Romosozumab Reduces Risk for New Vertebral Fractures in Postmenopausal Women with Osteoporosis

Lead author Felicia Cosman, MD and Susan V. Bukata, MD Comment

The investigational agent romosozumab significantly reduced the incidence of new vertebral fractures in postmenopausal women with osteoporosis through 12 and 24 months, according to findings from a multicenter randomized controlled trial published in the October 20 issue of The New England Journal of Medicine. Significant increases in bone mineral density in the spine also were linked to romosozumab use.
Older couple looking on a laptop The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) study involved 7,180 postmenopausal women with osteoporosis who were randomized to a monthly subcutaneous (SC) injection with either 210-mg romosozumab or placebo for the 12 months. After the placebo-controlled study period, patients entered the open-label phase where all patients received 60 mg denosumab SC every six months for 12 months, while remaining blinded to initial treatment.

Decreased Incidence of Vertebral Fractures Found with Romosozumab
As shown in the Table, romosozumab was associated with a 73% and 75% reduction in the relative risk of a new vertebral fracture at 12 and 24 months, respectively. Romosozumab also was linked to a 36% reduction in relative risk of a new clinical fracture at 12 months.

“More than 85% of these new clinical fractures were indeed nonvertebral fractures,” explained said lead author Felicia Cosman, MD, Medical Director of the Clinical Research Center at Helen Hayes Hospital in West Haverstraw, NY. “There was a trend toward reduction in incidence of nonvertebral fractures, but P values just missed statistical significance,” said Dr. Cosman, who also is Professor of Clinical Medicine at Columbia University College of Physicians and Surgeons in New York, NY.

Table. Incidence of New Vertebral Fractures and Clinical FracturesBeneficial Impact on Bone Mineral Density Found
The romosozumab group showed significant increases over the placebo group in bone mineral density at the lumbar spine (+13.3%), total hip (+6.9%), and femoral neck (+5.9%) at 12 months (P<0.001 for all comparisons). These increases continued after transition to denosumab through 24 months P<0.001 for all comparisons.

Unique Mechanism of Action
“Romosozumab is a targeted monoclonal antibody that binds and inhibits sclerostin,” Dr. Cosman told SpineUniverse. “Sclerostin inhibition produces a dual effect on bone—it both stimulates bone formation and inhibits bone resorption. While all other osteoporosis medications are either anabolic (bone building) or antiresorptive (inhibit bone breakdown), romosozumab is both anabolic and antiresorptive.”

Clinical Significance
“The bone density gains with romosozumab are bigger in both the spine and hip than that seen with any other osteoporosis agent, and the reductions in clinical fractures seen within 1 year reflect the rapid bone strengthening effect of romosozumab,” Dr. Cosman said. “Vertebral fractures are often the first osteoporotic fracture and are associated with a substantial increase in the risk of subsequent fractures in the spine and the rest of the skeleton.”

Adverse Events
The incidence of adverse events and serious adverse events were similar among the two groups. In addition, the rate of osteoarthritis, hyperostosis, cancer, hypersensitivity, and serious cardiovascular events were reportedly balanced between the two groups.

Arthralgia and nasopharyngitis were the most common adverse reactions (≥10 percent) reported in both study groups. Injection site reactions were reported in 5.2% and 2.9% of the romosozumab and placebo groups, respectively.

In the romosozumab group, two patients developed osteonecrosis of the jaw, one patient had atypical femoral fracture after three months of romosozumab treatment, and seven patients had serious adverse events that were potentially related to hypersensitivity.

The cases of osteonecrosis of the jaw and atypical femur fracture demonstrate that we do not fully understand these entities,” commented Susan V. Bukata, MD, Vice Chair and Associate Professor Orthopaedics at UCLA School of Medicine and a member of the National Osteoporosis Foundation Scientific Board. “Previously, it was thought that anabolic agents may be helpful in setting of both osteonecrosis of the jaw and atypical femur fracture; and further long-term analysis of the safety data may be helpful.” 

In addition, Dr. Bukata noted that both of these adverse events have been demonstrated in patients treated with denosumab monotherapy and, thus, the findings may reflect the rapid crossover to denosumab in this trial. Furthermore, the patients with femoral fractures noted pain in the fracture area at baseline, suggesting that further workup for patients who are complaining of hip or thigh pain prior to treatment is warranted as the symptoms may represent an occult atypical femur fracture, Dr. Bukata said.

Study Strengths and Weaknesses
“Treatment and placebo groups were well-balanced in terms risk factors,” Dr. Bukata commented. Weaknesses of the study include a short duration of treatment with romosozumab and low rates of nonvertebral fractures in both the treatment and placebo groups as well as the placebo group, which is not surprising given the short timeframe, Dr. Bukata said.  

“Perhaps a longer study on the treatment medication would have shown a more significant difference in nonvertebral fracture rates,” Dr. Bukata told SpineUniverse.

“In addition, while the safety profile is excellent over this timeframe, this is a relatively short exposure to romosozumab. Long-term safety data will need to be followed particularly if repeat dosing is warranted,” Dr. Bukata said.

“Overall, the data suggest that romosozumab is another anabolic agent that may soon be available to help patients actually gain bone mass and rebuild damage from osteoporosis,” Dr. Bukata concluded. “The monthly dosing interval was well-tolerated by patients and convenient, which will hopefully make this medication more desirable for patients who need to sustain this regimen over that one year of treatment to rebuild bone mass.”

The study was funded by Amgen and UCB Pharma. Dr. Bukata has served as a consultant for Amgen, Eli Lilly, and Merck and is on the speakers’ bureau for Eli Lilly. She participated in a previous phase 2 trial of romosozumab for tibia fractures.

Updated on: 10/26/17
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