Romosozumab and Alendronate Curb Fracture in Osteoporosis

Damian McNamara

November 15, 2017

SAN DIEGO — For postmenopausal women with osteoporosis, sequential treatment with romosozumab and alendronate is better than alendronate alone, according to results from the phase 3 Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH).

"Romosozumab is a highly efficacious new therapeutic agent that has a different mechanism of action," said investigator Kenneth Saag, MD, from the University of Alabama at Birmingham.

"It has been shown in an active-comparator study to dramatically reduce fracture risk at all sites measured," he said here at the American College of Rheumatology 2017 Annual Meeting.

Phase 2 studies demonstrated that romosozumab, a humanized monoclonal antibody, promotes bone growth at both vertebral and nonvertebral sites in women with osteoporosis.

The phase 3 active-control study is "more of a pragmatic clinical trial," Dr Saag told Medscape Medical News. The question the investigators hoped to answer was: "Would you consider romosozumab out of the gate, or would you think about using alendronate?" he explained.

At baseline, the 4093 postmenopausal women at high risk for fracture were randomly assigned to receive either romosozumab or alendronate for 12 months. Then, in a 12-month open-label extension, all participants received alendronate.

At 24 months, both primary end points were met. The relative risk for new vertebral fractures was 50% lower with the sequential regimen of romosozumab and alendronate than with alendronate alone (4.1 vs 8.0; P < .001). And the relative risk for clinical fracture was 27% lower with the sequential regimen (9.7% vs 13.0% P < .001).

"The residual question is about its cardiovascular safety, and that's being investigated further," Dr Saag reported.

A Real or Chance Safety Signal?

At 12 months, the subject incidence of serious cardiovascular adverse events was higher with the sequential regimen than with alendronate alone (2.5% vs 1.9%). Specifically, the incidence of cardiac ischemic events was higher (0.8% vs 0.3%), as was the incidence of cerebrovascular events (0.8% vs 0.3%).

"Everyone was a little surprised by the cardiovascular signal," Dr Saag explained. The FRAME study of 7180 postmenopausal women had previously shown no cardiovascular signals, as previously reported by Medscape Medical News.

In ARCH, however, "we actually saw a small number of cardiovascular events," he said. "There was a 0.6% risk difference." This raises a number of questions: "Could this be a real finding? Was it a chance finding? Or could alendronate be cardioprotective?"

"The bottom line from ARCH is that romosozumab has a stronger effect — increasing bone mass and reducing both spine and clinical fractures — than alendronate," said Clifford Rosen, MD, from the Tufts University School of Medicine in Boston, who wrote an editorial (N Engl J Med. 2017;377:1479-1480) that accompanied the publication of the ARCH results (N Engl J Med. 2017;377:1417-1427).

"It works by stimulating new bone formation and reducing resorption," he told Medscape Medical News.

The fact that there were more cardiovascular events in the romosozumab group could be problematic when approval from the US Food and Drug Administration (FDA) is sought, Dr Rosen added.

FDA Needs More Data

The FDA issued a complete response letter to the makers of romosozumab in July, rejecting their initial application for approval. The FDA wants more data, including findings from ARCH and a second study of romosozumab treatment in men with osteoporosis.

Only the FRAME results were submitted with the original application to the FDA.

In ARCH, secondary end points included 12- and 24-month changes in bone mineral density from baseline. These findings "were very similar to what we saw in FRAME," Dr Saag reported.

Table. ARCH Changes in Bone Mineral Density From Baseline

Site of Bone Mineral Density Romosozumab Plus Alendronate Regimen, % Alendronate Only Regimen, % P Value
Lumbar spine
12 months 13.7 5.0 <.001
24 months 15.3 7.2 <.001
Total hip
12 months 6.2 2.8 <.001
24 months 7.2 3.5 <.001
Femoral neck
12 months 4.9 1.7 <.001
24 months 6.0 2.3 <.001


"Romosozumab is a very interesting molecule that's been in development for several years," said Stanley Cohen, MD, a rheumatologist in private practice in Dallas, and tour guide for the poster session.

He asked Dr Saag why the team only looked at 1 year of romosozumab treatment: "Why didn't you continue treatment like you do with denosumab or alendronate?"

"This drug is a curious drug. Not only does it stimulate bone initially," Dr Saag explained, "you get an initial decrease in bone resorption. So it's almost a dual mechanism."

In contrast, "with an anabolic agent, you have an anabolic window," he pointed out. "That's going to be a more finite period of treatment."

Dr Saag was asked by a member of the audience to predict where the agent, which is currently undergoing FDA review, will fit in the treatment of osteoporosis.

"There is a tremendous need for new agents in osteoporosis treatment. We've seen a 50% reduction in treatment, overall, since the bisphosphonates peaked in the mid-2000s," Dr Saag said.

There is a role for romosozumab. Rheumatologists could treat high-risk patients — those with a T score of –3.0 or below and/or a history of multiple fractures — with romosozumab first, and follow that with antiresorptive therapy, as was done in this study, he added.

This study was funded by Amgen. Dr Saag reports receiving research grants from Amgen and Merck, and consulting for Amgen, Merck, and Radius. Dr Rosen has disclosed no relevant financial relationships. Dr Cohen reports receiving research grants from and consulting for Amgen, Boehringer-Ingelheim, Merck, Janssen, Pfizer, and Sandoz.

American College of Rheumatology (ACR) 2017 Annual Meeting: Abstract 318. Presented November 5, 2017.

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