Denosumab

• Osteoporosis
• Bone Metastases
• Bone Loss Prevention
• Giant Cell Tumor of Bone

Denosumab is a fully human monoclonal antibody that inhibits RANKL (receptor activator of nuclear factor kappa-B ligand), used for the treatment of osteoporosis, bone loss, and bone metastases. This biologic provides potent anti-resorptive effects through targeted inhibition of osteoclast formation and function.

Mechanism of Action

Denosumab binds to RANKL, a transmembrane protein essential for the formation, function, and survival of osteoclasts. RANKL is produced by osteoblasts and stromal cells and binds to RANK receptors on osteoclast precursors, stimulating their differentiation into mature osteoclasts. By binding RANKL with high affinity, denosumab mimics the effect of the natural decoy receptor osteoprotegerin (OPG), preventing RANKL from activating RANK. This results in decreased osteoclast formation and activity, reduced bone resorption, and increased bone mass and strength. The effect is reversible upon discontinuation.

Available Formulations

Denosumab is available in two distinct products: Prolia (60 mg/mL in prefilled syringes) for osteoporosis and Xgeva (120 mg/1.7 mL in vials) for bone metastases and giant cell tumor of bone. These products are not interchangeable and have different dosing schedules. Both are administered as subcutaneous injections. The medication should be brought to room temperature before injection and can be given in the upper arm, thigh, or abdomen.

Medical Uses

Prolia (denosumab 60 mg) is FDA-approved for treatment of postmenopausal women with osteoporosis at high risk for fracture, treatment to increase bone mass in men with osteoporosis at high risk for fracture, treatment of bone loss in patients receiving androgen deprivation therapy for prostate cancer or aromatase inhibitor therapy for breast cancer at high risk for fracture, and glucocorticoid-induced osteoporosis. Xgeva (denosumab 120 mg) is approved for prevention of skeletal-related events in patients with bone metastases from solid tumors, treatment of giant cell tumor of bone, and treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Dosing Guidelines

For osteoporosis (Prolia), the dose is 60 mg subcutaneously every 6 months. Patients should receive adequate calcium (1000 mg) and vitamin D (at least 400 IU) daily. For bone metastases (Xgeva), the dose is 120 mg subcutaneously every 4 weeks. For giant cell tumor, Xgeva 120 mg is given every 4 weeks with additional doses on days 8 and 15 of the first month. Hypocalcemia must be corrected before initiating therapy.

Important Safety Information

Denosumab carries important safety warnings for hypocalcemia (may be severe and symptomatic), osteonecrosis of the jaw (ONJ), atypical femoral fractures, and a significant rebound effect with vertebral fractures upon discontinuation. Patients should have adequate calcium and vitamin D intake and should be monitored for hypocalcemia, especially those with renal impairment. Dental examination is recommended before starting therapy, and invasive dental procedures should be avoided if possible during treatment. Multiple vertebral fractures can occur after stopping denosumab; transition to another osteoporosis therapy is recommended.

Drug Interactions

No formal drug interaction studies have been conducted. Denosumab is not metabolized by cytochrome P450 enzymes and is unlikely to have pharmacokinetic interactions. However, hypocalcemia should be corrected before starting therapy, and patients receiving medications that can also lower calcium should be monitored closely. Concurrent use with other bone-active agents has not been studied and is generally not recommended.

Special Populations

Denosumab may cause fetal harm based on animal data; women should avoid becoming pregnant during treatment and for at least 5 months after the last dose. It is unknown whether denosumab is excreted in human breast milk. Prolia is not indicated for use in pediatric patients; Xgeva is approved for adults and skeletally mature adolescents with giant cell tumor of bone. Elderly patients do not require dose adjustment. No dose adjustment is needed for renal impairment, but patients with severe renal impairment (CrCl less than 30 mL/min) or on dialysis are at greater risk for hypocalcemia. Hepatic impairment has not been studied.