Denosumab

Denosumab is a bone anti-resorptive drug used for the treatment of the following: 

FDA-approved 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[1]
2. Giant cell tumor of the bone. Indicated in adults and skeletally mature adolescents that have an unresectable tumor or when surgical resection would likely cause severe morbidity.[2]
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).[3]
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.[4]
6. Bone loss. Indicated for the treatment of 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.[5]

Denosumab is a total human IgG2 monoclonal antibody that binds to receptor activator of NF kappa B ligand (RANKL) and competitively inhibits its binding to receptor activator of NF kappa B (RANK). Soluble RANKL is a trimer and a member of the tumor necrosis factor (TNF) family of ligands. Each RANKL trimer can bind and oligomerize up to three receptors. When bound to RANK, RANKL potentiates osteoclast differentiation from hematopoietic stem cells and activates and prolongs the survival of mature osteoclasts. Osteoclasts' primary function then is to promote bone resorption. Denosumab binds to RANKL with high affinity and blocks it from binding to and oligomerizing its receptor RANK, thus inhibiting osteoclast maturation and bone resorption. 

The administration of denosumab should be via subcutaneous injection only and should not be administered intravenously or intramuscularly. Injection sites include the upper arm, upper thigh, or abdomen. No observation or premedication is required. Dosing is prescribed as 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial or as a single-use pre-filled syringe containing 60 mg in a 1 mL solution. Administer vitamin D and calcium as necessary to treat or prevent hypocalcemia — no dosing adjustments required for hepatic or renal impairment. The distribution and timing of doses depend on the pathology, as shown below. 

• Skeletal-related events secondary to multiple myeloma or bone metastases from solid tumors: administer 120 mg injection every four weeks
• Giant cell tumor of bone: 120 mg injection administered every four weeks with supplementary doses of 120 mg on the 8th and 15th day during the first month of treatment
• Hypercalcemia of malignancy: administer 120 mg injection every four weeks with supplemental doses of 120 mg on the 8th and 15th day during the first month of treatment
• Osteoporosis/bone loss: administer 60 mg every six months

Adverse effects include the following based on body systems:

Cardiovascular:

• Peripheral edema (4% to 20%)
• Hypertension (5%)
• Angina pectoris (4%)

Central nervous system:

• Fatigue (45% or less)
• Headache (18%)
• Sciatica (6%)

Dermatologic:

• Skin rash (14% or less)
• Dermatitis (11% or less)
• Eczema (11% or less)

Endocrine:

• Hypophosphatemia (32%)
• Severe hypophosphatemia (15%)
• Hypocalcemia (3% to 10%)
• Hypercholesterolemia (8%)
• Grade 3 hypokalemia (4%)
• Grade 3 hypomagnesemia (4%)
• Severe (symptomatic) hypocalcemia (<1% to 3%)

Gastrointestinal:

• Diarrhea (34%)
• Nausea (31%)
• Decreased appetite (25%)
• Vomiting (25%)
• Constipation (22%)
• Flatulence (3%)

Hematologic and oncologic:

• Anemia (22%)
• Thrombocytopenia (20%)
• New malignant neoplasm (4%)

Infection:

• Serious infection (5%)

Neuromuscular and skeletal:

• Weakness (45% or less)
• Back pain (15%)
• Arthralgia (11%)
• Limb pain (11%)
• Musculoskeletal pain (7%)
• Ostealgia (5%)
• Myalgia (4%)
• Osteonecrosis of the jaw (1% to 4%)[6]

Ophthalmic:

• Cataract (5% or less)

Respiratory:

• Dyspnea (24%)
• Cough (16%)
• Upper respiratory tract infection (6% to 16%)
• Pneumonia (9%)
• Nasopharyngitis (8%)

• Known severe hypersensitivity to denosumab or any component of the formulation 
• Preexisting hypocalcemia 
• Pregnancy