Monoclonal antibody | |
---|---|
Type | Whole antibody |
Source | Human |
Target | RANK ligand |
Clinical data | |
Trade names | Prolia, Xgeva, others |
Other names | AMG-162 |
Biosimilars | denosumab-bbdz, Jubbonti, [1] Wyost [2] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a610023 |
License data | |
Pregnancy category |
|
Routes of administration | Subcutaneous |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | N/A |
Metabolism | Proteolysis |
Identifiers | |
CAS Number | |
DrugBank | |
ChemSpider |
|
UNII | |
KEGG | |
ChEMBL | |
Chemical and physical data | |
Formula | C6404H9912N1724O2004S50 |
Molar mass | 144722.80 g·mol−1 |
(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. [7] [8]
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]
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]
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]
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]
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]
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.
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]
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]
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]
Health Canada approved Jubbonti, a biosimilar to Prolia, in February 2024; [1] and approved Wyost, a biosimilar to Xgeva, in March 2024. [2]
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.