The investigational humanized monoclonal antibody romosozumab (Amgen and UCB Pharma) increases bone mineral density (BMD) and bone formation and reduces bone resorption in postmenopausal women with low bone mineral density, a phase 2, multicenter, randomized, placebo-controlled study suggests.
The findings were published online January 1, 2014, in the New England Journal of Medicine by Michael R. McClung, MD, from the Oregon Osteoporosis Center, Portland, and colleagues.
“Romosozumab, administered subcutaneously at intervals of 1 month or 3 months over a period of 12 months, was associated with prompt, transitory increases in markers of bone formation; moderate, sustained decreases in markers of bone resorption; and rapid, large increases in bone mineral density in the spine and hip regions,” Dr. McClung and colleagues write.
Romosozumab increases bone formation by binding to sclerostin, an osteocyte-derived inhibitor of osteoblast activity. Sclerostin inhibition is an attractive drug mechanism of action because the gene that encodes sclerostin is expressed only in skeletal tissue and, therefore, off-target effects would be limited, the authors explain.
Indeed, in an editorial accompanying the report, Carolyn B. Becker, MD, an endocrinologist at Brigham and Women’s Hospital, Boston, Massachusetts, calls the new study results “a potential breakthrough in osteoporosis therapeutics,” as current antiresorptive drugs do not restore bone architecture, and the anabolic agent teriparatide is limited by inconvenient dosing, high cost, and a black box warning about osteosarcoma.
In contrast, she cautions that questions remain about romosozumab, including whether its effect on BMD will translate into antifracture efficacy and whether it will be safe for long-term use. In addition, Dr. Becker suggests, there may be a way to replicate the bone-remodeling effects of romosozumab by combining currently available osteoporosis therapies.
The 12-month study randomly assigned a total of 419 postmenopausal women aged 55 to 85 years from 28 centers worldwide, including 367 who received 1 of 5 dosing regimens of subcutaneous romosozumab injections (70, 140, or 210 mg once a month or 140 or 210 mg every 3 months) or to 1 of 2 open-label comparators (70 mg oral alendronate weekly or 20 μg daily subcutaneous teriparatide). The other 52 participants received placebo injections either monthly or every 3 weeks.
The women all had low BMD that was not severe enough to be diagnosed as osteoporosis (T score of −2.0 or less at the lumbar spine, total hip, or femoral neck and −3.5 or more at every one of the 3 sites).
The primary endpoint was the percentage change from baseline in BMD at the lumbar spine at month 12. Of the total of 383 women who completed the 12-month visit, those receiving romosozumab had significant increases in BMD at the lumbar spine compared with placebo, regardless of dose frequency and dose level (P < .001).
Increases in BMD from baseline at the lumbar spine at month 12 were significant at all dosing levels, ranging from 5.4% with 140 mg every 3 months and 70 mg monthly to 11.3% for 210 mg monthly. The placebo group saw no increase in BMD, whereas BMD increased by 4.1% in the alendronate group and 7.1% with teriparatide.
There were similarly significant increases in BMD at the total hip and femoral neck, Dr. McClung and colleagues report.
The increases in BMD seen at 12 months with the 210-mg monthly romosozumab dose (11.3% in the lumber spine, 4.1% in total hip, and 3.7% in femoral neck) were all significantly greater than those seen with alendronate and teriparatide (P < .001) for all 3 comparisons.
“The results were impressive,” Dr. Becker comments.
In contrast, no differences in BMD at 12 months were seen among the groups at the distal third of the radius, the authors note.
Increases in bone formation markers occurred at 1 week after the initial dose in all romosozumab groups, peaked at month 1, and then returned to baseline levels or fell below between months 2 and 9, despite continued administration of the drug.
In all romosozumab groups, the level of the bone-resorption marker serum β-CTX decreased initially from baseline, primarily in the first week. In the patients receiving monthly 210-mg romosozumab doses, β-CTX remained below baseline at month 12.
“The effects of romosozumab on bone turnover reflect a rapid, marked, and transitory increase in bone formation and a moderate but more sustained decrease in bone resorption,” Dr. McClung and colleagues write, adding that “[t]he reason for the transitory nature of the effect on bone formation is unclear.”
Indeed, Dr. Becker says this finding is unexpected and should be explored further. “If the changes in BMD for a presumed anabolic agent were predictable, the changes in bone-turnover markers were not.”
Reductions in serum calcium of 1.30% to 2.68% from baseline, in a dose–response pattern, were seen at month 1 but returned to baseline thereafter.
Serious event rates were 7% for the pooled romosozumab group and 10% among those receiving the 210-mg monthly dose. These rates did not differ from the rates seen among the patients taking placebo (14%), alendronate (8%), or teriparatide (9%). None were considered treatment-related.
Mild injection site reactions were more common with romosozumab than placebo, but there was no dose–response relationship, Dr. McClung and colleagues say.
Binding antibodies were seen in 20% of the romosozumab group, and antibodies with in vitro neutralizing activity in 3%. In contrast, no binding antibodies were seen in any of the other treatment groups. However, the development of antibodies appeared to have no effect on adverse events, pharmacokinetics, or pharmacodynamics, the investigators note.
According to the editorial, romosozumab’s “pattern of brief anabolic stimulation coupled with chronic suppression of bone resorption…is unprecedented among current therapies for osteoporosis.”
However, Dr. Becker also points out that small studies suggest it may be possible to reproduce the same effect on bone remodeling by combining teriparatide, which increases bone formation markers but also stimulates bone resorption markers with antiresorptive agents such as zoledronic acid or denosumab.
Remaining questions about romosozumab may be forthcoming from a phase 3 clinical trial of romosozumab currently underway in postmenopausal women with osteoporosis, Dr. Becker notes.
The study was supported by Amgen and UCB Pharma. Dr. McClung reports receiving research grants from Amgen and Regeneron, and serving on speakers bureaus for Amgen and Vivus. Dr. Becker has no relevant disclosures.
N Engl J Med. Published online January 1, 2014.