About FDA


On November 18, 2010, the U.S. Food and Drug Administration granted approval for denosumab (Xgeva, Amgen Inc.) for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma.

Denosumab is a monoclonal antibody that binds to RANKL, a protein involved in the formation, function, and survival of osteoclasts. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in bone metastases from solid tumors. 

The approval is based on results from three international, randomized (1:1), double-blind, double-dummy trials in patients with bone metastases comparing denosumab to zoledronic acid. Trial 20050103 enrolled 1,901 patients with castrate-resistant prostate cancer, Trial 20050136 enrolled 2,046 patients with breast cancer, and Trial 20050244 enrolled 1,776 patients with multiple myeloma or solid tumors other than breast or prostate cancer.

In all three trials, patients were randomized to receive either 120 mg denosumab subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously every 4 weeks (dose-adjusted for reduced renal function). Patients with creatinine clearances less than 30 mL/min were excluded and prior intravenous bisphosphonate therapy was not permitted. 

The primary outcome measure in each trial was the demonstration of non-inferiority in time-to-first SRE between patients treated with either denosumab or zoledronic acid. An SRE was defined as a pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression due to cancer. Other outcome measures were superiority of time-to-first SRE and superiority of time-to-first and subsequent SRE.

In Trial 20050244, 40% of patients had non-small cell lung cancer, 10% had multiple myeloma, 9% had renal cell carcinoma, and 6% had small cell lung cancer. Other tumor types individually comprised less than 5% of the enrolled population.

Denosumab therapy resulted in a statistically significant delay in the time-to-first SRE and in the time-to-first and subsequent SRE compared to zoledronic acid in patients with breast cancer (Trial 20050136) or castrate-resistant prostate cancer (Trial 20050103). In Trial 20050244, denosumab was non-inferior to zoledronic acid in delaying the time-to-first SRE and did not demonstrate superiority.

Efficacy Results for Xgeva Compared to Zoledronic Acid in Patients with Advanced Malignancies Involving Bone


Trial 20050103

Trial 20050136

Trial 20050244

Metastatic Castrate-resistant Prostate Cancer

Metastatic Breast Cancer

Metastatic Solid Tumors or Multiple Myeloma


Zoledronic Acid


Zoledronic Acid


Zoledronic Acid

Median Time to SRE (months)







Hazard Ratio (95% CI)

0.82 (0.71, 0.95)

0.82 (0.71, 0.95)

0.84 (0.71, 0.98)

Non-inferiority p-value

< 0.001

< 0.001

< 0.001

Superiority p-value




(NR= not reached)

No apparent differences in overall survival between arms in any of the three trials were observed. In a subgroup analysis of patients with multiple myeloma in Trial 20050244, mortality appeared to be higher for denosumab-treated patients compared to those in the control arm (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180). The limited number of patients in this subgroup precludes a definitive conclusion.

The most common adverse reactions in patients receiving denosumab (per-patient incidence greater than or equal to 25%) were fatigue or asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction in patients receiving denosumab was dyspnea. The most common adverse reactions resulting in denosumab discontinuation were osteonecrosis and hypocalcemia.

Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with denosumab and 1.3% receiving zoledronic acid. Osteonecrosis of the jaw was confirmed in 1.8% of patients treated with denosumab and 1.3% receiving zoledronic acid. 

The recommended dose and schedule for denosumab for the prevention of SREs in patients with bone metastases from solid tumors is 120 mg administered subcutaneously every 4 weeks. On June 1, 2010, denosumab was approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture and is marketed under the tradename Prolia. The dose for this indication is 60 mg administered subcutaneously every 6 months.

Full prescribing information, for Xgeva and Prolia is available at:

Xgeva - http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125320s007lbl.pdf

Prolia - http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125320s0000lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Page Last Updated: 09/15/2015
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