No Extra Adverse Events With Long-term Denosumab Treatment

By Anne Harding

June 01, 2017

NEW YORK (Reuters Health) - An open-label extension of the three-year FREEDOM trial shows no increased risk of adverse events with an additional seven years of denosumab treatment.

“What this study shows is that overall side effects don’t increase when you extend the period of treatment from three years to 10 years, despite the fact that you’ve got an aging population and in general the older people are, the more likely they are to get side effects,” Dr. Juliet Compston of the Cambridge Biomedical Campus in the UK, who wrote an editorial accompanying the study, told Reuters Health.

In the FREEDOM trial, postmenopausal women with osteoporosis had reduced bone turnover markers, increased bone mineral density (BMD) and fewer new vertebral fractures, hip fractures and non-vertebral fractures with denosumab, 60 mg subcutaneously every six months, compared to placebo. At the end of the trial, study participants could choose to participate in the seven-year extension, and either continue on denosumab or switch to the drug from placebo.

As reported online May 22 in Lancet Diabetes and Endocrinology by Dr. Henry G. Bone of the University of Michigan in Ann Arbor and colleagues, 2,626 women (1,343 long-term and 1,283 crossover) completed the extension study.

The yearly exposure-adjusted incidence of adverse events dropped from 165.3 to 95.9 per 100 participant years, while serious adverse event rates ranged from 11.5 to 14.4 per 100 participant years.

One patient in each group had an atypical femoral fracture, while seven patients in the long-term group and six in the crossover group developed osteonecrosis of the jaw. Rates of new vertebral and non-vertebral fractures remained similar during the extension period compared to what it was in the denosumab arm of the FREEDOM trial.

Because there was no placebo group in the extension, the authors used a simulation method to estimate expected fracture rates had the denosumab participants who enrolled in the extension received placebo throughout. They report that fracture rates were also lower than would have been expected in their virtual long-term placebo group.

Patients on long-term treatment showed BMD increases of 21.7% over baseline for the lumbar spine; 9.2% at total hip; 9.0 at the femoral neck; and 2.7% at the one-third radius. Crossover group BMD increases from the extension baseline were 16.5%, 7.4%, 7.1% and 2.3%, respectively.

The use of a virtual placebo group for the extension study was not ideal, Dr. Compston noted. The findings also suggest, she added, that osteonecrosis of the jaw might increase with duration of denosumab therapy. However, she noted, absolute risk remains low, at an exposure-adjusted patient incidence of 5.2 per 10,000 patient years over the course of the study.

Based on this finding, she added, doctors should discontinue the drug in patients who develop serious dental problems. But patients taken off denosumab should be switched to another treatment, according to Dr. Compston, because stopping treatment can lead to rapid bone loss and an increased risk of vertebral fractures.

Amgen, which makes denosumab, funded the study, and Dr. Compston has received speaking fees from the company.

Dr. Bone was not available for an interview by press time.


Lancet Diabetes Endocrinol 2017.