Denosumab, a RANK Ligand Inhibitor for Prevention of Skeletal-Related Events Due to Bone Metastases From Solid Tumors in Adults

April 18, 2011

Denosumab is an IgG2 monoclonal antibody that inhibits osteoclastic bone resorption (breakdown) via inhibition of RANKL (receptor activator of nuclear factor-kB ligand).

Approved Drug: Denosumab (marketed as Xgeva for this indication)

Indications

Drug is indicated for the prevention of skeletal-related events (SREs) in adult patients with bone metastases from solid tumors. SREs include pathological fractures, radiation or surgery to the bone, and spinal cord compression related to cancer. Denosumab is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Mechanism of Action

Denosumab is an IgG2 monoclonal antibody that inhibits osteoclastic bone resorption (breakdown) via inhibition of RANKL (receptor activator of nuclear factor-kB ligand). It does this by binding to RANKL, thus preventing RANKL from activating its receptor RANK on the surface of osteoclasts and their precursors. It mimics the effect of the RANK modulator osteoprotegerin, and turns off osteoclast formation, function, and survival. The net effect is increased bone mass and strength in both trabecular and cortical bone.

Metabolism

After subcutaneous administration, 62% of the drug is bioavailable. In oncology patients with bone metastases, every-4-week dosing of 120 mg resulted in up to a 2.8-fold increase in serum denosumab concentrations, with steady state achieved by 6 months. The mean elimination half-life is 28 days. In patients with renal impairment, there was no change in pharmacokinetics or pharmacodynamics of the drug. However, no studies have been done on patients with hepatic impairment.

Drug Administration

• Correct hypocalcemia prior to starting denosumab. Monitor serum calcium levels prior to treatment, and ensure adequate supplementation with calcium and vitamin D.

• Perform an oral exam and discuss with the provider referral of the patient to a dentist, to complete appropriate preventive dentistry prior to starting the drug, as osteonecrosis of the jaw (ONJ) is a rare complication of therapy.

• Drug is administered subcutaneously, at 120 mg/1.7 mL (70 mg/mL) every 4 weeks (in the upper arm, upper thigh, or abdomen). Store drug in refrigerator, and bring to room temperature prior to administration (15–30 min).

• Administer calcium, vitamin D, and magnesium supplements as necessary to treat or prevent hypocalcemia.

• Monitor serum calcium levels more frequently when patient is receiving other drugs that may cause hypocalcemia, has a creatinine clearance < 30 mL/min, or is receiving dialysis.

Patient Education

• Cancer may spread to your bones. This drug helps to prevent bone damage by stopping bone cells called osteoclasts from breaking down your bone. This helps your bones stay bigger and stronger. Because this drug can lower the amount of calcium in your blood that normally comes from bones, you will need to take calcium and vitamin D supplements.

• Report right away any signs or symptoms of hypocalcemia: pins and needles in your hands, feet, or face (paresthesias), muscle stiffness, twitching, spasms, or cramps.

• The medicine may rarely cause dying of the cells in your jaw bone. This is called osteonecrosis of the jaw (ONJ). To minimize the risk of ONJ, your doctor will examine your mouth before you start your treatment, and if needed, will ask you to see your dentist to complete any dental work before you start therapy. Studies have shown that risk factors for ONJ are tooth extraction right before or during treatment, poor oral hygiene, or use of a dental appliance. Thus, it is important to have any dental work completed prior to starting the drug, and to take good care of your teeth (for example, by brushing your teeth twice daily).

• During treatment, avoid any invasive dental procedures. Report right away any jaw or tooth pain, or changes in your teeth or gums.

Drug Interactions

• No formal studies have been performed, but there is no apparent effect from concurrent chemotherapy or hormonal therapy.

Special Considerations

• Drug may cause fetal harm. If a woman becomes pregnant while receiving the drug, she should be encouraged to enroll in Amgen’s Pregnancy Surveillance Program (1-800-77-AMGEN).

• The drug should be used in a pregnant woman only if the potential benefit is greater than the risk. In studies of laboratory animals that lacked the RANKL gene, their offspring had lymph node abnormalities, and impaired dentition and bone growth.

• Mothers should not breastfeed their infants, and a decision should be made regarding whether the patient should discontinue nursing or the drug. It is not known if the drug is excreted in human milk. In laboratory animals, mother mice lacking the RANKL gene had impaired mammary gland development and abnormal lactation.

• In clinical trials, although the incidence of ONJ was 2.2% with the drug, 79% of affected patients had a
history of tooth extraction, poor oral hygiene, or use of a dental appliance.

• Prior to starting therapy:

– Ensure that patient has had oral dentition problems corrected.

– Assess risk for ONJ: prior tooth extraction, persistent pain or slow healing of the mouth or jaw after dental surgery.

– Assess serum calcium and phosphate levels; correct hypocalcemia.

• During therapy:

– Ensure that patient is taking recommended calcium and vitamin D supplements.

– Monitor serum calcium and phosphate levels regularly, and more frequently in patients with creatinine clearance < 30 mL/min or who are receiving dialysis.

– Assess for signs/symptoms of hypocalcemia (paresthesias, muscle stiffness, twitching, spasms, cramps) or hypophosphatemia (weak muscles, muscle dysfunction, dysphagia, altered mental status, irritability).

– Assess for changes in dentition, and presenting signs/symptoms of ONJ: jaw pain, (eg, osteomyelitis, osteitis), bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion.

– If ONJ is suspected, discuss with the physician referral of the patient to a dentist or oral surgeon.

Clinical trials comparing denosumab with zoledronic acid showed denosumab was noninferior to zoledronic acid in first time to SRE; two of the trials showed denosumab was superior in delay to time to first SRE and subsequent SRE, compared with zoledronic acid. There was no difference in overall survival between the two groups. While patients with multiple myeloma were included in one of the trials, a subgroup analysis showed a higher mortality in the denosumab-treated group. Thus, denosumab is not indicated for patients with multiple myeloma at this time. Further investigation of denosumab safety and efficacy in patients with multiple myeloma is planned.

Contraindications/Precautions

• None

Adverse Reactions to Denosumab by Body System

(boldface type indicates more common events, with 25% or higher incidence)

CNS: Fatigue, asthenia, headache

Endocrine: Hypophosphatemia (severe in 15.4%), hypocalcemia (severe in 3.1%)

GI: Nausea, diarrhea

Pulmonary: Dyspnea, cough

Reproductive: (Based on laboratory animal studies): Fetal harm, abnormal breast development and lactation in nursing mothers

Other: Osteonecrosis of the jaw (ONJ) in 1.8% of patients

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.