What is the risk of cardiovascular events in osteoporotic patients treated with romosozumab?

Sclerostin is a protein produced in osteocytes. Its production is influenced by skeletal loading and by parathyroid hormone. It is released from the cell processes of osteocytes onto the bone surface where it acts to inhibit Wnt signaling in osteoblasts, thus reducing bone formation. The Wnt pathway also stimulates secretion of osteoprotegerin from osteoblasts, reducing osteoclast formation and bone resorption [1]. As a result, blocking sclerostin action with a monoclonal antibody, such as romosozumab, results in stimulation of bone formation and inhibition of bone resorption. Romosozumab produces the largest increases in bone density of currently available treatments [2]. Its anti-fracture efficacy has been established in two large phase 3 trials. In FRAME, 7180 participants were randomized to placebo or romosozumab for 1 year, followed by denosumab alone in both groups for a further year [3]. The ARCH study randomized 4093 women to monthly romosozumab or weekly alendronate (70 mg) for 12 months, followed by openlabel alendronate alone in both groups for up to 3 more years [4]. Romosozumab was found to be superior to each comparator in terms of fracture prevention. While romosozumab was well tolerated in these studies, there was a between-groups difference in cardiovascular event rates in the first year of ARCH, where romosozumab was directly compared with alendronate. Such a difference was not seen in FRAME, where romosozumab was compared with placebo (Table 1). In ARCH, serious cardiovascular adverse events (cardiac ischemia, heart failure, cerebrovascular events) occurred in 2.5% of the romosozumab group and in 1.9% of those randomized to alendronate (hazard ratio [HR] 1.32, 95% confidence interval 0.87 to 2.01). When the narrower category of major adverse cardiovascular events (MACE) was examined (by removing non-coronary vascular events and heart failure) the between-groups difference became significant (HR 1.87 [1.11, 3.17], P = 0.02) [5]. By comparison, in year 1 of the much larger FRAME study, cardiovascular event rates were virtually identical in the romosozumab and placebo groups (Table 1). Cardiovascular deaths showed similar discrepancies between the two studies: 17 vs 12 in ARCH, 17 vs 15 in FRAME. Cardiovascular safety with romosozumab has also been reported in two other small studies, one of 67 Korean women in which no events were reported [6]. In a second study of 245 men, adjudicated serious cardiovascular adverse events occurred in 4.9% of the romosozumab group and 2.5% of those randomized to placebo (statistical comparisons not provided) [7]. Cummings and McCulloch have provided a detailed analysis of the cardiovascular event data from ARCH [5]. They point out that there were no MACE events in the alendronate group in the first three months of the study, and that event rates remained low in this group out to 18 months (Figure 1). While published data are inconsistent regarding possible benefits of bisphosphonates on cardiovascular disease, there is no precedent for suggesting such an abrupt substantial reduction in cardiovascular events from the use of these drugs. In contrast, MACE rates in those initially randomized to romosozumab were consistent over three years of follow-up, with no abrupt change following the withdrawal of romosozumab and introduction of alendronate at 12 months. Therefore, Cummings and McCulloch conclude that the low event rates in the alendronate group are likely a chance finding, and that the consistent MACE incidence over 3 years in the romosozumab-alendronate group suggests that neither drug impacted on cardiac health. However, if analysis is restricted to cardiac ischemic events, there is a flattening of the event rate following the transition of the romosozumab group to alendronate, so some uncertainty remains. The different cardiovascular findings in ARCH and FRAME might be contributed to by differences in the study populations. Baseline cardiovascular risk was higher in the ARCH study than in FRAME, as a result of greater age (74 vs 71 years) and greater prevalence of cardiovascular disease (73 vs 65%). These differences are reflected in the higher cardiovascular event rate of the romosozumab group in ARCH compared with the romosozumab group in FRAME (Figure 1). Despite this, the MACE incidence in the alendronate group of ARCH was virtually identical to that in both groups in FRAME. This suggests that the ARCH alendronate group is the one behaving unexpectedly, either by chance or because bisphosphonates are cardioprotective. While event rates are lower in FRAME, its larger size resulted in comparable event numbers, so FRAME is not underpowered to detect an adverse cardiovascular effect if it were present. Miller et al have re-analyzed these two studies with respect to baseline renal function [8]. In FRAME, the placebo and romosozumab groups have the same cardiovascular event