Discussion
The results suggest that disproportionality for both cardiac events and cerebrovascular events was shown in only romosozumab users, and romosozumab may be associated with the risk of cardiac and cerebrovascular events. This result supports previous reports that cardiovascular events are more frequent with romosozumab.4,10 In fact, the association between use of romosozumab and cardiovascular events may be considered from the mechanism of action of romosozumab. Sclerostin, the site of action of romosozumab, is expressed not only in osteocytes but also in vascular smooth muscle. Therefore, romosozumab specifically binds to sclerostin and inhibits its signalling, and is pointed out to promote vascular calcification.11
The results of our study also suggest that comorbidity of hypertension or diabetes may increase cardiac and cerebrovascular events in romosozumab users. These conditions are well-known cardiovascular risk factors, and may further increase the risk of cardiovascular events in romosozumab users.12 The frequency of cerebrovascular events in romosozumab users was increased only in the presence of hypertension, possibly because the association of cerebrovascular events with hypertension is stronger than that with diabetes.13 Blood sclerostin levels are known to be increased in patients with hypertension or diabetes.14,15 Therefore, further research on sclerostin may be key to understanding the association between romosozumab and comorbidity.
Disproportionality for cardiac events was also observed in teriparatide users. It has been reported that teriparatide can cause a transient increase in heart rate but that the risk of major cardiac events is similar to that with placebo.16 However, teriparatide is widely used in patients with moderate to severe osteoporosis,17 who are already at higher risk of cardiac events.18 This might explain why the risk of cardiac events is higher in teriparatide users than in users of other osteoporosis drugs.
This study has four notable limitations. First, romosozumab was launched in March 2019 and its association with serious cardiovascular events was reported in September 2019.19 We investigated this study until May 2021 and collected romosozumab reports for three years. Because there is a correlation between awareness and number of reports,20 this report may improve education about cardiovascular events and increase reports of cardiovascular events with romosozumab. Second, romosozumab and teriparatide are used in patients with moderate to severe osteoporosis, who are already at higher risk of cardiac events,17 so the disproportionality in cardiac events may have been influenced by patient background factors. Third, although some confounding factors, including cardiovascular disease, hypertension and diabetes are adjusted for as much as possible in the JADER database, those related to cardiovascular events, such as abnormal cholesterol levels and smoking, cannot be adjusted for because of the limited search capability of JADER. Finally, we could not assess concomitant medications or the timing of events because of limitations in the dataset and missing data.
This study suggests that romosozumab may be associated with the risk of cardiac and cerebrovascular events, and comorbidities such as hypertension and diabetes may increase the risk of cardiovascular events in romosozumab users. Further study may be needed to clarify the association between the use of romosozumab and cardiovascular events.