Denosumab for prevention of fractures in postmenopausal women with osteoporosis.
BACKGROUND
Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis.


METHODS
We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures.


RESULTS
As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.


CONCLUSIONS
Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)
Cummings
Steven R
SR
San Francisco Coordinating Center, California Pacific Medical Center Research Institute and University of California, San Francisco, San Francisco, CA, USA. hglicklandes@sfcc-cpmc.net
San Martin
Javier
J
McClung
Michael R
MR
Siris
Ethel S
ES
Eastell
Richard
R
Reid
Ian R
IR
Delmas
Pierre
P
Zoog
Holly B
HB
Austin
Matt
M
Wang
Andrea
A
Kutilek
Stepan
S
Adami
Silvano
S
Zanchetta
Jose
J
Libanati
Cesar
C
Siddhanti
Suresh
S
Christiansen
Claus
C
D000368:Aged; D000369:Aged, 80 and over; 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; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology / Q000517:prevention & control*; D006620:Hip Fractures / Q000453:epidemiology / Q000517:prevention & control; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D053245:RANK Ligand / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012306:Risk; D016103:Spinal Fractures / Q000453:epidemiology / Q000517:prevention & control
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D053245:RANK Ligand; D000069448:Denosumab