Denosumab

Denosumab injection
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	RANK ligand
Clinical data
Trade names	Prolia, others
Other names	AMG-162
Biosimilars	denosumab-bbdz, Jubbonti,[1][2] Wyost[3]
AHFS/Drugs.com	Monograph
MedlinePlus	a610023
License data	US DailyMed: Denosumab
Pregnancy category	AU: D
Routes of administration	Subcutaneous
ATC code	M05BX04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[4] CA: ℞-only / Schedule D[3][1][5][6] US: ℞-only[7][8] EU: Rx-only[9][10][2]
Pharmacokinetic data
Bioavailability	N/A
Metabolism	Proteolysis
Identifiers
CAS Number	615258-40-7 N
DrugBank	DB06643 Y
ChemSpider	none
UNII	4EQZ6YO2HI
KEGG	D03684 Y
ChEMBL	ChEMBL1237023 N
Chemical and physical data
Formula	C6404H9912N1724O2004S50
Molar mass	144722.80 g·mol−1
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Denosumab, sold under the brand names Prolia 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]

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. 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.^[14] Denosumab binds to RANKL with high affinity and specificity, preventing the interaction between RANKL and RANK.^[14] Increased osteoclast activity stimulated by RANKL is a key mediator of bone destruction in metastatic bone disease.^[14] This leads to a reduction in osteoclast numbers and function, and a decrease in bone resorption, cancer-induced bone destruction.^[14] It also leads to a decrease in bone resorption in cortical and trabecular bones.^[15] It was developed by the biotechnology company Amgen.^[16]

Denosumab is used for those with osteoporosis at high risk for fractures, bone loss due to certain medications, and in those with bone metastases.^[17]

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.^[18]

In those with postmenopausal osteoporosis denosumab decreases the risk of fractures but increases the risk of infection.^[19] A 2013 review concluded that it is a reasonable treatment for postmenopausal osteoporosis.^[20] A 2017 review did not find benefit in males.^[21]

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]

It is contraindicated in people with hypocalcemia; sufficient calcium and vitamin D levels must be reached before starting on denosumab therapy.^[22] Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.^[22]

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.^[23] Invasive dental procedures should be avoided during this time.

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][22] Another trial showed significantly increased rates of eczema and hospitalization due to infections of the skin.^[24] It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the immune system.^[25] RANKL is expressed by T helper cells, and is thought to be involved in dendritic cell maturation.^[26]

Use of Prolia can increase the risk of severe hypocalcemia among those with advanced kidney disease, especially those on dialysis.^[27]

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.^[28] Vertebral compression fractures have also occurred in some people after discontinuing treatment.^[28]

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.^[29]

In October 2009, the FDA delayed approval of denosumab, stating that it needed more information.^[30]

In June 2010, denosumab was approved by the FDA for use in postmenopausal women with risk of osteoporosis^[31] under the brand name Prolia,^[32] and in November 2010, as Xgeva for the prevention of skeleton-related events in people with bone metastases from solid tumors.^[33] Denosumab is the first RANKL inhibitor to be approved by the FDA.^[31]

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.^[34]

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.^[35]

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.^[36][37]

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][38] and as Xgeva in July 2011.^[10][39]

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][40] 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.^[41] The applicant for this medicinal product is Sandoz GmbH.^[41] 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.^[42] 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.^[42]

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.^[43] The applicant for this medicinal product is Samsung Bioepis NL B.V.^[43] 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.^[43][44]

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.^[45] The applicant for this medicinal product is Samsung Bioepis NL B.V.^[45] 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.^[45][44]

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.^[14] The applicant for this medicinal product is Celltrion Healthcare Hungary Kft.^[14] Osenvelt is a biosimilar medicinal product.^[14] It is highly similar to the reference product Xgeva which was authorized in the EU in July 2011.^[14]

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.^[15] The applicant for this medicinal product is Celltrion Healthcare Hungary Kft.^[15] Stoboclo is a biosimilar medicinal product.^[15] It is highly similar to the reference product Prolia, which was authorized in the EU in May 2010.^[15]

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