Denosumab in the prevention of skeletal-related events

Cancer treatment-induced bone loss and skeletal-related events resulting from bone metastases cause significant morbidity for cancer patients.

Skeletal-related events may include pathologic fracture, spinal cord compression, pain, hypercalcemia and the need for radiation therapy or surgery to stabilize the bone. Until recently, treatment was limited to bisphosphonates and supplementation with oral calcium and vitamin D. Recent research has detailed the mechanisms associated with the development of cancers treatment-induced bone loss and bone metastases, which has led to the development of a unique therapy.

In cancer treatment-induced bone loss, osteoporosis and most bone metastases, the activity of the osteoclasts exceeds that of the osteoblasts, leading to a bone with poor structural integrity. Receptor activator of nuclear factor kappa B ligand (RANKL) is a cytokine that contributes to the differentiation and proliferation of osteoclasts and, thus, to increased bone resorption and decreased bone strength, besides potentially reduced tumor-induced bone destruction.

Lisa K. Lohr

Denosumab (Xgeva, Prolia; Amgen) is a newly developed, human IgG₂ antibody that binds to RANKL and inhibits its action. Denosumab leads to decreases in bone resorption and increases bone mineral density. This is in contrast to bisphosphonates, which work by binding to the bone mineral and inhibit osteoclasts via intracellular mechanisms.

Denosumab is approved for the treatment of postmenopausal osteoporosis. For this indication, the approved dose is 120 mg subcutaneous injection every 6 months and should be supplemented with oral calcium and vitamin D. It has also shown activity in the prevention of cancer treatment-induced bone loss in patients with breast cancer treated with aromatase inhibitors and in patients with prostate cancer treated with androgen deprivation therapy. Recently, denosumab was approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors, at a dose of 120 mg subcutaneous injection every 4 weeks.

Denosumab vs. zoledronic acid

In an international, multicenter, randomized, controlled trial, researchers studied denosumab vs. zoledronic acid in patients with advanced breast cancer. Patients were eligible for this trial if their creatinine clearance was more than 30 mL/minute and were excluded if they had received prior IV bisphosphonates, current or prior oral bisphosphonates (for the treatment of bone metastases) or had nonhealed dental or oral surgery. The primary outcome measure was the time to first on-study skeletal-related event, which was defined as pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression.

Patients received denosumab 120 mg subcutaneous injection or zoledronic acid 4 mg intravenously (dose adjusted for renal function) every 4 weeks. Supplementation with oral calcium and vitamin D was strongly encouraged. Median time on study was 17 months; 2,049 patients were enrolled. Major outcomes from the study are shown in Table 1.

The authors concluded that in patients with advanced breast cancer, the use of denosumab reduced the risk for skeletal-related event development compared with the use of zoledronic acid. The Kaplan-Meier curves depicting the primary outcomes show continued divergence starting at about 6 to 9 months of therapy, with no convergence during the 27- to 30-month follow-up.

Both therapies were fairly well tolerated. One known adverse effect of bisphosphonates is renal dysfunction. The rate of renal toxicity was significantly lower in the group treated with denosumab. In addition, bone pain and arthralgias were seen less frequently in the denosumab group. Hypocalcemia was seen somewhat more frequently in the denosumab group.

There was not a substantial difference in the incidence of osteonecrosis of the jaw in the two groups (denosumab, 2%; zoledronic acid, 1.4%), suggesting that this potentially devastating complication is not unique to the mechanism of action of bisphosphonates.

Other potential adverse effects of denosumab include diarrhea, constipation, nausea, vomiting, backache, limb pain, headache, asthenia, dermatitis/rash, hypocalcemia, hypophosphatemia and dyspnea. Denosumab is contraindicated in patients with pre-existing hypocalcemia.

Denosumab in other studies

More information regarding denosumab use in cancer patients has been presented in abstract form. One group (ASCO 2010; No. LBA4507) studied denosumab vs. zoledronic acid in prostate cancer patients with bone metastases and found that denosumab significantly delayed the time to first on-study skeletal-related event. Another group (ASCO 2010; Nos. 9133 and 9042) compared denosumab vs. zoledronic acid in patients with a variety of solid tumors (including multiple myeloma, but not breast or prostate cancer) and bone metastases. Denosumab was found to significantly delay the time to first and subsequent on-study skeletal-related event. In addition, the group treated with denosumab had delayed time to skeletal-related event, hypercalcemia and time to first radiation therapy to bone.

Ongoing research is being conducted with denosumab, regarding treatment of hypercalcemia of malignancy, as adjuvant treatment in patients with early-stage breast cancer and in comparison with oral bisphosphonates in osteoporosis patients. Although commonly given monthly, the optimal frequency of administration of denosumab (or bisphosphonates) is not known for these indications.

Pharmacokinetics of denosumab

The time to C_max is about 10 days and the average half-life in the serum is about 26 days. The elimination of denosumab is probably through the reticuloendothelial system (similar to other immunoglobulins.) Renal impairment does not alter the elimination of denosumab. No studies have been done in patients with hepatic impairment, but such impairment is unlikely to alter the effects of denosumab. No dosing adjustments are recommended for patients with either renal or hepatic impairment. No drug-drug interactions have been described.

Denosumab is more convenient and less time-consuming to administer and requires no renal function monitoring before dosing. Unfortunately, it is substantially more expensive (nearly twice the already expensive cost of zoledronic acid and 50 times more expensive that pamidronate). Cost-effectiveness studies have not been performed.

Denosumab shows promise in the prevention of skeletal-related events in patients with various solid tumors and exhibits a reasonable amount of adverse effects. More research is needed to exactly delineate its role and in its possible use in the treatment of hypercalcemia of malignancy.

Lisa K. Lohr, PharmD, BCPS, BCOP, is a clinical pharmacist in oncology and bone marrow transplantation in the department of pharmacy services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member. Disclosure: Lohr reports no relevant financial disclosures.

For more information:

• Muir VJ. BioDrugs. 2010;24:379-386.
• Stopeck AT. J Clin Oncol. 2010;28:5132-5139.