Denosumab

Description

Denosumab, which was approved in the United States in 2010, is a fully human sequence IgG2 monoclonal antibody that inhibits bone resorption by blocking the activity of receptor activator of nuclear factor-κB ligand (RANKL). RANKL is a TNF family protein that is expressed in both secreted and cell surface forms by a variety of bone marrow cell types andmediates bone resorption through its receptor (RANK),which is found on osteoclasts and osteoclast precursors . Denosumab was discovered using XenomouseTM transgenic mice comprising human immunoglobulin genes. The antibody is approved for treatment of postmenopausal women with osteoporosis at high risk for fracture, and for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Denosumab competes directly with bisphosphonates such as alendronic acid in postmenopausal osteoporosis and with zoledronic acid in both of these indications. It has been shown to have comparable efficacy and safety to bisphosphonates with some tolerability and patient acceptability advantages.

Originator

Amgen (United States)

Uses

Prevention and treatment of all forms of osteoporosis or bone loss.

Indications

1. Prevention of skeletal-related events (e.g., bone pain and fractures) secondary to multiple myeloma or bone metastases from solid tumors. Used in conjunction with treatments for primary malignancy.
2. Giant cell tumor of the bone. Indicated in adults and skeletally mature adolescents with an unresectable tumor or when surgical resection would likely cause severe morbidity.
3. Hypercalcemia of malignancy. This drug is indicated when hypercalcemia is refractory to bisphosphonate therapy.
4. Osteoporosis. Indicated as therapy for postmenopausal women with osteoporosis at high risk for fracture. Indications also include the treatment of men with osteoporosis at high risk of fracture. A high risk for fracture is defined as those with multiple risk factors for fracture, a known history of an osteoporotic fracture, or those who have failed prior osteoporosis treatment (e.g., bisphosphonates).
5. Glucocorticoid-induced osteoporosis. Indicated for treatment in patients of both sexes at high risk for fracture who are initiating or continuing systemic glucocorticoids at a dose greater than or equal to 7.5 mg of prednisone daily for an expected duration of at least six months.
6. Bone loss. Indicated for treating androgen deprivation-induced bone loss and aromatase inhibitor-induced bone loss. The goal of therapy is to increase bone mass in men with prostate cancer receiving androgen deprivation therapy. In women, the treatment goal is to increase bone mass when receiving aromatase inhibitor therapy for breast cancer.

brand name

Prolia;Xgeva

Mechanism of action

Briefly, denosumab is a fully human monoclonal antibody that inhibits RANKL and helps regulate turnover in healthy bone. Denosumab binds with high specificity and affinity to the cytokine  RANKL, inhibiting its action; as a result, osteoclast recruitment,  maturation and action are inhibited, and bone resorption slows.

Clinical Use

Human monoclonal antibody (IgG2):
Osteoporosis in postmenopausal women and men with prostate cancer after hormone ablation at risk of fractures
Reduction of bone damage in patients with bone metastases from solid tumours

Side effects

• red, dry, or itchy skin
• oozing or crusty blisters on skin
• peeling skin
• back pain
• pain in your arms
• swelling of arms or legs
• muscle or joint pain
• nausea

Metabolism

Metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.