Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer.
OBJECTIVE
Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, to protect against aromatase inhibitor-induced bone loss.


METHODS
Eligible women with hormone receptor-positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (< or = 6 v > 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD).


RESULTS
At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups.


CONCLUSIONS
In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.
Ellis
Georgiana K
GK
Seattle Cancer Care Alliance, Seattle, WA 98109-1023, USA. gellis@u.washington.edu
Bone
Henry G
HG
Chlebowski
Rowan
R
Paul
Devchand
D
Spadafora
Silvana
S
Smith
Judy
J
Fan
Michelle
M
Jun
Susie
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D047072:Aromatase Inhibitors / Q000009:adverse effects; D015519:Bone Density / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000453:epidemiology; D017024:Chemotherapy, Adjuvant; D015897:Comorbidity; D000069448:Denosumab; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology / Q000517:prevention & control; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D010024:Osteoporosis / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control*; D053245:RANK Ligand / Q000008:administration & dosage*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047072:Aromatase Inhibitors; D053245:RANK Ligand; D000069448:Denosumab