FRAME: Romosozumab Rapidly Reduces Fracture Risk in Osteoporosis

Pam Harrison

September 19, 2016

ATLANTA — Romosozumab (Amgen/UCB Pharma), an investigational monoclonal antibody that increases bone formation and decreases bone resorption, reduces vertebral fracture rates by 73% compared with placebo at the end of 1 year. There was also a further reduction in vertebral fracture risk in the second year following transition to the antiresorptive drug denosumab (Prolia, Amgen) in the phase 3 randomized trial in postmenopausal women with osteoporosis.

The Fracture Study in Postmenopausal Women With Osteoporosis (FRAME) was presented here at the American Society of Bone and Mineral Research 2016 Annual Meeting by Felicia Cosman, MD, professor of medicine, Columbia University, New York, who was also the lead author of the report simultaneously published online September 18, 2016 in the New England Journal of Medicine.

Dr Cosman said the data are unprecedented.

"Romosozumab has a unique mechanism of action in that it is an anabolic bone-forming drug as well as a mild antiresorptive agent, and those two mechanisms working together provide a very strong benefit to bone strength as manifested by the incredibly fast and robust bone-mineral density [BMD] measurements we saw and really rapid data against fractures," Dr Cosman told Medscape Medical News.

"So I would envision that people who have very low bone density as well as those who've had a prior fracture from osteoporosis wold be really good candidates for treatment with romosozumab, because we showed dramatic changes in a single year of treatment that no other osteoporosis drug has ever shown," she added.

In an accompanying editorial to the published FRAME study, associate New England Journal of Medicine editor Clifford Rosen, MD, and deputy editor Julie Ingelfinger, MD, say this trial represents a "new approach" for osteoporosis therapy — sequential anabolic therapy with two biologic agents.

"The changes in bone-mineral density [seen with romosozumab] are remarkable, and the lower risks of vertebral fracture and clinical fracture with romosozumab are considerable," they point out.

However, they note that romosozumab did not significantly reduce nonvertebral fractures, even though these were lower with the active treatment, something the authors attribute to geographical heterogeneity within the trial.

Also, two instances of osteonecrosis of the jaw and one atypical femoral fracture are "troubling," they observe.

FRAME Study: Rapid Reduction in New Vertebral Fractures

Romosozumab, which is administered subcutaneously once a month, is a novel investigational humanized monoclonal antibody that inhibits sclerosin, an osteocyte-derived inhibitor of osteoblast activity. The drug has the dual effect of promoting bone formation and inhibiting resorption and is awaiting approval in the US.

In the FRAME trial, romosozumab was used for only a year, after which women were transitioned to denosumab, an antiresorptive agent that inhibits osteoclast activation. Given that the romosozumab is such a potent stimulator of bone formation, this would likely be how it would be used in clinical practice, if approved.

FRAME enrolled a total of 7180 postmenopausal women between 55 and 90 years of age and randomized them to either subcutaneous romosozumab 210 mg or placebo once a month for 12 months.

This was followed by an open-label transition to subcutaneous denosumab, given at a dose of 60 mg every 6 months for an additional 12 months.

"Mean age of the patients was 70.9 years, and the mean bone-mineral density T scores were -2.72 at the lumbar spine, -2.47 at the total hip, and -2.75 at the femoral neck," Dr Cosman and colleagues report.

Patients were also instructed to take between 500 to 1000 mg of calcium a day along with between 600 to 800 IU of vitamin D3 and D2.

Some 89% of the group completed the first 12 months of the study during which romosozumab was administered, and almost 84% completed the open-label portion of the study with denosumab to month 24.

At 12 months, the incidence of new vertebral fractures was 0.5% in the group assigned to romosozumab vs 1.8% for placebo (P < .001), Dr Cosman reported.

"In fact, at 6 months, new vertebral fractures were already reduced, and in the later 6 months of the year, there were only two new additional vertebral fractures in the romosozumab group," Dr Cosman observed.

At 12 months, there was also a 36% relative risk reduction in clinical fractures with romosozumab compared with placebo (P = .008).

Major osteoporotic fracture rates were also reduced by about 40% in the monoclonal-antibody arm compared with placebo and approximately half the number of hip fractures occurred in the active-treatment arm compared with controls as well.

The study is the first to evaluate fracture-risk reduction as early as 1 year as a primary end point, Amgen and UCB Pharma note.

Does Romosozumab Also Reduce Nonvertebral Fractures?

Although nonvertebral fractures were numerically reduced with romosozumab (occurring in 1.6% of participants compared with 2.1% in the placebo group), the difference was not significant (P = .10)

By way of explanation, Dr Cosman pointed out that 43% of the entire FRAME cohort came from Latin America, where nonvertebral fracture rates were extremely low. The trial was powered for a 3.5% a priori incidence of nonvertebral fracture in the placebo group, yet this figure was only 2.1% in the trial overall, and a mere 1.2% in Latin America.

"Since this study region [Latin America] provided such a large proportion of subjects in the trial, it drove down the overall nonvertebral fracture rate," she observed.

When the Latin America cohort was excluded from the analysis, romosozumab led to a significant 42% reduction in the risk of nonvertebral fractures over 1 year compared with placebo patients.

She added that no other drug has been shown to reduce the incidence of nonvertebral fractures, which is another "really compelling effect" of this drug.

In their editorial, Drs Rosen and Ingelfinger agree that this "geographical heterogeneity" could be a possible explanation for this observation.

Transition to Denosumab

All the patients made the transition to denosumab in the second-year, open-label phase of the trial, Dr Cosman continued.

Upon transition to denosumab, BMD increased in both groups but to a greater extent among those who transitioned from romosozumab to denosumab, where a 17.6% increase in BMD at the lumbar spine was seen along with an 8.8% increase on average in total hip BMD.

During the second year, there was also a 75% reduction in new vertebral fractures among those who originally received romosozumab compared with patients who originally received placebo (0.6% vs 2.5%, P < .001).

This indicates "a persistent effect of romosozumab into the second year," Dr Cosman observed.

Asked by Medscape Medical News to comment on the study, John Eisman, MBBS, PhD, director, clinical translation and advanced education, and lab head, osteoporosis and translational research, Garvan Institute of Medical Research, Sydney, Australia, said that romosozumab holds "tremendous potential" for reducing long-term fracture risk and that it does indeed act quickly.

"I think the evidence suggests — and the way the FRAME study was designed — is that patients will need to continue on something to retain what they gain, because when you stop treatment with denosumab, the benefit is lost fairly rapidly, and I expect that is what we would see with romosozumab," Dr Eisman said.

"But yes, it's a very good agent, and when it is available, I hope we can use it for people who are at the highest risk for fracture and then follow them up with consolidation therapy to keep what bone they've gained."

Adverse Events: Three Concerning Bone

Regarding side effects seen in the study, Dr Cosman noted, "Overall, during the double-blind safety overview, both groups were well-balanced in terms of all adverse events and serious adverse events."

Injection-site reactions were reported by almost twice as many patients on romosozumab than placebo, but the incidence of these reactions was still low and reactions were largely mild.

But importantly, after 12 months of treatment with romosozumab and one dose of denosumab, one patient developed osteonecrosis of the jaw following a tooth extraction, while another developed the same complication after 12 months of active treatment in the context of ill-fitting dentures.

There was also one instance of atypical femoral fracture some 3.5 months after treatment with romosozumab had been initiated.

However, Dr Cosman told Medscape Medical News that all three of these cases were associated with "extenuating" circumstances and should not be given too much weight.

"When you look at the magnitude of the antiresorptive effect with romosozumab, it really is mild and not what we would expect to see associated with these bony complications, so I'm not worried about them," she said.

"Besides, we are only going to use this drug for 1 year at a time, so I think we should hold these complications as a highly unlikely event and celebrate the opportunity we have with this agent."

In their editorial, Drs Rosen and Ingelfinger say one case of osteonecrosis of the jaw could be attributed to use of denosumab, "but the other two bony complications that were observed in patients with romosozumab were unexpected, and it remains unclear how frequent this adverse event might be with greater use of the drug."

New Approach to Osteoporosis

In their editorial, Drs Rosen and Ingelfinger suggest that the sequential anabolic approach with two biologic agents as used in the FRAME study represents a new method in the treatment of osteoporosis. They note there is a crisis in osteoporosis care in the United States, where too few patients receive any treatment at all, and too many prematurely stop treatment once it has been initiated.

"The long-term treatment of osteoporosis remains challenging, and romosozumab may be one answer. More trials are needed before we can embrace a new approach."

According to Amgen/UCB Pharma, only one in five women who have experienced an osteoporotic fracture are started on treatment for the disease, despite the fact that patients who experience an osteoporotic fracture are twice as likely to suffer a future fracture.

A biologics licensing application for romosozumab, for which the FRAME data form the basis, was submitted to the US Food and Drug Administration in July, they note.

The study was funded by Amgen and UCB Pharma. Dr Cosman has received personal fees or honoraria from Amgen, Eli Lilly, Merck, Actavis, and AgNovos and research grants from Eli Lilly and Merck. Disclosures for the coauthors are listed on the journal website. Dr Ingelfinger reports that she is employed by the New England Journal of Medicine as deputy editor. Dr Rosen reports that he is an associate editor at the New England Journal of Medicine.

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N Engl J Med . Published online September 18, 2016. Article, Editorial

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