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.