乌鸦传媒

DENVER -- The rate of nonvertebral fractures continued to decline through 10 years of treatment with denosumab (Prolia) among postmenopausal women, researchers reported here.

Women in the receiving subcutaneous denosumab who enrolled in the trial's long-term extension phase had a rate of nonvertebral fractures during years 1 to 3 of 1.98 (95% CI 1.67-2.34) per 100 person-years and rates of 1.54 (95% CI 1.29-1.83) per 100 patient-years during years 4 to 7, for an adjusted rate ratio of 0.79, P=0.046, according to Serge Ferrari, MD, of Geneva University Hospital in Switzerland, and colleagues.

And among that group, the rate during years 4 to 10 was 1.44 (95% CI 1.24-1.66) per 100 person-years, for an adjusted RR of 0.74 (95% CI 0.60-0.93, P=0.008), Ferarri reported in a plenary session at the annual meeting.

"There are very few long-term trials that have examined the efficacy of osteoporosis drugs on fractures and in those few long-term trials, referring to some of the bisphosphonates, there is no substantial evidence that nonvertebral fractures are further reduced with prolonged therapy," Ferrari said.

"We have also learned, at least from postmarketing observations, that long-term treatment is associated with a progressively increasing risk of adverse events, such as osteonecrosis of the jaw and atypical femoral fractures, and that has led to questions whether the long-term benefit-risk is actually valuable or not, and the recommendation to limit osteoporosis therapy to 5 years because the benefit-risk beyond that was not established," he said.

Denosumab is a monoclonal antibody to the receptor activator of nuclear factor-ΚB ligand RANKL, which inhibits osteoclast development and activity thereby decreasing bone resorption and increasing bone density.

Ferrari's group analyzed outcomes from the FREEDOM extension, which enrolled 4,550 women, ages 60 to 90, who had a lumbar spine or total hip T-score below -2.5 and who had completed the initial placebo-controlled phase of the study. During the extension phase, patients all received open-label denosumab, 60 mg every 6 months.

Those who had initially received the active treatment (the long-term group) could have up to 10 years of exposure, while those who originally had been given placebo (the crossover group) could have up to 7 years of treatment. The rate of nonvertebral fractures in the first 3 years was compared with rates during years 4 to 7 for the long-term and crossover groups both separately and combined, and rates during years 4 to 10 were calculated for the long-term group.

The long-term group included 2,343 women, while the crossover group consisted of 2,207. Baseline characteristics in the groups were balanced, with a mean age of 72.3, previous vertebral fractures present in 23.6%, and prevalent nonvertebral fractures in 30%. Mean lumbar spine T score was -2.83.

In the crossover group, the nonvertebral fracture rate was 2.37 (95% CI 1.97-2.84) per 100 person-years during the first 3 years (when they were receiving placebo), declining to 1.52 (95% CI 1.24-1.87) per 100 in years 4 to 7, for an adjusted rate ratio of 0.65 (95% CI 0.50-0.86, P=0.002).

In the combined long-term (active treatment) and crossover (placebo) groups, the rate of nonvertebral fractures during years 1 to 3 was 2.15 (95% CI 1.90-2.43) and 1.53 (95% CI 1.34-1.75) during years 4 to 7, for an adjusted RR of 0.72 (95% CI 0.61-0.86, P<0.001).

Among the 6,089 women exposed to denosumab during FREEDOM or its extension phase, the rate of bone safety events such as osteonecrosis of the jaw and atypical femoral fractures was 0.06 per 100 patient-years.

"Long-term reduction in bone remodeling is not only associated with continued increases in BMD, but also with a favorable benefit-risk profile for bone," Ferrari concluded.