Denosumab in the Prevention of Skeletal-Related Events in Patients with Bone Metastases from Solid Tumors
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Denosumab in the Prevention of Skeletal-Related Events in Patients with Bone Metastases from Solid Tumorsy Profile Report Lesley J. Scott and Victoria J. Muir Adis, a Wolters Kluwer Business, Auckland, New Zealand
Tumor metastasis to the bone is common in certain primary tumors, including breast and prostate cancer.[1,2] Bone metastases develop in up to 80% of patients with advanced prostate or breast cancer and up to 40% of those with other advanced solid tumors.[2,3] In the US, over 400 000 people are affected by metastatic bone cancer.[1] The presence of such metastases is associated with increased skeletal morbidity due to skeletalrelated events (SREs), including radiation therapy to alleviate pain or prevent fracture, surgery to bone, pathological fracture, and spinal cord compression, and also bone pain and hypercalcemia.[1,2] Bisphosphonates (e.g. zoledronic acid and pamidronate) are the current standard of care for cancer patients with bone metastases.[1,2] However, bisphosphonate therapy does not completely prevent SREs and there is debate over the optimal duration of treatment.[1,2] In addition, intravenous bisphosphonates, such as zoledronic acid, must be administered via infusion and have been implicated in renal dysfunction.[2] Targeting the receptor activator of nuclear factor-kB (RANK)/ RANK ligand (RANKL)/osteoprotegerin signalling pathway provides another means of potentially treating bone metastases.[2,4,5] RANKL mediates osteoclast differentiation, proliferation, activation, and survival. There is also evidence that tumor cells stimulate RANK/RANKL, leading to increased osteoclast activity and bone degradation.[2,4,5] The fully human monoclonal antibody denosumab (XGEVA) binds to RANKL, thus inhibiting RANKL-mediated osteoclastogenesis and the resulting bone resorption.[5,6] In binding immunoassays, denosumab was specific for human RANKL and did not bind murine RANKL, human tumor necrosis factor
y Adapted and reproduced from Drugs 2011; 71 (8): 1059-1069.
(TNF)-related apoptosis-inducing ligand (TRAIL), or other TNF proteins.[6] In contrast, recombinant fusion protein of osteoprotegerin (OPG-Fc) bound human and murine RANKL and TRAIL (osteoprotegerin is the natural soluble decoy receptor for RANKL). The dissociation equilibrium constant for
Table I. Features and properties of denosumab (XGEVA)[7] Featured indication Prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors Denosumab is not recommended for the prevention of SREs in patients with multiple myeloma Mechanism of action Binds to receptor activator of nuclear factor-kB ligand (RANKL), thereby inhibiting RANKL-mediated osteoclastogenesis Dosage and administration Dose
120 mg
Route of administration
Subcutaneous injection
Frequency of administration
Once every 4 weeks
Pharmacokinetic profile after multiple doses of subcutaneous denosumab 120 mg once every 4 weeks in patients with bone metastases from cancer (mean v
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