Marlene Busko

October 15, 2015

SEATTLE — Data on women who received denosumab (Prolia, Amgen), in some cases for up to 10 years in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every Six Months (FREEDOM) study and its extension phase, show that there was no alteration in the benefit/risk profile of the drug over the course of the whole trial.

Henry G Bone III, MD, from the Michigan Bone and Mineral Clinic, in Detroit, presented data for the 7-year extension of the original 3-year trial at the recent American Society for Bone and Mineral Research (ASBMR) 2015 Annual Meeting.

Specifically, "denosumab over 10 years produced a persistent reduction in bone turnover, continued increases in bone density without an apparent plateau so far, and low incidences of fracture," Dr Bone said.

And "one of the striking findings is the result for lumbar-spine bone-mineral density," he added. There was a linear increase right through the end of the trial for a cumulative 21.7% gain after 10 years. Similarly, there was a 9.2% gain in total-hip bone-mineral density.

The number of serious adverse events was low. During the 7-year extension that was completed by more than 2000 women, there were 13 cases of osteonecrosis of the jaw and two cases of atypical femoral fracture.

Thus, "the benefit/risk profile for denosumab in an aging population of postmenopausal women remains favorable," Dr Bone and colleagues concluded.

Asked to comment, John Eisman, MB BS, PhD, from the Garvan Institute of Medical Research, in Sydney, Australia, told Medscape Medical News: "This is very encouraging. Osteoporosis is a chronic condition, so, like patients with hypertension or diabetes for example, it doesn't make sense for patients with osteoporosis to have 'drug holidays.' What you're seeing is that you're getting continuing ongoing benefit…with lower fracture rates."

Dr Eisman was also reassured by the low incidence of adverse events, which he commented, is "not zero, but there's no treatment for which there is no risk."

Long-term FREEDOM From Fractures?

Denosumab is a monoclonal antibody that targets the RANK ligand, an essential regulator of bone-removing cells (osteoclasts), and in June 2010 it was the first drug in this class to be approved by the US Food and Drug Administration for the treatment of postmenopausal women with osteoporosis at high risk for fracture.

However, because denosumab significantly suppresses bone turnover, it may increase the risk for osteonecrosis of the jaw, atypical fractures, and delayed fracture healing.

In the phase 3 FREEDOM trial, 7808 postmenopausal women aged 60 to 91 who had osteoporosis were randomized to receive a subcutaneous injection of 60 mg of denosumab or placebo every 6 months for 3 years.

Of the participants, 4550 agreed to take part in the 7-year extension study, in which everyone received the drug, and over half of these women (n=2626) completed the full study.

One of the challenges of a trial of treatment for osteoporosis is "we can't keep people with osteoporosis on a placebo forever," Dr Bone explained. This was the reason women in the placebo group were offered active treatment after 3 years.

To estimate what fracture rates might have been, had the women remained on placebo, the researchers created a "virtual twin" model.

During the 3-year FREEDOM trial, 2.3% of women who received active treatment vs 7.2% of women on placebo had a new vertebral fracture. During the 7-year extension, 7.0% of women on active treatment had this type of fracture compared with the estimate that 11.5% of women on placebo would have had a new vertebral fracture.

Similarly, 6.5% of women who received denosumab and 8.0% of women taking placebo had a nonvertebral fracture during the 3-year study. During the extension, 9.3% of women on active treatment had this type of fracture, and the model predicted that 14.5% of women on placebo would have had a nonvertebral fracture.

"We have to be somewhat restrained about this [virtual twin] comparison, but it gives an idea of how factors such as increasing age might alter the fracture rate," said Dr Bone.

Safety Shown, Too

With regard to safety, the incidence of serious infections and malignancies in the placebo group was similar during initial treatment (with placebo) and during the 7-year extension period when all participants then received denosumab.

And one audience member commented that "the 13 cases of [osteonecrosis of the jaw] and two of [atypical femoral fracture]" were "reassuring" but noted that with another type of osteoporosis treatment, long-term bisphosphonate therapy, the opposite pattern of adverse events is seen (ie, more atypical fractures and fewer cases of osteonecrosis of the jaw).

Sean E Harper, MD, executive vice president of research and development at Amgen, said these new results boost confidence in denosumab.

"These 10-year findings from the final year of this open-label extension study provide important additional data to the significant body of evidence generated to inform long-term safety, including more than 100 original publications and presentations over the past seven years," he said in a company statement.

This study received funding from Amgen. Dr Bone discloses support from Amgen, Merck, and Grunenthaler.

American Society for Bone and Mineral Research 2014 Annual Meeting; Seattle, Washington. Abstract 1157, presented October 12, 2015.

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