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Denosumab

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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/Drugs.comMonograph
MedlinePlusa610023
License data
Pregnancy
category
  • AU: D
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityN/A
MetabolismProteolysis
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6404H9912N1724O2004S50
Molar mass144722.80 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Denosumab, sold under the brand names Prolia and Xgeva among others, is a human monoclonal antibody used for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.[11][12]

Denosumab is contraindicated in people with low blood calcium levels. The most common side effects are joint and muscle pain in the arms or legs.[13]

Denosumab is an inhibitor of RANKL (receptor activator of nuclear factor kappa-Β ligand),[11] which works by decreasing the development of osteoclasts, which are cells that break down bone. It was developed by the biotechnology company Amgen.[14]

Medical uses

[edit]

Denosumab is used for those with osteoporosis at high risk for fractures, bone loss due to certain medications, and in those with bone metastases.[15]

Cancer

[edit]

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

Osteoporosis

[edit]

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

[edit]

Bone remodeling 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 osteoblasts (which secrete new bone) and osteoclasts (which break down bone); osteocytes are also present in bone.

Precursors to osteoclasts, called pre-osteoclasts, express surface receptors called RANK (receptor activator of nuclear factor-kappa B). RANK is a member of the tumor 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 of osteoprotegerin, an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased effectiveness) 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 with hypocalcemia; sufficient calcium and vitamin D levels 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 to bisphosphonates, denosumab appears to be implicated in increasing the risk of osteonecrosis 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

[edit]

The most common side effects are joint and muscle pain in the arms or legs.[13] There is an increased risk of infections such as cellulitis, hypocalcemia (low blood calcium), hypersensitivity allergy reactions, osteonecrosis of the jaw, and atypical femur fractures.[13][20] Another trial showed significantly increased rates of eczema and hospitalization due 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 the immune system.[23] RANKL is expressed by T helper cells, and is thought to be involved in dendritic cell maturation.[24]

Use of Prolia can increase the risk of severe hypocalcemia among 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]

[edit]

United States

[edit]

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 with bone metastases from solid tumors.[31] Denosumab is the first RANKL inhibitor to be approved by the FDA.[29]

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

In January 2024, the FDA added a black box warning 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.[33]

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

European Union

[edit]

In December 2009, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a positive opinion for denosumab for the treatment of postmenopausal osteoporosis in women and for the treatment of bone loss in men with hormone 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

[edit]

Health Canada approved 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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  1. ^ a b c "Regulatory Decision Summary for Jubbonti". Drug and Health Products Portal. 16 February 2024. Archived from the original on 1 April 2024. Retrieved 1 April 2024.
  2. ^ a b c d "Jubbonti EPAR". European Medicines Agency. 21 March 2024. Archived from the original on 23 March 2024. Retrieved 23 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ^ a b c "Regulatory Decision Summary for Wyost". Drug and Health Products Portal. 1 March 2024. Archived from the original on 1 April 2024. Retrieved 1 April 2024.
  4. ^ "Jubbonti (Sandoz Pty Ltd)". Therapeutic Goods Administration (TGA). 13 September 2024. Retrieved 15 September 2024.
  5. ^ "Summary Basis of Decision for Wyost". Drug and Health Products Portal. 1 September 2012. Retrieved 13 November 2024.
  6. ^ "Summary Basis of Decision for Jubbonti". Drug and Health Products Portal. 1 September 2012. Retrieved 13 November 2024.
  7. ^ "Prolia- denosumab injection". DailyMed. 24 January 2024. Archived from the original on 7 June 2023. Retrieved 6 March 2024.
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  14. ^ "Prolia (denosumab)". Products. Amgen. Archived from the original on 29 September 2015. Retrieved 6 May 2012.
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  16. ^ Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, et al. (November 2012). "Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials". European Journal of Cancer. 48 (16): 3082–92. doi:10.1016/j.ejca.2012.08.002. PMID 22975218.
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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. PMID 23297819. S2CID 206967103.
  19. ^ Nayak S, Greenspan SL (March 2017). "Osteoporosis Treatment Efficacy for Men: A Systematic Review and Meta-Analysis". Journal of the American Geriatrics Society. 65 (3): 490–495. doi:10.1111/jgs.14668. PMC 5358515. PMID 28304090.
  20. ^ a b c Haberfeld, H, ed. (2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Prolia-Injektionslösung in einer Fertigspritze. ISBN 978-3-85200-196-8.
  21. ^ "Injectable Prolia — Osteoporosis Update". Archived from the original on 9 March 2021. Retrieved 23 March 2016.
  22. ^ Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. (August 2009). "Denosumab for prevention of fractures in postmenopausal women with osteoporosis". The New England Journal of Medicine. 361 (8): 756–65. CiteSeerX 10.1.1.472.3489. doi:10.1056/NEJMoa0809493. PMID 19671655.
  23. ^ Khosla S (August 2009). "Increasing options for the treatment of osteoporosis". The New England Journal of Medicine. 361 (8): 818–20. doi:10.1056/NEJMe0905480. PMC 3901579. PMID 19671654.
  24. ^ EntrezGene 8600 TNFSF11 tumor necrosis factor (ligand) superfamily, member 11; Homo sapiens

    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.
  25. ^ "US FDA adds 'boxed warning' for Amgen's bone loss drug Prolia". Reuters, 19 January 2024.
  26. ^ a b Boyce AM (August 2017). "Denosumab: an Emerging Therapy in Pediatric Bone Disorders". Current Osteoporosis Reports. 15 (4): 283–292. doi:10.1007/s11914-017-0380-1. PMC 5554707. PMID 28643220.
  27. ^ "Amgen Issues Statement on Outcomes of Advisory Committee for Reproductive Health Drugs (ACRHD) Meeting". PRNewswire/FirstCall. 13 August 2009. Archived from the original on 3 November 2013. Retrieved 17 September 2009.
  28. ^ Pollack A (19 October 2009). "F.D.A. Says No to an Amgen Bone Drug". The New York Times. Archived from the original on 27 January 2018. Retrieved 24 February 2017.
  29. ^ a b "FDA Approves Denosumab for Osteoporosis". 2 June 2010. Archived from the original on 13 June 2018. Retrieved 27 November 2010.
  30. ^ Matthew Perrone (2 June 2010). "FDA clears Amgen's bone-strengthening drug Prolia". BioScience Technology. Archived from the original on 27 August 2010. Retrieved 2 June 2010.
  31. ^ "Amgen's Denosumab Cleared by FDA for Second Indication". 19 November 2010. Archived from the original on 7 April 2018. Retrieved 27 November 2010.
  32. ^ "FDA Approval for Denosumab". Archived from the original on 6 April 2015. Retrieved 31 August 2013.
  33. ^ "Prolia (denosumab): Drug Safety Communication - FDA Adds Boxed Warning for Increased Risk of Severe Hypocalcemia in Patients with Advanced Chronic Kidney Disease Archived 6 April 2024 at the Wayback Machine". U.S. Food and Drug Administration, 19 January 2024.
  34. ^ "Jubbonti BLA #761362" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on 6 March 2024. Retrieved 5 March 2024.
  35. ^ "Sandoz receives FDA approval for first and only denosumab biosimilars" (Press release). Sandoz. 5 March 2024. Archived from the original on 6 March 2024. Retrieved 6 March 2024 – via GlobeNewswire.
  36. ^ "Prolia PI". Union Register of medicinal products. 28 May 2010. Archived from the original on 21 January 2022. Retrieved 6 March 2024.
  37. ^ "Xgeva PI". Union Register of medicinal products. 15 July 2011. Archived from the original on 19 August 2018. Retrieved 6 March 2024.
  38. ^ "Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 18-21 March 2024". European Medicines Agency (Press release). 22 March 2024. Retrieved 13 June 2024.
  39. ^ a b "Wyost EPAR". European Medicines Agency. 21 March 2024. Archived from the original on 23 March 2024. Retrieved 23 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  40. ^ a b "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. Retrieved 23 May 2024.
  41. ^ a b c "Obodence EPAR". European Medicines Agency (EMA). 14 November 2024. Retrieved 16 November 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  42. ^ a b "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. Retrieved 16 November 2024.
  43. ^ a b c "Xbryk". European Medicines Agency (EMA). 14 November 2024. Retrieved 16 November 2024. 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. PMID 22543469. S2CID 7875371.
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