Denosumab

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Denosumab
Denosumab.jpg
Denosumab injection
Monoclonal antibody
Type Whole antibody
Source Human
Target RANK ligand
Clinical data
Trade names Prolia, Xgeva, others
Other namesAMG-162
Biosimilars denosumab-bbdz, Jubbonti, [1] Wyost [2]
AHFS/Drugs.com Monograph
MedlinePlus a610023
License data
Pregnancy
category
  • AU:D
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability N/A
Metabolism Proteolysis
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C6404H9912N1724O2004S50
Molar mass 144722.80 g·mol−1
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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. [7] [8]

Contents

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. [9]

Denosumab is an inhibitor of RANKL (receptor activator of nuclear factor kappa-Β ligand), [7] which works by decreasing the development of osteoclasts, which are cells that break down bone. It was developed by the biotechnology company Amgen. [10]

Medical uses

Denosumab is used for those with osteoporosis at high risk for fractures, bone loss due to certain medications, and in those with bone metastases. [11]

Cancer

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. [12]

Osteoporosis

In those with postmenopausal osteoporosis denosumab decreases the risk of fractures but increases the risk of infection. [13] A 2013 review concluded that it is a reasonable treatment for postmenopausal osteoporosis. [14] A 2017 review did not find benefit in males. [15]

Mechanism of action

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. [8]

Contraindications and interactions

It is contraindicated in people with hypocalcemia; sufficient calcium and vitamin D levels must be reached before starting on denosumab therapy. [16] Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions. [16]

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. [17] Invasive dental procedures should be avoided during this time.

Adverse effects

The most common side effects are joint and muscle pain in the arms or legs. [9] 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. [9] [16] Another trial showed significantly increased rates of eczema and hospitalization due to infections of the skin. [18] It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the immune system. [19] RANKL is expressed by T helper cells, and is thought to be involved in dendritic cell maturation. [20]

Use of Prolia can increase the risk of severe hypocalcemia among those with advanced kidney disease, especially those on dialysis. [21]

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. [22] Vertebral compression fractures have also occurred in some people after discontinuing treatment. [22]

United States

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. [23]

In October 2009, the FDA delayed approval of denosumab, stating that it needed more information. [24]

In June 2010, denosumab was approved by the FDA for use in postmenopausal women with risk of osteoporosis [25] under the brand name Prolia, [26] and in November 2010 as Xgeva for the prevention of skeleton-related events in people with bone metastases from solid tumors. [27] Denosumab is the first RANKL inhibitor to be approved by the FDA. [25]

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. [28]

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. [29]

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. [30] [31]

European Union

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. [9] Denosumab, as Prolia, was approved for medical use in the European Union in May 2010, [5] [32] and as Xgeva in July 2011. [6] [33]

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. [34] The applicant for this medicinal product is Sandoz GmbH. [34] 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. [35] The applicant for this medicinal product is Sandoz GmbH. [35]

Canada

Health Canada approved Jubbonti, a biosimilar to Prolia, in February 2024; [1] and approved Wyost, a biosimilar to Xgeva, in March 2024. [2]

Related Research Articles

<span class="mw-page-title-main">Osteoporosis</span> Skeletal disorder

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in fracture risk. It is the most common reason for a broken bone among the elderly. Bones that commonly break include the vertebrae in the spine, the bones of the forearm, the wrist, and the hip. Until a broken bone occurs there are typically no symptoms. Bones may weaken to such a degree that a break may occur with minor stress or spontaneously. After the broken bone heals, the person may have chronic pain and a decreased ability to carry out normal activities.

<span class="mw-page-title-main">Parathyroid hormone</span> Mammalian protein found in Homo sapiens

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

<span class="mw-page-title-main">Bisphosphonate</span> Pharmaceutical drugs for preventing bone loss

Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they have two phosphonate groups. They are thus also called diphosphonates.

<span class="mw-page-title-main">Teriparatide</span> Pharmaceutical drug for treating osteoporosis

Teriparatide, sold under the brand name Forteo, is a form of parathyroid hormone (PTH) consisting of the first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic agent used in the treatment of some forms of osteoporosis. Teriparatide is a recombinant human parathyroid hormone analog. It has an identical sequence to the 34 N-terminal amino acids of the 84-amino acid human parathyroid hormone.

<span class="mw-page-title-main">Amgen</span> American multinational biopharmaceutical company

Amgen Inc. is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen's Thousand Oaks staff in 2022 numbered approximately 5,000 and included hundreds of scientists, making Amgen the largest employer in Ventura County. As of 2022, Amgen has approximately 24,000 staff in total.

<span class="mw-page-title-main">Alendronic acid</span> Chemical compound

Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementation, and lifestyle changes.

Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. It is administered by subcutaneous injection. It works by inactivating tumor necrosis factor-alpha (TNFα).

<span class="mw-page-title-main">Zoledronic acid</span> Chemical compound

Zoledronic acid, also known as zoledronate and sold under the brand name Zometa by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, Paget's disease of bone and Duchenne muscular dystrophy (DMD). It is given by injection into a vein.

<span class="mw-page-title-main">Bazedoxifene</span> Chemical compound

Bazedoxifene, used as bazedoxifene acetate, is a medication for bone problems and possibly for cancer. It is a third-generation selective estrogen receptor modulator (SERM). Since late 2013 it has had U.S. FDA approval for bazedoxifene as part of the combination drug Duavee in the prevention of postmenopausal osteoporosis. It is also being studied for possible treatment of breast cancer and pancreatic cancer.

Ranibizumab, sold under the brand name Lucentis among others, is a monoclonal antibody fragment (Fab) created from the same parent mouse antibody as bevacizumab. It is an anti-angiogenic that is approved to treat the "wet" type of age-related macular degeneration, diabetic retinopathy, and macular edema due to branch retinal vein occlusion or central retinal vein occlusion.

<span class="mw-page-title-main">RANKL</span> Mammalian protein found in Homo sapiens

Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.

Eculizumab, sold under the brand name Soliris among others, is a recombinant humanized monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis, and neuromyelitis optica. In people with PNH, it reduces both the destruction of red blood cells and need for blood transfusion, but does not appear to affect the risk of death. Eculizumab was the first drug approved for each of its uses, and its approval was granted based on small trials. It is given by intravenous infusion.

<span class="mw-page-title-main">Strontium ranelate</span> Chemical compound

Strontium ranelate, a strontium(II) salt of ranelic acid, is a medication for osteoporosis marketed as Protelos or Protos by Servier. Studies indicate it can also slow the course of osteoarthritis of the knee. The drug is unusual in that it both increases deposition of new bone by osteoblasts and reduces the resorption of bone by osteoclasts. It is therefore promoted as a "dual action bone agent" (DABA).

A biosimilar is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original "innovator" products and can be manufactured when the original product's patent expires. Reference to the innovator product is an integral component of the approval.

<span class="mw-page-title-main">Medication-related osteonecrosis of the jaw</span> Medical condition

Medication-related osteonecrosis of the jaw is progressive death of the jawbone in a person exposed to a medication known to increase the risk of disease, in the absence of a previous radiation treatment. It may lead to surgical complication in the form of impaired wound healing following oral and maxillofacial surgery, periodontal surgery, or endodontic therapy.

Romosozumab, sold under the brand name Evenity, is a medication used to treat osteoporosis. It has been found to decrease the risk of fractures of the spine.

Abaloparatide, sold under the brand name Tymlos among others, is a parathyroid hormone-related protein (PTHrP) analog medication used to treat osteoporosis. It is an anabolic agent.

<span class="mw-page-title-main">Apremilast</span> Medication for psoriasis and psoriatic arthritis

Apremilast, sold under the brand name Otezla among others, is a medication for the treatment of certain types of psoriasis and psoriatic arthritis. The drug acts as a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4) and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. It is taken by mouth.

<span class="mw-page-title-main">Eldecalcitol</span> Chemical compound

Eldecalcitol is an analog of calcitriol, the active form of vitamin D.

Recombinant human parathyroid hormone, sold under the brand name Preotact among others, is an artificially manufactured form of the parathyroid hormone used to treat hypoparathyroidism. Recombinant human parathyroid hormone is used in the treatment of osteoporosis in postmenopausal women at high risk of osteoporotic fractures. A significant reduction in the incidence of vertebral fractures has been demonstrated. It is used in combination with calcium and vitamin D supplements.

References

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  2. 1 2 3 "Regulatory Decision Summary for Wyost". Drug and Health Products Portal. 1 March 2024. Retrieved 1 April 2024.
  3. ↑ "Prolia- denosumab injection". DailyMed. 24 January 2024. Archived from the original on 7 June 2023. Retrieved 6 March 2024.
  4. ↑ "Xgeva- denosumab injection". DailyMed. 9 June 2020. Archived from the original on 13 April 2023. Retrieved 6 March 2024.
  5. 1 2 "Prolia EPAR". European Medicines Agency. 26 May 2010. Archived from the original on 16 September 2021. Retrieved 6 March 2024.
  6. 1 2 "Xgeva EPAR". European Medicines Agency. 13 July 2011. Archived from the original on 21 September 2023. Retrieved 6 March 2024.
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  10. ↑ "Prolia (denosumab)". Products. Amgen. Archived from the original on 29 September 2015. Retrieved 6 May 2012.
  11. ↑ "Denosumab". The American Society of Health-System Pharmacists. Archived from the original on 30 April 2021. Retrieved 16 March 2015.
  12. ↑ 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.
  13. ↑ Zhou Z, Chen C, Zhang J, Ji X, Liu L, Zhang G, et al. (2014). "Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis". International Journal of Clinical and Experimental Pathology. 7 (5): 2113–22. PMC   4069896 . PMID   24966919.
  14. ↑ 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.
  15. ↑ 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.
  16. 1 2 3 Haberfeld, H, ed. (2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Prolia-Injektionslösung in einer Fertigspritze. ISBN   978-3-85200-196-8.
  17. ↑ "Injectable Prolia — Osteoporosis Update". Archived from the original on 9 March 2021. Retrieved 23 March 2016.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ "US FDA adds 'boxed warning' for Amgen's bone loss drug Prolia". Reuters, January 19, 2024.
  22. 1 2 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.
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  25. 1 2 "FDA Approves Denosumab for Osteoporosis". 2 June 2010. Archived from the original on 13 June 2018. Retrieved 27 November 2010.
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  27. ↑ "Amgen's Denosumab Cleared by FDA for Second Indication". 19 November 2010. Archived from the original on 7 April 2018. Retrieved 27 November 2010.
  28. ↑ "FDA Approval for Denosumab". Archived from the original on 6 April 2015. Retrieved 31 August 2013.
  29. ↑ "Prolia (denosumab): Drug Safety Communication - FDA Adds Boxed Warning for Increased Risk of Severe Hypocalcemia in Patients with Advanced Chronic Kidney Disease". U.S. Food and Drug Administration, January 19, 2024.
  30. ↑ "Jubbonti BLA #761362" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on 6 March 2024. Retrieved 5 March 2024.
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  32. ↑ "Prolia PI". Union Register of medicinal products. 28 May 2010. Archived from the original on 21 January 2022. Retrieved 6 March 2024.
  33. ↑ "Xgeva PI". Union Register of medicinal products. 15 July 2011. Archived from the original on 19 August 2018. Retrieved 6 March 2024.
  34. 1 2 "Jubbonti EPAR". European Medicines Agency. 21 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.
  35. 1 2 "Wyost EPAR". European Medicines Agency. 21 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.

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