What is the use of denosumab (Prolia/Xgeva)?

From the Guidelines

Denosumab is recommended for patients with castration-resistant prostate cancer (CRPC) and bone metastases to prevent or delay disease-associated skeletal-related events (SREs), with a dosing regimen of 120 mg subcutaneously every 4 weeks 1.

Key Points

• Denosumab has been shown to delay the median time to SRE by 3.6 months compared to zoledronic acid in patients with CRPC and bone metastases 1.
• The absolute incidence of SREs was similar in the denosumab and zoledronic acid groups, but denosumab had a longer median time to SRE (20.7 vs 17.1 months) 1.
• Treatment-related toxicities reported for denosumab and zoledronic acid were similar, including hypocalcemia, arthralgias, and osteonecrosis of the jaw 1.
• Oral hygiene, baseline dental evaluation, and avoidance of invasive dental surgery during therapy are recommended to reduce the risk of osteonecrosis of the jaw 1.
• Supplemental calcium and vitamin D are recommended to prevent hypocalcemia in patients receiving denosumab or zoledronic acid 1.

Important Considerations

• Denosumab may be administered to patients with impaired renal function or those on hemodialysis, but the risk of severe hypocalcemia and hypophosphatemia is greater, and the dose, schedule, and safety of denosumab have not yet been defined 1.
• Monitoring of creatinine clearance is required to guide dosing of zoledronic acid, but not denosumab 1.
• Discontinuation of denosumab can lead to rapid bone loss, so transition to another osteoporosis therapy should be considered if treatment is stopped 1.

From the FDA Drug Label

Denosumab is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Prolia (denosumab) injection is a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous use. Each 1 mL single-dose prefilled syringe of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.

Denosumab is a medication used to treat osteoporosis in women after menopause, men with osteoporosis, and patients with glucocorticoid-induced osteoporosis.

• The main ingredient is denosumab, a human IgG2 monoclonal antibody.
• Administration is via subcutaneous injection, 60 mg every 6 months.
• Common side effects include back pain, pain in arms and legs, high cholesterol, and muscle pain.
• Serious side effects may include low blood calcium, serious allergic reactions, severe jaw bone problems, and unusual thigh bone fractures 2.
• Pharmacokinetics: The mean area-under-the-concentration-time curve up to 16 weeks of denosumab was 316 mcg∙day/mL, and the mean maximum denosumab concentration was 6.75 mcg/mL 2.
• Mechanism of action: Denosumab binds to RANKL, preventing the formation, function, and survival of osteoclasts, which are responsible for bone resorption 2.

From the Research

Denosumab Overview

• Denosumab is a fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling 3.
• It is used for the prevention of skeletal-related events in patients with bone metastases from solid tumors 4, 5.
• Denosumab has also been shown to improve bone mineral density (BMD) and reduce the incidence of new vertebral, hip, and nonvertebral fractures in postmenopausal women 6, 7.

Clinical Trials and Efficacy

• Three large randomized trials have investigated the effects of denosumab on skeletal-related events (SREs) in patients with breast cancer, prostate cancer, and multiple myeloma or solid tumors other than breast or prostate cancer 3.
• Denosumab was found to be non-inferior and superior to zoledronic acid in terms of the primary outcome time to first on-study SRE in breast cancer and prostate cancer studies 3.
• In a third study, denosumab was non-inferior to zoledronic acid but not superior in solid tumors excluding breast and prostate cancer with bone metastases 3.
• Median overall survival and disease progression rates were similar between zoledronic acid and denosumab in the three studies 3.

Safety and Tolerability

• The tolerability profile of denosumab was manageable in patients with bone metastases from solid tumors 5.
• Osteonecrosis of the jaw occurred in 1.8% and 1.3% of patients in the denosumab and zoledronic acid groups during the primary treatment phase 5.
• Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established 7.

Administration and Dosage

• Denosumab is administered via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments 7.
• The recommended dosage of denosumab is 120 mg every 4 weeks for the prevention of skeletal-related events in patients with bone metastases from solid tumors 5.