Denosumab for prevention of fractures in postmenopausal women with osteoporosis.

Abstract

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.)

• Authors: Steven R Cummings, Javier San Martin, Michael R McClung, Ethel S Siris, Richard Eastell, Ian R Reid, Pierre Delmas, Holly B Zoog, Matt Austin, Andrea Wang, Stepan Kutilek, Silvano Adami, Jose Zanchetta, Cesar Libanati, Suresh Siddhanti, Claus Christiansen, FREEDOM Trial
• Journal: The New England journal of medicine (N Engl J Med) Vol. 361 Issue 8 Pg. 756-65 (Aug 20 2009) ISSN: 1533-4406 [Electronic] United States
• PMID: 19671655 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Massachusetts Medical Society

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Bone Density Conservation Agents
• RANK Ligand
• Denosumab

Topics

• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (adverse effects, pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Bone Density (drug effects)
• Bone Density Conservation Agents (adverse effects, pharmacology, therapeutic use)
• Bone Remodeling (drug effects)
• Denosumab
• Female
• Fractures, Bone (epidemiology, prevention & control)
• Hip Fractures (epidemiology, prevention & control)
• Humans
• Incidence
• Middle Aged
• Osteoporosis, Postmenopausal (drug therapy)
• RANK Ligand (adverse effects, pharmacology, therapeutic use)
• Risk
• Spinal Fractures (epidemiology, prevention & control)