FRAME: Romosozumab reduces new vertebral fractures in postmenopausal women with osteoporosis

In postmenopausal women with osteoporosis, the monoclonal antibody romosozumab was associated with a lower risk for new vertebral fractures vs. placebo at both 12 and 24 months, according to study data presented at the American Society for Bone and Mineral Research annual meeting and simultaneously published online in The New England Journal of Medicine.

In a randomized, double blind, placebo-controlled, parallel-group trial, researchers found that patients assigned romosozumab (Amgen/UCB Pharma) also showed improvements in bone mass, with sustained benefits upon the transition to denosumab (Prolia, Amgen) after 12 months.

Romosozumab works by binding and inhibiting the activity of the protein sclerostin and, as a result, has a dual effect on bone, both increasing bone formation and decreasing bone breakdown, according to study background.

“Because of its dual effect to both stimulate bone formation and inhibit bone resorption, romosozumab improves bone density and bone strength quickly and markedly, resulting in rapid reductions in vertebral and clinical fracture occurrence across the skeleton,” Felicia Cosman, MD, medical director of the Clinical Research Center at Helen Hayes Hospital and professor of medicine at Columbia University College of Physician and Surgeons in New York, told Endocrine Today.

Study design

Cosman and colleagues analyzed data from 7,180 postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck participating in the Fracture Study in Postmenopausal Women with Osteoporosis (FRAME; mean age, 71 years; mean BMD T-scores, –2.72 at lumbar spine; –2.47 at total hip and –2.75 at femoral neck). Within the cohort, 18.3% of patients had a prevalent vertebral fracture; 21.7% had a previous nonvertebral fracture.

Researchers randomly assigned patients to once-monthly subcutaneous injections of 210 mg romosozumab or placebo for 12 months. Patients in each group then received open-label 60 mg denosumab every 6 months for 1 year; patients and investigators remained unaware of the initial treatment assignment. Primary endpoints were the cumulative incidences of new vertebral fractures at 12 and 24 months; secondary endpoints included a composite of nonvertebral and symptomatic vertebral and nonvertebral fractures.

At 12 months, 16 patients (0.5%) sustained new vertebral fractures in the romosozumab group; 59 patients (1.8%) sustained new vertebral fractures in the placebo group (RR = 0.27; 95% CI, 0.16-0.47). Clinical fractures occurred in 58 patients (1.6%) in the romosozumab group vs. 90 patients (2.5%) in the placebo group (HR = 0.64; 95% CI, 0.46-0.89). Nonvertebral fractures constituted the majority of clinical fractures, according to researchers; 56 patients (1.6%) in the romosozumab group sustained a nonvertebral fracture at 12 months vs. 75 patients (2.1%) in the placebo group (HR = 0.75; 95% CI, 0.53-1.05).

At 24 months, the cumulative incidence of new vertebral fracture was lower in the group originally assigned romosozumab (0.6%) vs. the original placebo group (2.5%). In the second year, five patients in the romosozumab group sustained a new vertebral fracture vs. 25 in the original placebo group. Researchers observed no significant between-group differences in risk for nonvertebral fracture at 24 months.

Researchers observed one atypical femoral fracture and two cases of osteonecrosis of the jaw in the romosozumab group; other adverse events were similar between groups.

In a substudy of 126 participants, romosozumab increased bone mineral density vs. placebo, with gains of 9.7% and 4.7% from baseline by 6 months at the lumbar spine and total hip, respectively, and gains of 13.3% and 6.8% at 12 months (P < .001 for all).

BMD continued to increase in the romosozumab group after transitioning to denosumab, reaching a 17.6% and 8.8% increase from baseline at the lumbar spine and total hip, respectively, at 24 months vs. placebo.

Future of osteoporosis treatment

The FRAME results follow mixed news for two other osteoporosis therapies. In the ACTIVE trial, researchers found that postmenopausal women assigned once-daily abaloparatide (Radius Health) injection experienced a lower rate of vertebral and nonvertebral fractures during 18 months vs. those assigned teriparatide (Forteo, Eli Lilly) or a placebo. However, researchers discontinued development of the cathepsin K inhibitor odanacatib (Merck) for the treatment of osteoporosis. Drug developer Merck previously reported that there was an imbalance in adjudicated stroke events during the phase 3 fracture outcomes trial in postmenopausal women; discontinuation comes after an analysis of major cardiovascular events confirmed an increased risk for stroke.

“The decision to discontinue the development of odanacatib was a tremendous disappointment for all of us and will have far reaching detrimental consequences for patients, physicians and scientists, in addition to our friends and colleagues at Merck,” Cosman said. “We still have so much work to do to help physicians and patients understand how to balance benefits and risks of medication, as well as appreciate the consequences of not treating high-risk patients.”

Clinicians and patients should put rare adverse events associated with osteoporosis medications in context, Cosman said, paying more attention to the disability, deformity, loss of independence and mortality associated with osteoporosis-related fractures.

“My hope is that the excitement around two new incredibly effective and unique agents for osteoporosis will reinvigorate the interest in this disease,” Cosman said. “Specifically, I think we will be using more anabolic therapy in the future, and limiting antiresorptive therapy to shorter courses with, ultimately, better outcomes.

It is likely, Cosman said, that an individual who receives one anabolic agent would be eligible to receive a bone-building agent with a distinct mechanism of action at a later time.

“Rotating therapies across a patient’s life span, rather than using one treatment indefinitely, is likely to take greatest advantage of benefits and avoid risks,” Cosman said. – by Regina Schaffer

Reference:

Cosman F, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1607948. Presented at: ASBMR 2016; Sept. 16-19, 2016; Atlanta.

Disclosure: The study was supported by Amgen and UCB Pharma. Cosman reports financial ties with Amgen, Eli Lilly, Merck, Radius and Tarsa.