Romosozumab outshines alendronate in high-risk osteoporosis, but CV concerns remain
An initial strategy of 1-year romosozumab followed by alendronate is superior over alendronate alone in reducing new vertebral fractures in postmenopausal women with osteoporosis at high risk for fracture, according to the ARCH* study.
Over 2 years, the risk of developing new vertebral fractures was 48 percent lower with romosozumab-to-alendronate than with alendronate alone (incidence, 6.2 percent vs 11.9 percent, risk ratio, 0.52; p<0.001). [N Engl J Med 2017;377:1417-1427]
“It is worth noting that romosozumab outperformed an effective drug [alendronate],” the researchers stated.
Overall, clinical fractures were less common in the romosozumab-to-alendronate arm than in the alendronate alone arm (cumulative incidence, 13.0 percent vs 9.7 percent), which translates to a 27 percent lower risk of clinical fractures with romosozumab (hazard ratio [HR], 0.73; p<0.001).
Specifically, starting with romosozumab led to a 19 percent lower risk of nonvertebral fractures (cumulative incidence, 8.7 percent vs 10.6 percent, HR, 0.81; p=0.04) and a 38 percent lower risk of hip fractures (cumulative incidence, 2.0 percent vs 3.2 percent, HR, 0.62; p=0.02) compared with alendronate alone.
The multinational, double-blind, phase III trial randomized 4,093 postmenopausal women with osteoporosis who had a fragility fracture in a 1:1 ratio to subcutaneous romosozumab 210 mg monthly or oral alendronate 70 mg weekly for 12 months. Thereafter, all participants received open-label alendronate and were followed up for 2 years on fractures.
“[T]he effect of romosozumab on the risk of fracture was rapid: the risks of new vertebral fracture and clinical fracture were significantly lower with romosozumab than with alendronate at 12 months, findings that imply both a near-term and persistent reduction in fracture risk with the initiation of romosozumab before antiresorptive therapy in patients at high risk for fracture,” said the investigators.
“After the transition to alendronate, the significant difference between treatment groups was maintained,” they added.
However, more adjudicated serious cardiovascular (CV) adverse events occurred with romosozumab vs alendronate during the double-blind phase (2.5 percent vs 1.9 percent, odds ratio [OR], 1.31). The imbalance was driven mainly by greater rates of cardiac ischaemic events (0.8 percent vs 0.3 percent, OR, 2.65) and cerebrovascular events (0.8 percent vs 0.3 percent, OR, 2.27) in the romosozumab vs the alendronate arms.
Such CV signals were not observed in FRAME, a placebo-controlled trial involving “a somewhat younger population with less advanced osteoporosis”, according to the investigators. [N Engl J Med 2016;375:1532-1543] They also noted that the comparison drug used in the current trial, alendronate, has been associated with a reduced CV disease risk. [Osteoporos Int 2013;24:271-277]
“[R]omosozumab has great potential as a short-term anabolic treatment for osteoporosis … [but] the CV signal for romosozumab is particularly troubling,” wrote Dr Clifford Rosen of Tufts University Medical School in Boston, Massachusetts, US, in an accompanying editorial. [N Engl J Med 2017;377:1479-1480]
“[U]ntil the CV and endocrine effects of this antibody are clarified, romosozumab will remain more a part of our expectations than our armamentarium,” he stated.