Denosumab in men receiving androgen-deprivation therapy for prostate cancer.
BACKGROUND
Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.


METHODS
In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures.


RESULTS
At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups.


CONCLUSIONS
Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674.)
Smith
Matthew R
MR
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. smith.matthew@mgh.harvard.edu
Egerdie
Blair
B
Hernández Toriz
Narciso
N
Feldman
Robert
R
Tammela
Teuvo L J
TL
Saad
Fred
F
Heracek
Jiri
J
Szwedowski
Maciej
M
Ke
Chunlei
C
Kupic
Amy
A
Leder
Benjamin Z
BZ
Goessl
Carsten
C
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000187:drug effects; D000069448:Denosumab; D004311:Double-Blind Method; D050723:Fractures, Bone / Q000453:epidemiology / Q000517:prevention & control; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006801:Humans; D015994:Incidence; D007279:Injections, Subcutaneous; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D010024:Osteoporosis / Q000139:chemically induced / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D053245:RANK Ligand / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016103:Spinal Fractures / Q000453:epidemiology / Q000517:prevention & control*
D000726:Androgen Antagonists; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D053245:RANK Ligand; D007987:Gonadotropin-Releasing Hormone; D000069448:Denosumab