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\begin{document}

\title{Association between use of romosozumab and cardiovascular events:
analysis of the Japanese Adverse Event Report database}



\author[1]{Kazumasa Kotake}%
\author[2]{Satoru Mitsuboshi}%
\author[1]{Yuki Omori}%
\author[1]{Yukio Kawakami}%
\author[1]{Yasuhiro Kawakami}%
\affil[1]{Okayama Saiseikai General Hospital}%
\affil[2]{Kaetsu Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
There is concern about an increased risk of cardiovascular events in
romosozumab users. This study evaluated the association between use of
romosozumab and cardiovascular events using the Japanese Adverse Drug
Event Report database. In total, 868 romosozumab users were identified.
Disproportionality of cardiac events (reporting odds ratio {[}ROR{]}:
11.5, 95\% confidence interval {[}CI{]}: 8.58--15.2; P \textless{} 0.01)
and cerebrovascular events (ROR: 7.03, 95\% CI: 5.46--8.93; P
\textless{} 0.01) was observed. Cardiac events were significantly
increased in patients with cardiac disease (odds ratio {[}OR{]}: 2.74,
95\% CI: 1.37--5.49; P \textless{} 0.01), hypertension (OR: 1.97, 95\%
CI: 1.07--3.63; P = 0.03), and diabetes (OR: 2.36, 95\% CI: 1.16--4.80;
P = 0.02). Similar results were found regarding the risk factors for
cerebrovascular events. This study suggests that comorbidities such as
hypertension and diabetes may increase the risk of cardiovascular events
in romosozumab users.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Osteoporosis is a public health problem associated with risk fractures,
and this risk has been increasing with
aging.\textsuperscript{1}Approximately 50\% of women and 20\% of men
over the age of 50 years sustain an osteoporotic fracture, which can
lead to long-term pain and disability,\textsuperscript{2} and even to
death.\textsuperscript{1}Hence, drug therapy for osteoporosis is
important to improve quality of life and prognosis.

Romosozumab is approved for use in patients with moderate to severe
osteoporosis. This drug has the dual effect to stimulate bone formation
and inhibit bone resorption by inhibiting sclerostin, an osteocyte
protein.\textsuperscript{3} Because of its dual effect, the risk of
clinical fracture has been found to be 27\% lower in patients on
romosozumab than in those on oral
alendronate.\textsuperscript{4}However, romosozumab may increase the
risk of cardiovascular events. A randomized controlled trial
demonstrated that serious cardiovascular events occurred more frequently
in romosozumab users (2.5\%) than in alendronate users
(1.9\%).\textsuperscript{4} However, bisphosphonates can reduce arterial
wall calcification,\textsuperscript{5} and have been associated with
decreased risk of cardiovascular events compared with
placebo.\textsuperscript{6} Therefore, it is unclear whether romosozumab
itself increase the risk of cardiovascular events. Identification of
risk factors for cardiovascular events may be useful to avoid adverse
events with romosozumab and provide appropriate osteoporosis treatments.
Herein, we evaluated the association between use of romosozumab and
cardiovascular events using the Japanese Adverse Drug Event Report
(JADER) database.

\textbf{Methods}

\emph{Data source}

The JADER database is a spontaneous reporting system for drug-related
adverse events in Japan and is managed by the Pharmaceuticals and
Medical Devices Agency, which is the Japanese regulatory authority. This
reporting system enables detection of infrequent drug-related adverse
events and includes four categories: ``DEMO'' for patient demographic
information, ``DRUG'' for drug information, ``REAC'' for adverse events,
and ``HIST'' for primary disease. DRUG includes three categories of
adverse events: ``suspected drug,'' ``concomitant drug,'' and
``interacting drug.''

\emph{Data collection}

Institutional review board approval was not required for this
observational study using anonymized patient data in the JADER database,
which is freely available to the public. Data recorded from April 2004
to May 2021 were downloaded from the Pharmaceuticals and Medical Devices
Agency website (\emph{http://www.pmda.go.jp/}) on October 3, 2021. Two
authors (K.K. and S.M.) independently collected and collated the data.

\emph{Definitions}

Romosozumab, bisphosphonates, teriparatide, and denosumab, which widely
used to treat osteoporosis, were investigated regardless of whether the
data reporter suspected possible adverse events. Bisphosphonates were
defined as alendronate, etidronate, ibandronate, minodronate, and
risedronate: only oral bisphosphonate users were included based on
earlier studies.\textsuperscript{4,6} The patient selection process is
shown in Fig 1.

Cardiac and cerebrovascular events were evaluated. Cardiac events were
defined by the Preferred Terms ``myocardial infraction,'' and/or
``angina pectoris,'' and cerebrovascular events by the Preferred Term
``cerebral infarction,'' in REAC. Data on sex, age, and presence of
cardiac disease, cerebrovascular disease, hypertension, and diabetes
were collected from DEMO. Cardiac disease was defined as identified
comorbidities, including the reported Preferred Terms ''heart failure,''
and/or ''angina pectoris,'' and/or ''atrial fibrillation,'' in HIST.
These comorbidities have been reported to be associated with development
of cardiac disease.\textsuperscript{7-9} Cerebrovascular disease was
defined as identified comorbidities, including the reported Preferred
Terms ``cerebral infarction,'' in HIST. Hypertension and diabetes were
defined as identified comorbidities, including ''hypertension'' and/or
''diabetes,'' in HIST respectively. Duplicate reports from patients with
non-oral bisphosphonate users and concomitant use of osteoporosis drugs
and were excluded.

\emph{Statistical analysis}

The frequency of cardiovascular events according to type of osteoporosis
drug was compared using Fisher's exact test. The reporting odds ratio
(ROR), which can identify drug-associated adverse events, 95\%
confidence interval (CI), and P-values were calculated. Multivariate
logistic analysis was then used to identify cardiac events and
cerebrovascular events in romosozumab users. Sex, age [?]80 years, and
presence of cardiac disease, cerebrovascular disease, hypertension, and
diabetes were included in the analysis. Modelling was based on a
complete-case analysis. Odds ratio (OR), 95\% CI, and P-values were
calculated. All analyses were performed using R version 4.1.2 (R
Foundation for Statistical Computing, Vienna, Austria). A P-value
\textless{} 0.05 was considered statistically significant.

\textbf{Results}

We identified 705,924 reports, of which 702,072 were applicable
excluding non-oral bisphosphonate users and concomitant use of other
osteoporosis drugs. As shown in Table 1, disproportionality for cardiac
events was observed in romosozumab users (ROR: 11.5, 95\% CI:
8.58--15.2; P \textless{} 0.01) and teriparatide users (ROR: 1.82, 95\%
CI: 1.22--2.63; P \textless{} 0.01). Disproportionality for
cerebrovascular events was observed in only romosozumab users (ROR:
7.03, 95\% CI: 5.46--8.93; P \textless{} 0.01).

Table 2 shows that the risk of cardiac events was significantly
increased in the presence of cardiac disease (OR: 2.74, 95\% CI:
1.37--5.49; P \textless{} 0.01), hypertension (OR: 1.97, 95\% CI:
1.07--3.63; P = 0.03), and diabetes (OR: 2.36, 95\% CI: 1.16--4.80; P =
0.02). The risk of cerebrovascular events was significantly increased in
the presence of cerebrovascular disease (OR: 4.76, 95\% CI: 1.97--11.5;
P \textless{} 0.01), and hypertension (OR: 2.53, 95\% CI: 1.49--4.31; P
\textless{} 0.01).

\textbf{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{13} Blood sclerostin levels are known to be
increased in patients with hypertension or
diabetes.\textsuperscript{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.\textsuperscript{16} However, teriparatide
is widely used in patients with moderate to severe
osteoporosis,\textsuperscript{17} who are already at higher risk of
cardiac events.\textsuperscript{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.\textsuperscript{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,\textsuperscript{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,\textsuperscript{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.

\textbf{Conflicts of Interest}

The authors have no conflicts of interest to declare.

\textbf{Funding}

No funding was received for this research.

\textbf{Data Availability Statement}

Data supporting the findings of this study are available from the
corresponding author upon reasonable request (kottanketty@gmail.com).

\textbf{Reference}

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15. Chang YC, Hsu BG, Liou HH, Lee CJ, Wang JH. Serum levels of
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2006;296(9):1086-1093. doi:10.1001/jama.296.9.1086

\textbf{Table 1 Proportions of cardiovascular events in patients using
osteoporosis drugs}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Onset of cardiac events / Total, n (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Reporting odds ratio (95\% confidence interval)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P-value*\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-use of romosozumab\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4,097 / 701,204 (0.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11.5 (8.58--15.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Use of romosozumab\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
55 / 868 (6.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-use of oral bisphosphonate\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4,064 / 685,957 (0.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.94 (0.76--1.16)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.64\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Use of oral bisphosphonate\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
90 / 16,115 (0.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-use of teriparatide\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4,125 / 699,359 (0.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.82 (1.22--2.63)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Use of teriparatide\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
29 / 2,713 (1.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-use of denosumab\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4,140 / 697,883 (0.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.56 (0.31--0.94)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.03\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Use of denosumab\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 / 4,189 (0.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Onset of cerebrovascular events / Total, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Reporting odds ratio (95\% confidence interval)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
P-value*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-use of romosozumab\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9,176 / 701,204 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7.03 (5.46--8.93)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Use of romosozumab\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
74 / 868 (8.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-use of oral bisphosphonate\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9,130 / 685,957 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.56 (0.46--0.67)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Use of oral bisphosphonate\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
120 / 16,115 (0.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-use of teriparatide\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9,217 / 699,359 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.92 (0.63--1.30)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.74\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Use of teriparatide\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
33 / 2,713 (1.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-use of denosumab\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9,233 / 697,883 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.30 (0.18--0.49)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Use of denosumab\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17 / 4,189 (0.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* Fisher's exact test.

A P-value \textless{} 0.05 was considered statistically significant.

\textbf{Table 2 Multivariate logistic analysis of potential risk factors
for cardiovascular events in romosozumab users}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Cardiac events / Total, n (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Odds Ratio (95\% confidence interval)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Odds Ratio (95\% confidence interval)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
P-value*\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Crude\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Adjusted\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Male sex\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11/128 (8.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Female sex\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
44/705 (6.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.59 (0.32--1.09)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.72 (0.38--1.38)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.33\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Not reported sex\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0/35 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
NA\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age \textless{} 80 years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24/328 (7.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age [?] 80 years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26/426 (6.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.79 (0.52--1.19)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.79 (0.49--1.27)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.33\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Not reported age\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5/114 (4.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.78 (0.44--1.34)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.67 (0.38--1.20)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.18\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Without cardiac disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
41/786 (5.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
With cardiac disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14/82 (17)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3.74 (1.94--7.21)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.74 (1.37--5.49)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Without cerebrovascular disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
52/842 (6.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
With cerebrovascular disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3/26 (12)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.98 (0.58--6.82)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.05 (0.28--3.96)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.95\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Without hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29/650 (4.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
With hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26/218 (12)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.90 (1.67--5.04)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.97 (1.07--3.63)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.03\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Without diabetes\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40/784 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
With diabetes\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15/84 (18)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4.04 (2.13--7.69)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.36 (1.16--4.80)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.02\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cerebrovascular events / Total, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Odds Ratio (95\% confidence interval)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Odds Ratio (95\% confidence interval)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
P-value*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Crude\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Adjusted\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Male sex\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7/128 (5.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Female sex\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
64/705 (9.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.41 (0.78--2.54)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.64 (0.86--3.14)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.13\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Not reported sex\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3/35 (8.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.29 (0.88--1.90)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.27 (0.86--1.87)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.70\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age \textless{} 80 years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25/328 (7.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age [?] 80 years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
45/426 (11)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.91 (0.64--1.31)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.90 (0.61--1.33)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.59\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Not reported age\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4/114 (3.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.21 (0.73--2.00)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.07 (0.63--1.80)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.80\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Without cardiac disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
63/786 (8.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
With cardiac disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11/82 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.78 (0.90--3.53)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.51 (0.72--3.18)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.27\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Without cerebrovascular disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
65/842 (7.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
With cerebrovascular disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9/26 (35)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6.33 (2.71--14.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4.76 (1.97--11.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Without hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
41/650 (6.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
With hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33/218 (15)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.65 (1.63--4.31)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.53 (1.49--4.31)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Without diabetes\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
67/784 (8.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 {[}Reference{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
With diabetes\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7/84 (8.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.97 (0.43--2.19)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.53 (0.22--1.32)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.17\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*Multivariate logistic regression analysis.

A P-value \textless{} 0.05 was considered statistically significant.

Modeling was based on a complete case analysis.

NA, not applicable

\textbf{Hosted file}

\verb`Figure.docx`  available at \url{https://authorea.com/users/740656/articles/713419-association-between-use-of-romosozumab-and-cardiovascular-events-analysis-of-the-japanese-adverse-event-report-database}

\selectlanguage{english}
\FloatBarrier
\end{document}

