Denosumab

Mechanism of Action

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. 

Administration

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 are required for hepatic or renal impairment. As shown below, the distribution and timing of doses depend on the pathology. 

• 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

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%)

Contraindications

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

Monitoring

Clinicians should evaluate for possible pregnancy before initiation of treatment. Obtaining vitamin D levels and clearance from a dentist is suggested before initiating therapy. Within the first few weeks of treatment, recommended monitoring of serum creatinine, calcium, phosphorus, and magnesium. Monitor for signs and symptoms of hypocalcemia as well as hypercalcemia upon discontinuation of denosumab.[7] A dental exam is a recommendation if osteonecrosis of the jaw is suspected. The evaluation of bone mineral density should occur anywhere between one to two years after initiating treatment. The recommendation is for periodic monitoring of vitamin D and serum calcium throughout the treatment duration.[8]

Toxicity

Atypical bone fractures: Although the incidence remains low, an association with atypical bone fractures exists with prolonged bisphosphonate therapy. However, clinicians have also observed these fractures in those receiving denosumab for osteoporosis or metastatic bone disease. These fractures are usually located in the subtrochanteric region or along the shaft of the femur. Patients tend to feel prodromal pain from weeks to months leading up to the fracture. Fractures commonly occur with little to no trauma in the area. Experts are unsure at this time if the atypical fractures occur secondary to denosumab toxicity or the patient’s underlying osteoporosis. Patients should receive counseling regarding the potential for new hip or thigh pain and the contralateral limb examined if an atypical fracture is suspected. Upon diagnosis of an atypical fracture, possible discontinuation of denosumab is an option. If discontinued, consider initiating a different osteoporosis therapy due to increased fracture risk.[9]

Hypersensitivity: Reports exist of clinically severe and anaphylactic reactions. Symptoms may include rash, pruritus, urticaria, facial edema, airway edema, and possibly hypotension. If these symptoms occur, initiate appropriate treatment and subsequently discontinue denosumab. 

Hypocalcemia: Due to its anti-resorptive effects, denosumab has the potential to cause hypocalcemia. There is documentation of severe, even fatal, cases of denosumab-induced hypocalcemia. Those with severe renal dysfunction may have an increased risk of developing hypocalcemia. Clinicians should obtain serum calcium and preexisting hypocalcemia corrected at the initiation of treatment. In patients with preexisting hypocalcemia, serum calcium requires frequent monitoring. Use denosumab with caution in those who have predisposing conditions to hypocalcemia.[10]

Osteonecrosis of the jaw (ONJ): Reports of ONJ have been observed in those receiving denosumab. Symptoms may include jaw pain, tooth infection, bone, gingival erosion, and toothache. An increased risk of being diagnosed with ONJ correlates directly to the duration of denosumab exposure. Those with predisposing factors, such as poor dentition and recent tooth extraction, have a higher risk. If osteonecrosis of the jaw is suspected, make arrangements for a thorough dental exam. The risk of ONJ is considerably higher in patients with malignancy receiving denosumab than in patients with osteoporosis receiving denosumab. Denosumab should not be initiated until dental health is optimized. While on denosumab for cancer therapy, dental procedures are contraindicated. If ONJ is suspected, discontinue denosumab.[6]

Dermatologic reactions: Reports of dermatitis, eczema, and rash have been observed. If symptoms are severe, consider discontinuation of denosumab.

Enhancing Healthcare Team Outcomes

Healthcare workers, including primary care physicians and nurse practitioners who prescribe denosumab, should monitor the patients. Pharmacists should assist in monitoring for side effects. The patient should get a baseline evaluation from the dentist before initiating treatment. The patient's electrolytes and renal function also require monitoring at regular intervals. The most severe complication of therapy is osteonecrosis of the jaw, and thus an oral exam is necessary at each visit. Periodic bone density evaluation every 1 to 2 years is the recommended interval for follow-up. Only through close monitoring of the patient can the morbidity of this agent be decreased.