Introduction
Xgeva (denosumab) is a fully human monoclonal antibody that inhibits bone resorption by targeting the RANK ligand (RANKL). It is manufactured by Amgen and was first approved by the FDA in 2010. Xgeva represents a significant advancement in the management of bone-related complications in various malignancies and conditions characterized by excessive bone destruction.
Mechanism of Action
Xgeva binds to RANKL, a transmembrane protein essential for the formation, function, and survival of osteoclasts. By inhibiting RANKL, denosumab prevents osteoclast maturation and activation, thereby reducing bone resorption and turnover. This mechanism differs from bisphosphonates, which induce osteoclast apoptosis. Xgeva's targeted action on the RANK/RANKL pathway makes it particularly effective in conditions with increased osteoclast activity.
Indications
Xgeva is FDA-approved for:
- Prevention of skeletal-related events (pathological fractures, radiation to bone, spinal cord compression, or surgery to bone) in patients with bone metastases from solid tumors
- Treatment of giant cell tumor of bone in adults and skeletally mature adolescents
- Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy
Dosage and Administration
- Standard dose: 120 mg administered subcutaneously every 4 weeks
- Administration: Inject subcutaneously in the upper arm, upper thigh, or abdomen
- Renal impairment: No dosage adjustment required
- Hepatic impairment: No dosage adjustment required
- Special populations: Safety and effectiveness in pediatric patients have been established for giant cell tumor of bone
Pharmacokinetics
- Absorption: Bioavailability is approximately 62% following subcutaneous administration
- Distribution: Volume of distribution is approximately 3.69 L; minimal distribution to red blood cells
- Metabolism: Expected to be metabolized via proteolytic pathways similar to other immunoglobulin G1 monoclonal antibodies
- Elimination: Half-life approximately 28 days; cleared via the reticuloendothelial system
- Excretion: Not eliminated renally or hepatically
Contraindications
- Hypersensitivity to denosumab or any component of the formulation
- Pre-existing hypocalcemia (must be corrected prior to initiation)
- Pregnancy (category D - can cause fetal harm)
Warnings and Precautions
Hypocalcemia: Significant risk; must correct pre-existing hypocalcemia before initiation. Monitor calcium levels and provide adequate calcium and vitamin D supplementation. Osteonecrosis of the Jaw (ONJ): Reported incidence of 1-2%. Complete dental exam prior to initiation. Avoid invasive dental procedures during therapy. Atypical Femoral Fractures: Has been reported with extended use. Evaluate patients with thigh or groin pain. Hypersensitivity Reactions: Including anaphylaxis has been reported. Multiple Myeloma: Not indicated for prevention of SREs in multiple myeloma (use zoledronic acid instead).Drug Interactions
- No formal drug interaction studies conducted
- Theoretical interactions with drugs that affect calcium metabolism
- Concomitant use with immunosuppressants may increase infection risk
- Avoid concurrent use with other bone-modifying agents
Adverse Effects
Common (≥10%):- Fatigue (45%)
- Hypophosphatemia (32%)
- Nausea (31%)
- Dyspnea (21%)
- Diarrhea (20%)
- Hypocalcemia (18%)
- Headache (16%)
- Back pain (15%)
- Anemia (13%)
- Hypocalcemia (severe)
- Osteonecrosis of the jaw (1-2%)
- Atypical femoral fractures
- Serious infections
- Dermatological reactions
- Pancreatitis
Monitoring Parameters
- Serum calcium levels prior to each dose and for 2 weeks after initial dose
- Electrolytes, especially phosphate and magnesium
- Renal function (BUN, creatinine)
- Dental health assessment at baseline and periodically
- Signs and symptoms of hypocalcemia
- Bone pain and mobility assessment
- Signs of infection
- Dermatological examinations
Patient Education
- Importance of calcium and vitamin D supplementation as prescribed
- Need to report signs of hypocalcemia (muscle spasms, twitching, numbness, seizures)
- Dental hygiene importance and need for pre-treatment dental evaluation
- Report any thigh, hip, or groin pain immediately
- Notify all healthcare providers about Xgeva therapy
- Importance of adherence to scheduled doses
- Report signs of infection or skin reactions
- Notify provider if pregnancy is suspected or planned
References
1. FDA Prescribing Information: Xgeva (denosumab). 2021 2. Lipton A, et al. Superior efficacy of denosumab compared with zoledronic acid for prevention of skeletal-related events. J Clin Oncol. 2012;30(15):1715-1720 3. Henry DH, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer. J Clin Oncol. 2011;29(9):1125-1132 4. Stopeck AT, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer. J Clin Oncol. 2010;28(35):5132-5139 5. NCCN Guidelines: Prevention and Treatment of Cancer-Related Bone Metastases. Version 2.2022 6. Cummings SR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765