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DENVER -- Two studies presented here demonstrated the efficacy of romosozumab, a new treatment for osteoporosis, but in one of the trials a cardiovascular safety signal emerged that led the FDA to reject manufacturer Amgen's application for approval in July.

Romosozumab is a monoclonal antibody that binds sclerostin, increasing bone formation and decreasing resorption through inhibition of the Wnt signaling pathway.

The larger of the two studies, FRAME, was presented by E. Michael Lewiecki, MD, of New Mexico Clinical Research & Osteoporosis Center in Albuquerque, at the (ASBMR) annual meeting. The second, ARCH, was presented by Kenneth G. Saag, MD, of the University of Alabama at Birmingham.

In FRAME, there was a 66% reduction in new vertebral fractures among patients who had been treated with romosozumab followed by denosumab (Xgeva and Prolia), and in ARCH, there was a 48% reduction in relative risk for new vertebral fractures among patients treated with romosozumab followed by alendronate (Fosamax). ARCH was simultaneously published online in the .

Romosozumab is "highly effective," Saag told 番茄社区app. "All of us in the bone world would like there to be more therapies. We're very challenged at the moment by not having enough drugs for our patients to choose from. Having additional therapeutic options would really help the field dramatically."

"What many of us would like to see is this drug move toward approval, with the recognition that if this cardiovascular safety signal is real, that certain patients might not be candidates for it," Saag added.

FRAME Details

FRAME initially enrolled 7,180 women, randomizing them to romosozumab, 210 mg subcutaneously or placebo each month for 1 year, followed by open-label denosumab 60 mg subcutaneously every 6 months through 36 months.

Participants in FRAME had a mean age of 71. Mean T-scores at the spine and hip were -2.7 and -2.5, respectively. At baseline, 18.5% had prevalent vertebral fractures and 22% had a history of nonvertebral fractures. The first 12-month phase was completed by 89%, the 24-month phase by 84%, and the 36-month phase by 80%.

At the 2016 ASBMR meeting, the 12-month data were presented, showing a 73% relative risk reduction in new vertebral fractures among women receiving romosozumab compared with those given placebo. There also was a 33% decrease in clinical fractures and a 25% decrease in nonvertebral fractures.

At 24 months, new vertebral fractures were seen in 0.6% of the romosozumab group compared with 2.5% of the placebo group, which was 75% lower.

At 36 months, the increase in lumbar spine bone mineral density (BMD) was 18.1% in the romosozumab/denosumab group compared with 7.5% in the placebo/denosumab group, for a statistically significant 10.5% difference in lumbar spine BMD, according to Lewiecki.

Also at 36 months, the increase in total hip BMD was 9.4% in the romosozumab/denosumab group compared with 4.2% in the placebo/denosumab group, for a difference of 5.2%. New vertebral fractures were reported in 2.8% of the placebo/denosumab group compared with 1% of the romosozumab/denosumab group, for a relative risk reduction of 66% (P<0.001).

Other changes included relative risk reductions of 27% in clinical fractures (P=0.004), of 21% in nonvertebral fractures (P=0.039), of 27% in major nonvertebral fractures (P=0.015), and of 30% in major osteoporotic fractures (P=0.006).

Adverse events were generally balanced between groups. At 24 months, there was one case of osteonecrosis of the jaw and one atypical femoral fracture in the romosozumab group compared with none in the placebo groups, and by 24 months, an additional case of osteonecrosis had been reported in the romosozumab group. No further cases were seen through 36 months.

At 12 months, adjudicated serious cardiovascular events were reported in 1.1% of placebo patients and 1.2% of romosozumab patients, while by 24 months, the numbers were 2.2% and 2.3%, respectively.

At 12 months, adjudicated cardiovascular deaths were reported in 0.4% of placebo patients and 0.5% of romosozumab patients, and in 0.8% and 0.9% by 24 months.

There was no signal of a difference in the adjudicated cardiovascular events between the groups at 36 months, Lewiecki said.

ARCH Details

The ARCH study included 4,093 women whose mean age was 74 and whose mean total hip T-score was -2.8.

Participants were randomized to receive 210 mg romosozumab subcutaneously once monthly or 70 mg alendronate orally once weekly for 12 months. Thereafter, all patients received open-label alendronate, 70 mg once weekly through month 24.

New vertebral fractures were seen in 11.9% of the alendronate/alendronate group and in 6.2% of the romosozumab/alendronate group by 24 months, for a risk reduction of 48% (P<0.001), while new clinical fractures occurred in 13% and 9.7%, respectively, for a 27% relative risk reduction (P<0.001). For nonvertebral fractures, the rates were 10.6% and 8.7%, respectively, representing a relative risk reduction of 19% (P=0.040).

"It is worth noting that romosozumab outperformed an effective drug; in large meta-analyses, alendronate has been shown to consistently reduce vertebral, nonvertebral, and hip fractures by up to 50% among patients with osteoporosis," Saag's group wrote.

Significantly greater increases in BMD also were seen at both months 12 and 24 in the romosozumab group compared with alendronate alone.

During the open-label alendronate period, six patients had atypical femoral fractures, with two being in the romosozumab group and four in the alendronate group, and two (one in each group) had osteonecrosis of the jaw.

Cardiovascular serious events were independently adjudicated and were found to have an observed imbalance, with an incidence at 12 months of 2.5% in the romosozumab group and 1.9% in the alendronate group. Cardiac ischemic events occurred in 0.8% of the romosozumab group and 0.3% of the alendronate group at month 12, and in 1.5% of the romosozumab/alendronate and 1% of the alendronate/alendronate groups by month 24.

"There is not a clear explanation for the safety signal, and there are a number of hypotheses," Saag said. "It is possible that this is related to the drug -- there is some biological plausibility for the association."

"Sclerostin is constitutively expressed in the aorta and up-regulated in foci of vascular and valvular calcification. The function of sclerostin in the vasculature is unknown," the group wrote.

It's also possible that alendronate may have protective effects for cardiovascular events, according to some observational data. However, two meta-analyses did not show protective effects, "so the jury is still out," Saag said.