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On September 16, 2011, the U.S. Food and Drug Administration granted approval for denosumab (Prolia, Amgen Inc.) as a treatment to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer. In men with nonmetastatic prostate cancer, denosumab also reduced the incidence of vertebral fracture.
Denosumab is a monoclonal antibody that binds to RANKL, a protein involved in the formation, function, and survival of osteoclasts, the cells responsible for bone resorption.
The approvals were based on results from two international, randomized (1:1), double-blind, placebo-controlled trials in patients receiving ADT for nonmetastatic prostate cancer or adjuvant AI therapy for breast cancer. Trial 20040138 was a 3-year trial that enrolled 1,468 men with prostate cancer (median age 76 years). Men less than 70 years of age were required to have either a baseline bone mineral density (BMD) T-score at the lumbar spine, total hip, or femoral neck between -1.0 and -4.0, or history of osteoporotic fracture. Trial 20040135 was a 2-year trial that enrolled 252 women with breast cancer (median age 59 years). Women had a baseline BMD T-score at the lumbar spine, total hip, or femoral neck between -1.0 and -2.5 and had not experienced fracture after age 25.
Patients were randomized to receive subcutaneous injections of either placebo or 60 mg denosumab, once every 6 months, for a total of 6 doses in Trial 20040138 and for a total of 4 doses in Trial 20040135.
The primary outcome measure in each trial was the percent change in lumbar spine BMD, from baseline to month 24 in Trial 20040138 and baseline to month 12 in Trial 20040135. A secondary outcome measure in Trial 20040138 was the incidence of new vertebral fractures through month 36.
In Trial 20040138, randomization was stratified by age (< 70 years vs. ≥ 70 years) and duration of ADT at trial entry (≤ 6 months vs. > 6 months). Seventy nine percent received ADT for more than 6 months at trial entry.
In Trial 20040135, randomization was stratified by duration of adjuvant AI therapy at trial entry (≤ 6 months vs. > 6 months). Sixty-two percent received adjuvant AI therapy for more than 6 months at trial entry.
Denosumab resulted in a statistically significant effect on BMD as compared to placebo in patients with nonmetastatic prostate or breast cancer, at 24 and 12 months respectively. In men with prostate cancer, Prolia also significantly reduced the incidence of new vertebral fractures at 36 months. At 36 months, the proportion of men with new vertebral fracture was 1.5% in Prolia-treated men compared to 3.9% in men on the placebo arm [ARR 2.4%, 95% CI (0.7, 4.1); RRR 62% (22, 81); p=0.0125].
Efficacy Results for Prolia in Patients at High Risk for Fracture Receiving ADT for Nonmetastatic Prostate Cancer or Adjuvant AI Therapy for Breast Cancer
Non-metastatic Prostate Cancer
Non-metastatic Breast Cancer
Change in lumbar spine BMD from baseline to end of study period*
Treatment difference (95% CI)
* at 24 months in Trial 20040138; at 12 months in Trial 20040135
Adverse reactions reported in ≥ 10% of Prolia-treated patients and more frequently than in placebo-treated patients were arthralgia and back pain. Pain in extremity and musculoskeletal pain were also noted. Hypocalcemia (serum calcium less than 8.4 mg/dL) was observed only in Prolia-treated patients (2.4%) at the month 1 visit.
The recommended dose and schedule for denosumab as a treatment to increase bone mass in patients at high risk for fracture receiving ADT for nonmetastatic prostate cancer or adjuvant AI therapy for breast cancer is 60 mg subcutaneously every 6 months. On June 1, 2010, denosumab (Prolia) at the same dose and schedule was approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture. On November 18, 2010, denosumab (marketed under the tradename Xgeva) was approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors. The dose for this indication is 120 mg subcutaneously every 4 weeks.
Full prescribing information, for Prolia and Xgeva, is available at:
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).