Commentary
Osteoporosis-related fragility fractures carry a substantial risk of morbidity and mortality [1]. The goal of osteoporosis treatment is to ameliorate this risk. The current FDA-approved medications for osteoporosis can be divided into anabolic (teriparatide, abaloparatide) and anti-resorptive (bisphosphonate, denosumab, selective estrogen receptor modulators) categories. Sclerostin is a glycoprotein produced by osteocytes that inhibits the Wnt signaling pathway, thereby impeding osteoblast proliferation and activity. Romosozumab is a monoclonal antisclerostin antibody that results in both increased bone formation and decreased bone resorption [1]. By apparently uncoupling bone formation and resorption to increase bone mass, this medication holds promise to become the ideal osteoporosis drug.
Initial studies have shown that 12 months of romosozumab treatment significantly increased BMD at the lumbar spine (+11.3%), as compared to placebo (–0.1%), alendronate (+4.1%), and teriparatide (+7.1%) [2]. The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) was a large (7180 patients) randomized controlled trial that demonstrated that 12 months of romosozumab resulted in a 73% lower risk of vertebral fracture and 36% lower risk of clinical fracture compared to placebo [3]. However, there was no significant reduction in non-vertebral facture [3]. This may be due to the fact that FRAME excluded women at the highest risk for fracture. That is, exclusion criteria included history of hip fracture, any severe vertebral facture, or more than 2 moderate vertebral fractures. The current phase 3 ARCH trial (Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk) attempts to clarify the potential benefit of romosozumab treatment in this very high-risk patient population, compared to a common first-line osteoporosis treatment, alendronate.
Indeed, ARCH demonstrates that sequential therapy with romosozumab followed by alendronate is superior to alendronate alone in improving BMD at all sites and preventing new vertebral, clinical, and non-vertebral fractures in postmenopausal women with osteoporosis and a history of fragility fracture. While ARCH was not designed as a cardiovascular outcomes trial, the higher rate of serious cardiovascular adverse events in the romosozumab group raises concern that romosozumab may have a negative effect on vascular tissue. Sclerostin is expressed in vascular smooth muscle [4] and upregulated at sites of vascular calcification [5]. It is possible that inhibiting sclerostin activity could alter vascular remodeling or increase vascular calcification. However, it is interesting that in the larger FRAME trial, no increase in adverse cardiovascular events was seen in the romosozumab group compared to placebo. This may be due to the fact that the average age of patients in FRAME was lower than ARCH. However, it also raises the hypothesis that alendronate itself may be protective in terms of cardiovascular risk. It has been postulated that bisphosphonates may have cardiovascular protective effects, given animal studies have demonstrated that alendronate downregulates monocyte chemoattractant protein 1 and macrophage inflammatory protein 1 [6]. However no cardioprotective benefit was seen in meta-analysis [7].
ARCH has several strengths, including its design as an international, double-blind, and randomized clinical trial. The primary outcome of cumulative fracture incidence is a hard endpoint and is clinically relevant. The intervention is simple and the results are clearly defined. The statistical assessment yields significant results. However, there are some limitations to the study. The lead author has received research support from Amgen and UCB Pharma, the makers of romosuzumab. Amgen and UCB Pharma designed the trial, and Amgen was responsible for trial oversight and data analyses per a pre-specified statistical analysis plan. An external independent data monitoring committee monitored unblinded safety data. Because there was no placebo-controlled arm, it is difficult to determine whether the unexpected cardiovascular signal was due to romosuzumab itself or a protective effect of alendronate. In addition, the majority of study participants were non-Hispanic from Central or Eastern Europe and Latin America, with only ~2% of patients from North America. As a result, ARCH findings may not be generalizable to other regional or ethnic populations. Furthermore, the majority of the patients were ≥ 75 years of age and were at very high fracture risk. It is unclear if younger patients or those with lower risk of fracture would see the same fracture prevention and BMD gain. In addition, because of the relatively short length of the trial, the durability of the metabolic bone benefit and cardiovascular risk is unknown. While the authors reported the increased anti-romosozumab antibodies in the romosozumab group had no detectable effect on efficacy or safety, given the short duration of the trial, this has not been proven.
Applications for Clinical Practice
The dual anti-resorptive and anabolic effect of romosozumab makes it an attractive and promising new osteoporosis therapy. ARCH suggests that sequential therapy with romosuzumab and alendronate is superior in terms of fracture prevention to alendronate alone in elderly postmenopausal women with osteoporosis and a history of fragility fractures, although longer term studies are needed to define the durability of this effect. While the absolute number of serious adjudicated cardiovascular events was low, the increased incidence in the romosuzumab group will likely prevent the FDA from approving this medication for widespread use at this time. Additional studies are needed to clarify the cause and magnitude of this cardiovascular risk and to determine whether prevention of fracture-associated morbidity and mortality is enough to mitigate it.
—Simona Frunza-Stefan, MD, and Hillary B. Whitlach, MD, University of Maryland School of Medicine, Baltimore, MD