J | last3 = McClung | first3 = MR | last4 = Siris | first4 = ES | last5 = Eastell | first5 = R | last6 = Reid | first6 = IR | last7 = Delmas | first7 = P | last8 = Zoog | first8 = HB | last9 = Austin | first9 = M | title = Denosumab for prevention of fractures in postmenopausal women with osteoporosis | journal = ] | volume = 361 | issue = 8 | pages = 756–65 | year = 2009 | month = August | pmid = 19671655 | doi = 10.1056/NEJMoa0809493 | url = http://www.nejm.org/doi/pdf/10.1056/NEJMoa0809493 | format = PDF }}</ref>
			In those with postmenopausal osteoporosis denosumab decreases the risk of fractures but increases the risk of infection.<ref>{{cite journal | vauthors = Zhou Z, Chen C, Zhang J, Ji X, Liu L, Zhang G, Cao X, Wang P | title = Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis | journal = International Journal of Clinical and Experimental Pathology | volume = 7 | issue = 5 | pages = 2113–22 | date = 2014 | pmid = 24966919 | pmc = 4069896 }}</ref> A 2013 review concluded that it is a reasonable treatment for postmenopausal osteoporosis.<ref>{{cite journal | vauthors = Josse R, Khan A, Ngui D, Shapiro M | title = Denosumab, a new pharmacotherapy option for postmenopausal osteoporosis | journal = Current Medical Research and Opinion | volume = 29 | issue = 3 | pages = 205–16 | date = March 2013 | pmid = 23297819 | doi = 10.1185/03007995.2013.763779 | s2cid = 206967103 }}</ref> A 2017 review did not find benefit in males.<ref>{{cite journal | vauthors = Nayak S, Greenspan SL | title = Osteoporosis Treatment Efficacy for Men: A Systematic Review and Meta-Analysis | journal = Journal of the American Geriatrics Society | volume = 65 | issue = 3 | pages = 490–495 | date = March 2017 | pmid = 28304090 | pmc = 5358515 | doi = 10.1111/jgs.14668 }}</ref>
			==Mechanism of action==
	*The second phase 3 clinical trial involved 1,468 ] patients receiving hormone-deprivation therapy, who were randomised to receive either denosumab or a ] every 6 months over a 36 month period. All patients also received supplemental calcium and vitamin D. Of those taking the placebo, 3.9% experienced bone fractures during the 36 months, compared with 1.5% of those who received denosumab.<ref>{{cite web |url=http://www.docguide.com/news/content.nsf/news/852576140048867A85257632006F9B70 |title=Experimental Drug Reduces Fractures Related to Prostate Cancer Treatment: Presented at ASBMR |author=John Otrompke |publisher=Doctor's Guide |date=September 15, 2009}}</ref>
			] is 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 notably ]s (which secrete new bone) and ]s (which break down bone); ]s are also present in bone.
			Precursors to osteoclasts, called pre-osteoclasts, express surface receptors called ] (receptor activator of ]). RANK is a member of the ] (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 of ], an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased ]) in people with osteoporosis. This protects bone from degradation, and helps to counter the progression of the disease.<ref name="pmid16495394" />
	Both studies showed a decrease of fractures comparable to ] and ], and slightly more than under oral nitrogenous ]s.{{Citation needed|date=April 2011}}
			==Contraindications and interactions==
	Other studies have been discussed by Baqir and Copeland (Clinical Pharmacist 2010; 2:400). These are DEFEND, DECIDE and STAND.
			It is contraindicated in people with ]; sufficient calcium and ] levels must be reached before starting on denosumab therapy.<ref name="AustriaCodex">{{cite book|title=Austria-Codex|at=Prolia-Injektionslösung in einer Fertigspritze|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2017|isbn=978-3-85200-196-8|language=de}}</ref> Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.<ref name="AustriaCodex" />
	Bone ''et al.''{{Citation needed|date=April 2011}} investigated the effects of denosumab on bone mineral density (BMD), in women with BMD T scores between -1 and -2.5, using a randomised trial comparing the treatment with placebo. The primary endpoint, BMD change from baseline in the lumbar spine after two years, was +6.5% for denosumab and -0.6% for placebo (ARR =7%; p<0.0001). Brown ''et al.''{{Citation needed|date=April 2011}} compared denosumab with alendronate using BMD in total hip as the primary outcome measure. There was an increase in total hip BMD of 3.5% and 2.6% in the densoumab and alendronate groups respectively (ARR =1%; p<0.0001; NNT = 100). Although this study was not powered to compare fractures, fractures were reported in 4% of the denosumab and 3.2% of the alendronate group. Kendler ''et al.''{{Citation needed|date=April 2011}} investigated denosumab therapy following on from alendronate. Women on alendronate 70mg weekly for a run in period of 1 month were switched to denosumab or alendroanate (with matching placebo). The primary hypothesis was that denosumab was non-inferior to alendronate and the primary endpoint was percentage change in total hip BMD at 12 months. BMD was +1.9% vs +1.05% in patients given denosumab vs those continuing on alendronate (ARR = 0.85%; p<0.0001; NNT = 118). Again this study was not powered to compare fracture rates but fractures were reported as adverse events in 8 patients (3.2%) in the denosumab group and 4 patients (1.6%) in the alendronate group.
			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 to ]s, denosumab appears to be implicated in increasing the risk of ] (ONJ) following extraction of teeth or oral surgical procedures but, unlike bisphosphonate, the risk declines to zero approximately 6 months after injection.<ref>{{cite web|url=http://www.todaysgeriatricmedicine.com/archive/110310p6.shtml|title=Injectable Prolia — Osteoporosis Update|access-date=23 March 2016|archive-date=9 March 2021|archive-url=https://web.archive.org/web/20210309195950/https://www.todaysgeriatricmedicine.com/archive/110310p6.shtml|url-status=live}}</ref> Invasive dental procedures should be avoided during this time.
	==Adverse effects==		==Adverse effects==
	The most common side effects include infections of the ] and ], ], ], ]es and joint pain.<ref name="EMEA" /> A small study found a slightly increased risk of ] and severe infections, but these results did not reach ].<ref name="pmid16495394" /> Another trial showed significantly increased rates of ] and ] due to infections of the skin.<ref name="Cummings" /> It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the ].<ref>{{cite journal|doi=10.1056/NEJMe0905480|last=Khosla|first=S|title=Increasing options for the treatment of osteoporosis|journal=New England Journal of Medicine|year=2009|volume=361|issue=8|pages=818–820|pmid=19671654}}</ref> It is expressed by ] and thought to be involved in ] maturation.<ref>{{cite web | title = Entrez Gene: TNFSF11 tumor necrosis factor (ligand) superfamily, member 11| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8600}}</ref>		The most common side effects are ] and ] in the arms or legs.<ref name="EMEA" /> There is an increased risk of ]s such as ], ] (low blood calcium), hypersensitivity allergy reactions, ], and atypical ]s.<ref name="EMEA" /><ref name="AustriaCodex" /> Another trial showed significantly increased rates of ] and ] due to infections of the skin.<ref name="Cummings">{{cite journal | vauthors = Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C | title = Denosumab for prevention of fractures in postmenopausal women with osteoporosis | journal = The New England Journal of Medicine | volume = 361 | issue = 8 | pages = 756–65 | date = August 2009 | pmid = 19671655 | doi = 10.1056/NEJMoa0809493 | citeseerx = 10.1.1.472.3489 }}</ref> It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the ].<ref>{{cite journal | vauthors = Khosla S | title = Increasing options for the treatment of osteoporosis | journal = The New England Journal of Medicine | volume = 361 | issue = 8 | pages = 818–20 | date = August 2009 | pmid = 19671654 | pmc = 3901579 | doi = 10.1056/NEJMe0905480 }}</ref> RANKL is expressed by ], and is thought to be involved in ] maturation.<ref>{{EntrezGene|8600}} TNFSF11 tumor necrosis factor (ligand) superfamily, member 11; Homo sapiens {{blockquote|also known as ''RANKL''. This protein was shown to be a dentritic cell survival factor and is involved in the regulation of T cell-dependent immune response.}}</ref>
			Use of Prolia can increase the risk of severe ] among those with advanced kidney disease, especially those on dialysis.<ref>"". ''Reuters'', 19 January 2024.</ref>
	==Contraindications and interactions==
	The drug is contraindicated in patients with ]. Sufficient calcium and ] levels must be reached before starting a denosumab therapy.<ref name="AustriaCodex">{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2009|edition=2009/2010|isbn=3-85200-196-X|language=German}}</ref>
			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.<ref name=Boy2017/> Vertebral compression fractures have also occurred in some people after discontinuing treatment.<ref name=Boy2017>{{cite journal | vauthors = Boyce AM | title = Denosumab: an Emerging Therapy in Pediatric Bone Disorders | journal = Current Osteoporosis Reports | volume = 15 | issue = 4 | pages = 283–292 | date = August 2017 | pmid = 28643220 | pmc = 5554707 | doi = 10.1007/s11914-017-0380-1 }}</ref>
	Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.<ref name="AustriaCodex" />
	== Regulatory approval ==		== Legal status ==
	===United States===
	On 13 August 2009, an Amgen press release regarding the meeting that day with the Advisory Committee for Reproductive Health Drugs (ACRHD) of the (FDA), to review the potential uses of Prolia, said:
			=== United States ===
	<blockquote>After reviewing safety and efficacy data from 30 clinical studies involving more than 12,000 patients, the Committee recommended approval of Prolia for the treatment of postmenopausal osteoporosis, and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer.<ref>{{cite web |title=Amgen Issues Statement on Outcomes of Advisory Committee for Reproductive Health Drugs (ACRHD) Meeting |publisher=PRNewswire/FirstCall |date=August 13, 2009 |url=http://www.urotoday.com/3401/browse_categories/prostate_cancer/amgen_issues_statement_on_outcomes_of_advisory_committee_for_reproductive_health_drugs_acrhd_meeting08192009.html}}</ref></blockquote>
			In August 2009, a meeting was held between Amgen and the Advisory Committee for Reproductive Health Drugs (ACRHD) of the U.S. ] (FDA) to review the potential uses of denosumab.<ref>{{cite web |title=Amgen Issues Statement on Outcomes of Advisory Committee for Reproductive Health Drugs (ACRHD) Meeting |publisher=PRNewswire/FirstCall |date=13 August 2009 |url=http://www.urotoday.com/3401/browse_categories/prostate_cancer/amgen_issues_statement_on_outcomes_of_advisory_committee_for_reproductive_health_drugs_acrhd_meeting08192009.html |access-date=17 September 2009 |archive-url=https://web.archive.org/web/20131103205109/http://www.urotoday.com/3401/browse_categories/prostate_cancer/amgen_issues_statement_on_outcomes_of_advisory_committee_for_reproductive_health_drugs_acrhd_meeting08192009.html |archive-date=3 November 2013 |url-status=dead }}</ref>
	October 2009: The ] (FDA) delayed approval of denosumab because they needed more information.<ref>{{cite news|url=http://www.nytimes.com/2009/10/20/business/20amgen.html |work=] |title=F.D.A. Says No to an Amgen Bone Drug|date=19 October 2009|last=Pollack|first=Andrew}}</ref>		In October 2009, the FDA delayed approval of denosumab, stating that it needed more information.<ref>{{cite news|url=https://www.nytimes.com/2009/10/20/business/20amgen.html|work=]|title=F.D.A. Says No to an Amgen Bone Drug|date=19 October 2009|last=Pollack|first=Andrew|access-date=24 February 2017|archive-date=27 January 2018|archive-url=https://web.archive.org/web/20180127135657/http://www.nytimes.com/2009/10/20/business/20amgen.html|url-status=live}}</ref>
			In June 2010, denosumab was approved by the FDA for use in postmenopausal women with risk of osteoporosis<ref name=FDA-deno/> under the brand name Prolia,<ref>{{cite web |url=http://www.biosciencetechnology.com/News/FeedsAP/2010/06/fda-clears-amgens-bone-strengthening-drug-prolia/ |title=FDA clears Amgen's bone-strengthening drug Prolia |author=Matthew Perrone |publisher=BioScience Technology |date=2 June 2010 |access-date=2 June 2010 |archive-url=https://web.archive.org/web/20100827180700/http://www.biosciencetechnology.com/News/FeedsAP/2010/06/fda-clears-amgens-bone-strengthening-drug-prolia/ |archive-date=27 August 2010 |url-status=dead }}</ref> and in November 2010, as Xgeva for the prevention of skeleton-related events in people with ] from solid ]s.<ref name=Nov2010>{{cite news |url=http://www.genengnews.com/gen-news-highlights/amgen-s-denosumab-cleared-by-fda-for-second-indication/81244270/ |title=Amgen's Denosumab Cleared by FDA for Second Indication |date=19 November 2010 |access-date=27 November 2010 |archive-date=7 April 2018 |archive-url=https://web.archive.org/web/20180407054018/https://www.genengnews.com/gen-news-highlights/amgen-s-denosumab-cleared-by-fda-for-second-indication/81244270/ |url-status=dead }}</ref> Denosumab is the first ] to be approved by the FDA.<ref name=FDA-deno>{{cite news |url=http://www.medpagetoday.com/Endocrinology/Osteoporosis/20432 |title=FDA Approves Denosumab for Osteoporosis |date=2 June 2010 |access-date=27 November 2010 |archive-date=13 June 2018 |archive-url=https://web.archive.org/web/20180613015439/https://www.medpagetoday.com/endocrinology/osteoporosis/20432 |url-status=live }}</ref>
	June 2010: Denosumab was approved for postmenopausal osteoporosis by the US FDA on June 2, 2010.<ref name=FDA-deno/>
			In June 2013, the FDA approved denosumab for treatment of adults and skeletally mature adolescents with ] that is unresectable or where resection would result in significant morbidity.<ref>{{cite web|url=http://www.cancer.gov/cancertopics/druginfo/fda-denosumab|title=FDA Approval for Denosumab|access-date=31 August 2013|archive-date=6 April 2015|archive-url=https://web.archive.org/web/20150406011426/http://www.cancer.gov/cancertopics/druginfo/fda-denosumab|url-status=dead}}</ref>
	Common side effects include osteonecrosis of the jaw, back pain, pain in the extremities, musculoskeletal pain, high cholesterol levels, and urinary bladder infections.<ref name=Nov2010/>
			In January 2024, the FDA added a ] to 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.<ref>" {{Webarchive|url=https://web.archive.org/web/20240406170114/https://www.fda.gov/safety/medical-product-safety-information/prolia-denosumab-drug-safety-communication-fda-adds-boxed-warning-increased-risk-severe-hypocalcemia |date=6 April 2024 }}". U.S. Food and Drug Administration, 19 January 2024.</ref>
	November 2010: FDA approved denosumab (to be marketed as Xgeva) for the prevention of skeletal-related events in patients with bone metastases from solid tumors.<ref name=Nov2010>{{cite news |url=http://www.genengnews.com/gen-news-highlights/amgen-s-denosumab-cleared-by-fda-for-second-indication/81244270/ |title=Amgen's Denosumab Cleared by FDA for Second Indication |date=19 Nov 2010 }}</ref> (Dosing is a 60&nbsp;mg subcutaneous injection every six months for postmenopausal osteoporosis and 120 mg every 4 weeks for patients with solid tumors).
			In March 2024, the FDA approved applications from ] for Jubbonti (denosumab-bbdz), a ] to Prolia; and Wyost (denosumab-bbdz), a biosimilar to Xgeva.<ref>{{Cite web |title=Jubbonti BLA #761362 |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761362s000lbl.pdf |access-date=5 March 2024 |website=U.S. ] (FDA) |archive-date=6 March 2024 |archive-url=https://web.archive.org/web/20240306132521/https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761362s000lbl.pdf |url-status=live }}</ref><ref>{{cite press release | title=Sandoz receives FDA approval for first and only denosumab biosimilars | publisher=Sandoz | via=GlobeNewswire | date=5 March 2024 | url=https://www.globenewswire.com/news-release/2024/03/05/2840809/0/en/Sandoz-receives-FDA-approval-for-first-and-only-denosumab-biosimilars.html | access-date=6 March 2024 | archive-date=6 March 2024 | archive-url=https://web.archive.org/web/20240306002156/https://www.globenewswire.com/news-release/2024/03/05/2840809/0/en/Sandoz-receives-FDA-approval-for-first-and-only-denosumab-biosimilars.html | url-status=live }}</ref>
	===Europe===
	The ] (CHMP) issued a Positive Opinion for denosumab on 17 December 2009, for the treatment of postmenopausal osteoporosis in women and for the treatment of bone loss in men with hormone ablation for prostate cancer.<ref name="EMEA">{{cite web|url=http://www.ema.europa.eu/pdfs/human/opinion/Prolia_77616809en.pdf|publisher=]|title=Summary of Positive Opinion for Prolia|date=17 December 2009|accessdate=7 January 2010}}</ref><ref>{{cite news|url=http://www.amgen.com/media/media_pr_detail.jsp?year=2009&releaseID=1367560|publisher=Amgen|title=Amgen Receives CHMP Positive Opinion for Prolia (Denosumab) in the European Union|date=18 December 2010|accessdate=7 January 2010}}</ref> Denosumab was approved for marketing by the European Commission on May 28, 2010.
	==Sales and pricing==		=== European Union ===
			In December 2009, the ] (CHMP) of the ] issued a positive opinion for denosumab for the treatment of postmenopausal osteoporosis in women and for the treatment of bone loss in men with ].<ref name="EMEA">{{cite web | publisher = ] (EMA) | title = European Public Assessment Report (EPAR) for Prolia. | date = 16 October 2014 | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/001120/WC500093527.pdf | access-date = 13 April 2015 | archive-date = 4 March 2016 | archive-url = https://web.archive.org/web/20160304191819/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/001120/WC500093527.pdf | url-status = dead }}</ref> Denosumab, as Prolia, was approved for medical use in the European Union in May 2010,<ref name="Prolia EPAR">{{cite web | title=Prolia EPAR | website=European Medicines Agency | date=26 May 2010 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/prolia | access-date=6 March 2024 | archive-date=16 September 2021 | archive-url=https://web.archive.org/web/20210916120807/https://www.ema.europa.eu/en/medicines/human/EPAR/prolia | url-status=live }}</ref><ref>{{cite web | title=Prolia PI | website=Union Register of medicinal products | date=28 May 2010 | url=https://ec.europa.eu/health/documents/community-register/html/h618.htm | access-date=6 March 2024 | archive-date=21 January 2022 | archive-url=https://web.archive.org/web/20220121045940/https://ec.europa.eu/health/documents/community-register/html/h618.htm | url-status=live }}</ref> and as Xgeva in July 2011.<ref name="Xgeva EPAR">{{cite web | title=Xgeva EPAR | website=European Medicines Agency | date=13 July 2011 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/xgeva | access-date=6 March 2024 | archive-date=21 September 2023 | archive-url=https://web.archive.org/web/20230921135101/https://www.ema.europa.eu/en/medicines/human/EPAR/xgeva | url-status=live }}</ref><ref>{{cite web | title=Xgeva PI | website=Union Register of medicinal products | date=15 July 2011 | url=https://ec.europa.eu/health/documents/community-register/html/h703.htm | access-date=6 March 2024 | archive-date=19 August 2018 | archive-url=https://web.archive.org/web/20180819160038/http://ec.europa.eu/health/documents/community-register/html/h703.htm | url-status=live }}</ref>
	Internationally, because of Amgen's relatively weak GP sales force, Amgen is partnering{{When|date=April 2011}} with ] (GSK) in Europe, Australia, New Zealand and Mexico to distribute Prolia.<ref name="YF-21Dec09">{{cite news |work=Yahoo Finance News |date=December 21, 2009|title=Amgen Closer to Prolia Approval |author=Zacks Equity Research |url=http://finance.yahoo.com/news/Amgen-Closer-to-Prolia-zacks-2903308367.html }}
	</ref>
			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.<ref name="Jubbonti EPAR" /><ref>{{cite press release | title=Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 18-21 March 2024 | website=European Medicines Agency | date=22 March 2024 | url=https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-18-21-march-2024 | access-date=13 June 2024}}</ref> The applicant for this medicinal product is Sandoz GmbH.<ref name="Jubbonti EPAR">{{cite web | title=Jubbonti EPAR | website=European Medicines Agency | date=21 March 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/jubbonti | access-date=23 March 2024 | archive-date=23 March 2024 | archive-url=https://web.archive.org/web/20240323162213/https://www.ema.europa.eu/en/medicines/human/EPAR/jubbonti | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> 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.<ref name="Wyost EPAR" /> The applicant for this medicinal product is Sandoz GmbH.<ref name="Wyost EPAR">{{cite web | title=Wyost EPAR | website=European Medicines Agency | date=21 March 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/wyost | access-date=23 March 2024 | archive-date=23 March 2024 | archive-url=https://web.archive.org/web/20240323162040/https://www.ema.europa.eu/en/medicines/human/EPAR/wyost | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> 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.<ref name=":0">{{Cite web |date=22 May 2024 |title=Sandoz receives European Commission approval for Wyost® and Jubbonti®, the first and only biosimilars of denosumab in Europe |url=https://finance.yahoo.com/news/sandoz-receives-european-commission-approval-050000909.html |access-date=23 May 2024 |website=Yahoo Finance |language=de-DE}}</ref> 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.<ref name=":0" />
	In September 2009, the firm ] projected that annual worldwide sales of the drug would reach $5 billion in the year 2015.<ref>{{cite news |work=The Wall Street Journal |title=Analysts React to FDA Panel: 'It Wasn't a Perfect Day for Amgen' |url=http://blogs.wsj.com/health/2009/08/14/analysts-react-to-fda-panel-it-wasnt-a-perfect-day-for-amgen/ |author=Jacob Goldstein |date=August 14, 2009}}</ref> It projected 2010 sales of over $650 million, mostly from use as a twice-yearly injectable for ] treatment in ] women over 50.<ref>{{cite news |date=September 7, 2009 |author=Dimitra Defotis |title=At Amgen, a Prescription for Success |url=http://online.barrons.com/article/SB125211286339588089.html |work=] }}</ref>
			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.<ref name="Obodence EPAR" /> The applicant for this medicinal product is Samsung Bioepis NL B.V.<ref name="Obodence EPAR" /> 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.<ref name="Obodence EPAR">{{cite web | title=Obodence EPAR | website=European Medicines Agency (EMA) | date=14 November 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/obodence | access-date=16 November 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref name="CHMP 202411">{{cite press release | title=Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 11-14 November 2024 | website=] (EMA) | date=15 November 2024 | url=https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-11-14-november-2024 | access-date=16 November 2024}}</ref>
			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.<ref name="Xbryk EPAR" /> The applicant for this medicinal product is Samsung Bioepis NL B.V.<ref name="Xbryk EPAR" /> 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.<ref name="Xbryk EPAR">{{cite web | title=Xbryk | website=European Medicines Agency (EMA) | date=14 November 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/xbryk | access-date=16 November 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref name="CHMP 202411" />
			In December 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Osenvelt, 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.<ref name="Osenvelt EPAR" /> The applicant for this medicinal product is Celltrion Healthcare Hungary Kft.<ref name="Osenvelt EPAR" /> Osenvelt is a biosimilar medicinal product.<ref name="Osenvelt EPAR" /> It is highly similar to the reference product Xgeva which was authorized in the EU in July 2011.<ref name="Osenvelt EPAR">{{cite web | title=Osenvelt EPAR | website=European Medicines Agency (EMA) | date=12 December 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/osenvelt | access-date=16 December 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>
			In December 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Stoboclo, intended for the treatment of osteoporosis in women who have been through menopause, bone loss linked to hormone ablation in men at increased risk of fractures and bone loss associated with long-term treatment with systemic glucocorticoid.<ref name="Stoboclo EPAR" /> The applicant for this medicinal product is Celltrion Healthcare Hungary Kft.<ref name="Stoboclo EPAR" /> Stoboclo is a biosimilar medicinal product.<ref name="Stoboclo EPAR" /> It is highly similar to the reference product Prolia, which was authorized in the EU in May 2010.<ref name="Stoboclo EPAR">{{cite web | title=Stoboclo EPAR | website=European Medicines Agency (EMA) | date=12 December 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/stoboclo | access-date=16 December 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>
			=== Canada ===
			] approved Jubbonti, a biosimilar to Prolia, in February 2024;<ref name="Jubbonti CA" /> and approved Wyost, a biosimilar to Xgeva, in March 2024.<ref name="Wyost CA" />
	== References ==		== References ==
	{{Reflist|30em}}		{{reflist}}
	== External links ==		== Further reading ==
			{{refbegin}}
	* {{Official website|http://www.prolia.com/|name=Prolia}}
			* {{cite journal | vauthors = Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, San Martin J, Dansey R | title = Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab | journal = Nature Reviews. Drug Discovery | volume = 11 | issue = 5 | pages = 401–19 | date = May 2012 | pmid = 22543469 | doi = 10.1038/nrd3705 | s2cid = 7875371 }}
	* {{Official website|http://www.xgeva.com/|name=Xgeva}}
			{{refend}}
	*
	*
	{{Drugs for treatment of bone diseases}}		{{Drugs for treatment of bone diseases}}
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			{{Cytokine receptor modulators}}
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