Romosozumab, which is a novel monoclonal anti-sclerostin antibody that simultaneously increases bone formation and reduces bone resorption, has been undergoing multiple phase III clinical trials.1,2 In 2016, the FRAME study showed that 1-year romosozumab reduced the risk of new vertebral fracture by 73% in postmenopausal women with osteoporosis.1 This year, the ARCH study, which was presented in the 2017 American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meeting, further demonstrated that sequential romosozumab and alendronate produced better outcome as compared to alendronate alone.2
The ARCH study recruited 4,093 postmenopausal women, and assigned them to either alendronate or romosozumab for 1 year (both arms received alendronate afterwards). Over a period of 24 months, 48% lower risk of new vertebral fractures (primary endpoint of the study) was observed in patients who received sequential romosuzumab and alendronate, as compared to those who received alendronate only (6.2% vs. 11.9%, p<0.001).2 Similar reduction in the risk of fracture can also be observed in other fracture sites (Table 1). In addition, the sequential regimen showed significant increment in bone mineral density in lumbar spine, total hip, and femoral neck as well.2
Dr. Kenneth Saag, the lead investigator of the ARCH study, explained the underlying rationale for the study design. “The phase 3 active-control study is more of a pragmatic clinical trial. The question the investigators hoped to answer was: would you consider romosozumab out of the gate, or would you think about using alendronate?” He also believed that this phase III, active-comparator study showed that romosozumab and alendronate can “dramatically reduce fracture risk at all sites measured.”3
However, Dr. Saag noted the concern of the cardiovascular safety of romosozumab, as patients who took romosozumab had a higher incidence of serious cardiovascular events (2.5% vs. 1.9%), cardiac ischemic events (0.8% vs. 0.3%), and cerebrovascular events (0.8% vs. 0.3%).2 As the recruited patients showed no specific cardiovascular signals, the cardiovascular events observed were indeed intriguing, and might lead to several questions: “Could this be a real finding? Or could alendronate be cardioprotective?” said Dr. Saag.3
The cardiovascular concern was also raised in an editorial written by Dr. Clifford Rosen from the Tufts University School of Medicine, Boston, as he believed the approval from FDA may be influenced. The initial application for romosozumab, which solely included data from FRAME, was rejected by the US Food and Drug Administration (FDA) in July 2017, since more data from clinical trials were desired.4 Yet, Dr. Rosen was affirmative of the ARCH study, believing that “the bottom line from ARCH is that romosozumab has a stronger effect – increasing bone mass and reducing both spine and clinical fractures – than alendronate.”5
Being asked to predict the position of romosozumab in the treatment of osteoporosis, Dr. Saag concluded that “there is a role for romosozumab, rheumatologists could treat high-risk patients — those with a T score of –3.0 or below and/or a history of multiple fractures — with romosozumab first, and follow that with antiresorptive therapy, as was done in this study [ARCH].”3
1. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532-1543.
2. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377:1417-1427.
3. Romosozumab and Alendronate Curb Fracture in Osteoporosis. Medscape, 2017. (Accessed December 23, 2017, at https://www.medscape.com/viewarticle/888661).
4. FDA Rejects Romosozumab for Osteoporosis, Wants More Data. Medscape. 2017. (Accessed December 23, 2017, at https://www.medscape.com/viewarticle/882966).
5. Rosen JC. Romosozumab – Promising or Practice Changing? N Engl J Med. 2017;377-1479-1480.