Denosumab reverses bone loss, lowers wrist fracture rates in women with osteoporosis

Osteoporosis is a common condition where bones become weak, affecting both men and women, mainly as they grow older. Osteoporosis results from a loss of bone mass, measured as bone density, and from a change in bone structure. Osteoporosis can increase fracture risk. Risk factors for developing osteoporosis include a sedentary lifestyle, use of glucocorticoids, smoking and having inflammatory arthritis, among others. Osteoporosis is more common in older women, mainly non-Hispanic white and Asian women. In the U.S., about 4.5 million women and 0.8 million men over the age of 50 have osteoporosis.

Denosumab, a fully human monoclonal antibody drug, binds specifically to RANK-ligand (RANKL) and inhibits osteoclast-induced bone resorption by preventing the binding of RANKL to RANK. Cortical bone loss is a major determinant of increased fracture risk. Denosumab has been shown to increase bone mineral density at sites of cortical bone, including the radius, a skeletal site not responsive to most osteoporosis treatments, raising the question of whether these changes affect the risk of fracture at this site.

Researchers in Canada, the United States, France, Austria, Australia, Poland, New Zealand and Estonia conducted a study (FREEDOM) to evaluate changes over time in radius bone mineral density and wrist fracture incidence.

"We examined evaluated changes over time in radius BMD and wrist fracture incidence during three years of placebo (Pbo) and up to five subsequent years of denosumab therapy in FREEDOM and its Extension (EXT)," says study investigator Jacques Brown, MD.

The researchers evaluated 2,207 women who received placebo during the initial three-year trial and then enrolled in the extension trial to receive 60 mg of denosumab once every six months. All the women also received daily calcium and vitamin D supplements. A subset of 115 women participated in a distal radius DXA sub-study. They were evaluated at baseline and during both the FREEDOM and EXT trials. Analysis of mean percentage changes in bone mineral density over time from the two study baselines consisted of a repeated measure model. Wrist fracture rates (per 100 subject-years), rate ratios and 95 percent CI were computed to measure the results.

At the FREEDOM trial baseline, participants' mean 1/3 radius T-score was -2.53 (1.18). During the original trial, daily calcium and vitamin D alone was associated with a progressive and significant loss of bone mineral density at the 1/3 radius (-1.2%). However, during the extension, denusomab halted and reversed bone loss in the patients.

With five years of denusomab treatment, the researchers observed a significant gain in bone mineral density (1.5 percent) compared with the extension baseline. The wrist fracture rate during the placebo period in FREEDOM was 1.02 (0.80-1.29) per 100 subject-years. During the first three years of denusomab use, the participants' bone mineral density recovered to the original baseline levels. Their wrist fracture rate remained comparable to the rate during the time they took placebo. With two additional years of denusomab treatment, their bone mineral density increased further and the wrist fracture rate declined to levels significantly lower than the FREEDOM placebo rate (rate ratio=0.57, 95% CI=0.34-0.95; p=0.03).

"In untreated women with postmenopausal osteoporosis, cortical bone density at the radius declined significantly. Denosumab treatment for three years fully reversed this bone loss, and two additional years of treatment resulted in further BMD gains that translated to significantly lower wrist fracture rates. This highlights the clinical importance of reversing cortical bone loss," says Dr. Brown.