Denosumab (trade names Prolia and Xgeva) is a human

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

for the treatment of

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

, treatment-induced bone loss,

metastases Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

to bone, and

giant cell tumor of bone Giant-cell tumor of the bone (GCTOB), is a relatively uncommon tumor of the bone. It is characterized by the presence of multinucleated giant cells (osteoclast-like cells). Malignancy in giant-cell tumor is uncommon and occurs in about 2% of all ...

. Denosumab is contraindicated in people with low blood calcium levels. The most common side effects are

joint A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw ...

and

muscle pain Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likel ...

in the arms or legs. Denosumab is a inhibitor of RANKL (receptor activator of nuclear factor kappa-Β ligand), which works by preventing the development of

osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...

s, which are cells that break down bone. It was developed by the biotechnology company

Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was esta ...

Medical uses

Denosumab is used for those with

at high risk for

fracture Fracture is the separation of an object or material into two or more pieces under the action of stress. The fracture of a solid usually occurs due to the development of certain displacement discontinuity surfaces within the solid. If a displa ...

s, bone loss due to certain medications, and in those with

bone metastases Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that results from primary tumor invasion to bone. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare; the most common ...

Cancer

A 2012 meta-analysis found that denosumab was better than placebo,

zoledronic acid 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 ...

and

pamidronate Pamidronic acid or pamidronate disodium or APD (marketed as Aredia among others), is a nitrogen-containing bisphosphonate used to prevent osteoporosis. It was patented in 1971 and approved for medical use in 1987. Medical uses It is used to pre ...

, in reducing the risk of fractures in those with cancer.

Osteoporosis

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

Adverse effects

The most common side effects are

and

in the arms or legs. There is an increased risk of

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

s such as

cellulitis Cellulitis is usually a bacterial infection involving the inner layers of the skin. It specifically affects the dermis and subcutaneous fat. Signs and symptoms include an area of redness which increases in size over a few days. The borders of t ...

hypocalcemia Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mmol ...

(low blood calcium), hypersensitivity allergy reactions,

osteonecrosis of the jaw Osteonecrosis of the jaw (ONJ) is a severe bone disease (osteonecrosis) that affects the jaws (the maxilla and the mandible). Various forms of ONJ have been described since 1861, and a number of causes have been suggested in the literature. Osteo ...

, and atypical

femur fracture A femoral fracture is a bone fracture that involves the femur. They are typically sustained in high-impact trauma, such as car crashes, due to the large amount of force needed to break the bone. Fractures of the diaphysis, or middle of the femu ...

s. Another trial showed significantly increased rates of

eczema Dermatitis is inflammation of the Human skin, skin, typically characterized by itchiness, erythema, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become lichenification, thick ...

and

hospitalization A hospital is a health care institution providing patient treatment with specialized Medical Science, health science and auxiliary healthcare staff and medical equipment. The best-known type of hospital is the general hospital, which typically ...

due to infections of the skin. It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

. RANKL is expressed by

T helper cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

, and is thought to be involved in

dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...

maturation. Discontinuation of denosumab is associated with a rebound increase in bone turnover. In rare cases this has led to severe hypercalcemia, especially in children. Vertebral compression fractures have also occurred in some people after discontinuing treatment.

Contraindications and interactions

It is contraindicated in people with

; sufficient calcium and

vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...

levels must be reached before starting on denosumab therapy. Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions. 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

bisphosphonate 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 ...

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. Invasive dental procedures should be avoided during this time.

Mechanism of action

Bone remodeling Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue is removed from the skeleton (a process called ''bone resorption'') and new bone tissue is formed (a process called ''ossification'' or ''new bone formation''). T ...

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

osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...

s (which secrete new bone) and

s (which break down bone);

osteocyte An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and ...

s are also present in bone. Precursors to osteoclasts, called pre-osteoclasts, express surface receptors called

RANK Rank is the relative position, value, worth, complexity, power, importance, authority, level, etc. of a person or object within a ranking, such as: Level or position in a hierarchical organization * Academic rank * Diplomatic rank * Hierarchy * H ...

(receptor activator of nuclear factor-kappa B). RANK is a member of the

tumor necrosis factor receptor The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growth ...

(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 Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the ...

, an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased

effectiveness Effectiveness is the capability of producing a desired result or the ability to produce desired output. When something is deemed effective, it means it has an intended or expected outcome, or produces a deep, vivid impression. Etymology The ori ...

) in patients with osteoporosis. This protects bone from degradation, and helps to counter the progression of the disease.

Regulatory approval

United States

On 13 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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) to review the potential uses of denosumab. In October 2009, the FDA delayed approval of denosumab, stating that they needed more information. On 2 June 2010, denosumab was approved by the FDA for use in postmenopausal women with risk of osteoporosis under the trade name ''Prolia'', and in November 2010 as ''Xgeva'' for the prevention of skeleton-related events in patients with

from solid

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s. Denosumab is the first

RANKL inhibitor Receptor activator of nuclear factor kappa- ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiati ...

to be approved by the FDA. On 13 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.

Europe

On 17 December 2009, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding ...

(CHMP) 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. Denosumab was approved for marketing by the European Commission on 28 May 2010.

References

External links

* * {{Portal bar , Medicine Amgen Monoclonal antibodies Osteoporosis drugs