Nancy A. Melville

October 15, 2013

BALTIMORE — A long-term extension trial with the antiresorptive osteoporosis drug denosumab (Prolia, Amgen) shows that the therapy continues to increase bone-mineral density (BMD) and reduce the risk for fracture in women for up to 8 years, according to presentations at the American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting last week.

However, the lead author of one of the studies, Serge Ferrari, MD, from Geneva University Hospital, Switzerland, said one possible limitation of such an extension study is that only the healthier subjects remain for the long term. Nevertheless, he believes the findings are still impressive.

"Long-term therapy with denosumab showed further nonvertebral fracture risk reduction over time, despite the fact that women in the study became older and were not excluded for having a previous fracture during the trial," he observed.

He also noted the significance of the findings, given that the US Food and Drug Administration does not recommend treatment with bisphosphonate therapy beyond 5 years, due to a lack of evidence on additional fracture-prevention benefits beyond that period.

Outside commentators said the "healthy-cohort" effect was a potential drawback of these new findings, as was the fact that there was no control group in the extension phase of the study. Nonetheless, they agreed that the results are notable.

Four Years of Denosumab Therapy Cuts Fractures in All Groups

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study was an international, randomized, placebo-controlled trial involving 7868 women 60 to 90 years of age with a BMD T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip who were assigned to denosumab, 60 mg every 6 months, or placebo for 3 years. At the end of this, approximately 70% of the original participants continued in the follow-up study, with those in the placebo group all crossing over to denosumab therapy. The extension phase of the trial is slated to continue for 7 years for a total duration of 10 years.

In presenting 7-year results at the ASBMR meeting, Dr. Ferrari described nonvertebral fracture rates that showed an interesting decline at year 4 of treatment in the long-term group (n = 2343) who had received the denosumab treatment over the full 7 years, as well as in the crossover group (n=2207), who had received placebo for the first 3 years before crossing over to treatment with denosumab at year 4.

Among those who had received the active treatment for the full 7 years, the nonvertebral fracture rate decreased from 1.98 per 100 subject-years in the first 3 years to 1.43 in year 4 (P = .096), and the rate remained at 1.45 during years 4 through 7 (P = .01).

In the crossover group, the fracture rate was 2.20 during years 4 through 6 of the study (so for their first 3 years of denosumab treatment after crossover from placebo), showing a significant decrease in year 7 of treatment (4 years of denosumab therapy) to 1.03 (P = .004).

When they combined the long-term-treatment and placebo-crossover groups, they found a combined fracture rate of 2.08 in years 1 through 3 of denosumab therapy (whether that was years 1 through 3 for the active group or years 4 through 6 of the study for the crossover group), and the combined fracture rate decreased to 1.27 at year 4 of denosumab treatment (P = .002).

Dr. Ferrari noted that such reductions have not been seen in previous trials, but there could be several explanations.

"First, this is the largest long-term observation study following a randomized controlled trial in osteoporosis," he told Medscape Medical News.

"Second, differences in the mechanism of action between denosumab and other drugs, particularly bisphosphonates, could account for these results, as also shown by the continuous increase in hip BMD observed with denosumab, but not bisphosphonates."

As well as the increase in BMD seen with denosumab, there was a sustained reduction in bone resorption and a decrease in cortical porosity, as well as gains in bone mass and increases in cortical/trabecular strength with the active treatment, he said.

"Denosumab has now demonstrated clear benefits of prolonged therapy," he observed.

Eight-Year Results Show BMD Increases, Continued Benefit

Also reported at the ASBMR meeting in a late-breaking poster were the 8-year results from FREEDOM, which included 1382 subjects in the long-term denosumab group, who have so far received a cumulative 8 years of treatment, and 1296 patients in the group that crossed over from placebo.

The long-term-treatment arm showed BMD increases of 18.5% in the lumbar spine and 8.2% in total hip, compared with baseline, and the crossover arm showed BMD gains of 13.8% in the lumbar spine and 4.8% in total hip (P < .05 for both groups compared with the FREEDOM and extension baselines).

Each denosumab dose was followed by rapid reductions in serum C-terminal telopeptide (CTX), which attenuated toward the end of the dosing period, as is characteristic with the drug.

Incidence rates of new vertebral and nonvertebral fractures were low throughout the extension. The incidence of hip fractures during year 8 was 0.2% for the long-term denosumab group and less than 0.1% for the crossover group.

"Denosumab treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in BMD, and low fracture incidence," the authors noted.

Healthy-Cohort Effect, No Control Group, but Results Still Impressive

Angela M . Cheung, MD, PhD, a professor of medicine and director of the osteoporosis program at the University of Toronto, Ontario, said improvements in hip BMD and decreases in cortical porosity of bone likely explain the reduced fracture risk following 4 years of treatment with denosumab, as reported by Dr. Ferrrari, but she stressed that several important constraints need to be considered.

"One major limitation is that there is no control group," she told Medscape Medical News. "In addition, we may be seeing a 'healthy-cohort' effect, as those who are at increased risk of fractures may have dropped out of the long-term extension."

Ian Reid, MD, a distinguished professor in medicine at the University of Auckland, New Zealand, who was a coauthor on the original 3-year FREEDOM study, said the healthy-cohort effect is one possible explanation of the improvements, but it likely doesn't tell the whole story.

"The ongoing results from the FREEDOM study are surprising," he told Medscape Medical News. "It is possible that the continuing decline in fracture rates is related to the sicker patients dropping out, but the data presented at the meeting did not suggest that.

"I think this is unlikely to be the entire explanation, because the increases in bone density, which accompanied the decreases in fracture rates, are much greater than we have seen with the bisphosphonates," he explained.

For example, long-term data on zoledronate extending to 9 years that were also presented at the ASBMR meeting did not show similar progressive improvements in bone density or declines in fracture rates, casting some doubt as to the role of a healthy cohort, he observed.

"Thus, denosumab seems to exert superior effects in the long term compared with the bisphosphonates, even though in the original 3-year studies they were broadly comparable," Dr. Reid said.

"However, because there is no true control group and the study is no longer blinded, some people will remain skeptical of these findings."

Dr. Ferrari disclosed relationships with Amgen, Bioiberica, GlaxoSmithKline, Lilly, and Novartis. Dr. Reid disclosed that he was a coauthor on the 3-year FREEDOM study and is an ongoing investigator for Amgen. Dr. Cheung has relationships with Amgen, Lilly, and Merck.

American Society for Bone and Mineral Research 2013 Annual Meeting. Abstract 1017, presented October 5, 2013; Abstract LB-MO26, presented October 7, 2013.

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