Risk factors for ischemic stroke post bone fracture

abstract
Stroke is one of the most devastating complications after bone fracture. However, due to
the rarity of the complication, the risk factor for post fracture stroke remains unknown.
We retrospectively reviewed 2914 fractured adults referred to the first affiliated hospital
of Xi’an Jiaotong University, a regional referral center of China, from January 2008 to
May 2013. As a result, among the 2914 patients, 13 of them had newly onset stroke
within a median of 4 days after bone fractures (ranging from 1 to 25 days). The overall
prevalence of post fracture stroke was 0.446%. The post fracture stroke prevalence in
patients older than 68 years old was 3.542%. Compared to patients with vertebral
(0.124%) and femur (0.619%) fractures, patients with hip fractures had a higher
prevalence of post fracture stroke (2.320%) (P < 0.001). Univariate analysis showed that
hyperlipidemia, history of prior fracture, more comorbidities, higher CHADS2 score
and higher neutrophil counts at admission were more often observed among patients
who had post fracture stroke (P < 0.05). With the multiple logistic regression analysis,
we identified that history of prior fracture was an independent risk factor for post
fracture ischemic stroke (OR = 6.417, 95% CI = 1.581–26.051, P = 0.009). Our study
illustrates that the history of prior fracture is associated with a 6.4-fold increase in the
risk of post fracture ischemic stroke.
2018 Elsevier Ltd. All rights reserved.

1. Introduction
Bone fracture is a common health problem that can cause longterm disability. After
adjusting for competing risks of death, the residual life time risk of fracture for women
and men from age of 60 was 44% and 25%, respectively [1]. Some types of fractures,
such as vertebral fractures, hip fractures, wrist-forearm fractures, are osteoporosis-
related and increasing with age [2,3]. Worldwide, the disability adjusted life years
(DALYs) lost due to osteoporotic fracture is 5.8 million, accounting for 0.83% of the
global burden of noncommunicable diseases [4].
Stroke is another common cause of disability [5,6]. Moreover, stroke, per se, is one of
the most devastating complications for bone fractured patients. Research on the
prevalence of stroke after bone fractures is rare. Bone fractured patients with post
fracture stroke have poorer functional recovery and require more care during the 1st
year than those without [7]. In addition, the treatments for post fracture stroke are
challenging. Currently, intravenous thrombolysis is widely accepted and is still the
leading therapy approved by the US Food and Drug Administration for the
management of acute ischemic stroke [8,9]. However, fracture is a contraindication for
thrombolysis. For these who have not received thrombolysis, either antiplatelet or
anticoagulation therapy is recommended to decrease the prevalence of recurrent stroke
[8,10,11]. Meanwhile, all these therapies might increase the risk of hemorrhage after
fractures. Thus, it is a better alternative medical strategy to prevent post fracture stroke
through identifying and interfering with related risk factors. However, to the best of our
knowledge, there was rare research on risk factors of post fracture stroke. The aim of
this study was to identify these risk factors for post fracture stroke.
2. Methods
This was a retrospective study and included patients hospitalized for fracture in the
First Affiliated Hospital of Xi’an Jiaotong University, a regional referral center in
China, from January 1st, 2008, to May 31st, 2013. All fractures were confirmed by
radiology (i.e. X-ray or computed tomography). The exclusion criteria were: younger
than 18 years of age, diagnosed as pathological fractures, and with delayed bone
healing. Patients with fracture caused by excessive trauma (e.g., motor vehicle
accident) were also excluded. This study was approved by the Ethics Committee of
The First
 Q. An et al. /Journal of Clinical Neuroscience 59 (2019) 224–228 225 Fig. 1.
Study
flow diagram.
Affiliated Hospital of Xi’an Jiaotong University. Written informed consent was
signed by each patient before entering into this study.
We searched the hospital information system in our center. In the study period, a
total of 3605 patients were diagnosed as ‘‘fracture” and admitted. After eliminating
691 patients according to the exclusion criteria, 2914 patients were enrolled in the
present study ultimately, including 806, 323 and 431 patients who fractured their
vertebral, femur and hip, respectively (Fig. 1). The median following-up time was 20
days (ranging from 4 to 90 days). We extracted demographic and medical records in
the hospital information system, including age, gender and fracture type etc. History
of hypertension, diabetes mellitus, hyperlipidemia, stroke, fracture and routine
examination and biochemistry results were also recorded. The results of routine
examination and biochemistry, including levels of white blood cell (WBC),
neutrophile, hemoglobin, platelet, albumin, fibrinogen, D-dimer, etc., were tested
within 24 h after admission.
Brain computed tomography (CT) or magnetic resonance imaging (MRI) was
conducted among patients who were suspected to have post fracture stroke based on
symptoms and physical examinations. And all these patients satisfied the World
Health Organization criteria for acute stroke [12]. All the ischemic strokes were
further classified based on the Oxford shire Community Stroke Project (OCSP)
 criteria: total anterior circulation infarction (TACI), partial anterior circulation
infarction (PACI), posterior circulation infarction (POCI), and lacunar infarction
(LACI) [13]. The diagnostic criteria of the complications are demonstrated in Table 1.
CHADS2 and its derived scales were first designed to predict the risk of ischemic
stroke among patients with chronic atrial fibrillation and to guide the antithrombotic
treatment [14,15]. Recently,
Table 1
The diagnostic criteria of the complications.
several studies showed that CHADS2 and its derived scales were still simple and
reliable methods for predicting ischemic stroke risks in patients with a history of
coronary artery disease, and those without atrial fibrillation [16,17]. The CHADS2
scores in patients with hip fractures were evaluated according to the medical records,
and were further classified as Group 0–1 and Group 2– 6 for clinical purposes,
respectively.
Statistical analyses were conducted by SPSS software (version 13.0). Numerical data
was expressed as mean ± SD (standard deviation) or median (range min–max), while
categorical data was expressed as percentages or numbers. Numerical data was
compared with the independent sample t-test. Categorical data was compared with the
Chi-square test or the Fisher’s exact test, where appropriate. Finally, we used Multiple
Logistic Regression analysis to determine independent factors for post-fracture ischemic
stroke. Enter method of Logistic Regression was used. The enter and removal levels
were 0.05 and 0.10, respectively. For the Logistic Regression analysis, continuous
neutrophil cell counts were transformed into Dichotomous variables based on the cutoff
point of 75th percentile (i.e. 7.34 109/L) for clinical purposes. P < 0.05 was deemed to
indicate a significant difference.
3. Results
A total of 13 patients had post fracture stroke during our study period. And all strokes
were ischemic. The prevalence of stroke after fracture was 0.446%. Table 2 shows the
clinical characteristics of the 13 patients. Compared to patients with vertebral (0.124%)
and femur (shaft/ distal, 0.619%) fractures, patients with hip fractures had a higher
 prevalence of stroke (2.320%) (P < 0.001). The median time between fracture and the
onset of stroke was 4 days (ranging from 1 to 25 days). LACI was the most common
stroke type (7 out of 13 patients), no TACI was observed. Concerning about the test
validity, the following study was focused on patients with hip fractures only.
Among these 431 hip-fractured patients, the median age were 76 years old (ranging
from 34 to 101 years old). The demographic characteristics and comorbidities of hip
fractured patients at admission are shown in Table 3. There were more females (59%)
than males. About 25% (1 0 9) patients had a history of prior stroke, 89 were ischemic
stroke, 16 were haemorrhagic stroke, and 4 had both. Most patients had fractures on left
hips (54.52%). However, the stroke prevalence was not correlated with gender and the
location of hip fractures (P = 0.95 and P = 0.76, respectively). Hyperlipidemia, previous
fracture and comorbidities were more common in patients with post fracture stroke
compared to those without (P = 0.027, P = 0.004, P = 0.036, respectively, Table 3).
Most of the
Items Definition
Hypertension BP >140/90 mmHg on repeated measurements during the hospitalization
or on antihypertensive medication
Diabetes Mellitus a history of diabetes mellitus, or FBG 7.0 mmol/L or use of antidiabetic
Hyperlipidemia drugs
TC >5.18 mmol/L or use of lipid-lowering agents
Coronary Heart a history of myocardial infarction or angina pectoris, or cardiac bypass
Disease surgery or stent angioplasty
Atrial Fibrillation a history of atrial fibrillation, or diagnosed using the patient’s in-hospital
EKG
History of Stroke a history of stroke, including IS, TIA, ICH or SAH
Congestive Heart a history of congestive heart failure, or with symptoms of heart failure and
Failure at least one echocardiographic abnormality in hospital
Current Smoking smoking at the time of fracture or quit smoking <1 year
History of Fracture a history of discontinuousness of bone cortex, including primary fracture
 and discontinuousness secondary to medical procedures, joint arthroplasty,
etc
Comorbidities CKD eGFR <60 mL/min/1.73 m2 [19,20]
COPD a history of COPD [21]
BP, blood pressure; FBG, fasting blood glucose; TC, total cholesterol; IS, ischemic
attack; TIA, transient ischemic attack; ICH, intracerebral hemorrhage; SAH,
subarachnoid hemorrhage; CKD, chronic kidney disease; eGFR, estimated glomerular
filtration rate; COPD, Chronic Obstructive Pulmonary Disease.
226 Q. An et al. /Journal of Clinical Neuroscience 59 (2019) 224–228
Table 2
Characteristics of patients with post-bone fracture stroke.
No. Gender Age Fracture type Comorbidities Fracture to IS (day) OCSP
1 F 88 Hip N 9 LACI
2 F 84 Hip N 7 LACI
3 F 80 Hip N 20 POCI
4 M 73 Hip N 25 LACI
5 M 84 Hip Y 2 LACI
6 F 80 Hip N 3 LACI
7 M 79 Hip N 4 POCI
8 F 76 Hip N 2 PACI
9 M 75 Hip, Humerus Y 1 PACI
10 F 68 Hip, Radial Y 13 PACI
11 M 81 Femur Shaft N 13 LACI
12 F 78 Femur Distal N 2 LACI
13 M 77 Vertebral N 2 POCI
IS, ischemic stroke; N, without comorbidities; Y, with comorbidities; OCSP,
Oxfordshire Community Stroke Project; LACI, lacunar infarction; POCI, posterior
circulation infarction; PACI, partial anterior circulation infarction.
Table 3
 Demographic Characteristics and Comorbid Medical Disorders of Hip-Fracture at
hospital admission.

Variable Mean/n SD/% Mean/n SD/% P

value
Female 6 60 248 58.91 0.945
Age 78.70 5.91 75.97 8.49 0.230
Left Side 6 60 229 54.39 0.761
Multiple Fractures 2 20 34 8.08 0.442
Hypertension 8 70 218 51.78 0.148
Diabetes Mellitus 3 30 128 30.40 0.978
Coronary Heart Disease 0 0 85 20.19 0.222
Atrial Fibrillation 1 10 25 5.94 0.594
Congestive Heart Failure 0 0 11 2.61 1.000
Hyperlipidemia 4 40 49 11.64 0.027
Previous Stroke 2 20 107 25.42 0.983
Previous Fractures 5 50 5 1.88 0.004
Current Smoking 1 10 9 2.14 0.692
Comorbidities 4 40 52 12.35 0.036
Table 4
Relationship between CHADS2 score
and post hip fracture IS.
CHADS2 Score Patients with post fracture IS Patients without post fracture IS
p value
(n = 10) (n = 421)

n % n %
0–1 1 10 196 46.56 0.049
 2–6 9 90 225 53.44

patients with post fracture stroke had a CHADS2 7.98 ± 2.79 109/L, P = 0.074; 221.20 ± 83.74
score 2 (P = 0.049, Table 4). 109/L VS 177.77 ± 75.41 109/L, P = 0.073).
Patients with post fracture ischemic stroke had Patients with and without post fracture stroke had
significantly higher neutrophile counts than those similar levels on hemoglobin, albumin, fibrinogen
without (7.76 ± 3.59 109/ L VS 6.04 ± 2.54 109/L, and D-dimer.
P = 0.037). Meanwhile, the hip-fractured patients In multiple logistic regression analysis, the only
had higher WBC and platelet levels. However, no independent predictor of ischemic stroke was
statistical difference was observed history of prior fracture (OR = 6.417, 95% CI =
(9.59 ± 3.85 109/L VS 1.581–26.051, P = 0.009) (Table 5).
Table 5
Multivariate logistic regression for prediction of post-
fracture stroke.
Model variables Coefficient SE Wald P OR (95% CI)
Hyperlipidemia 1.390 0.736 3.564 0.059 4.016(0.948–
17.008)
Prior fracture 1.859 0.715 6.763 0.009 6.417(1.581–
26.051)
More comorbidities 1.268 0.748 2.874 0.090 3.554(0.820–
15.392)
CHADS2 score 2-6 2.053 1.105 3.455 0.063 7.793(0.894–
67.922)
Higher neutrophile count 1.226 0.696 3.107 0.078 3.409(0.872–
13.330)
Constant 7.008 1.268 30.526 0.000
SE, standard error; OR, odds ratio; CI, credit interval.
Q. An et al. /Journal of Clinical Neuroscience 59 (2019) 224–228
227
4. Discussion
In our study, the prevalence of post fracture stroke was 0.446%, which is higher
than 0.104% of the general population [18]. Patients with advanced age and hip
fractures were more likely to have post fracture stroke. In multiple logistic regression
analysis, we found that history of prior fracture was an independent risk factor for
post fracture stroke. To the best of our knowledge, this is the first study analyzed the
prevalence and risk factors of post fracture stroke among Chinese populations.
The etiology of post fracture ischemic stroke is largely unclear. Fat embolism could
be one of the causative factors, especially in long bone and pelvic fractures [19]. The
general prevalence of fat embolism after hip fractures varies from 0.7 to 3.3% [20].
The risk of fat embolism is highest with the first 3–4 days after trauma [21]. In our
study, the results that patients with post hip fracture ischemic stroke had higher lipid
levels than those without implied fat embolism might be a latent etiology. However,
only about half of our patients (7 out of 13) developed ischemic stroke within 4 days,
suggesting existence of other mechanisms. Paradoxical embolism of vein thrombosis
is an underlying etiology for ischemic stroke [22]. We reviewed the transthoracic
echocardiography of our 10 patients with post hip fracture ischemic stroke, however,
no proof of intracardiac right-to-left shunts were recorded. Thus, paradox embolism
might not be the etiology for post fracture ischemic stroke among our patients.
As suspected, older patients had higher risks for post bone fracture ischemic stroke.
After long bone or proximal femur fractures, interleukin 6 (IL-6) was significantly
increased only in older patients [23]. Fornage et al found that IL-6 was associated
with white matter leisions (WML) and brain infarcts among elderly participants of the
Cardiovascular Health Study [24]. Furthermore, fractures could stimulate
hematopoietic marrow resulting in augmented inflammation through HMGB1 (high
mobility group box 1) and macrophage/microglia infiltration in brain tissue [25]. It’s
worth noting that WML and lacunar infarction are correlated tightly with each other
and both are associated with cerebral small vessel disease [26,27]. These intriguing
results could partially explain why elderly patients were more vulnerable to post
 fracture ischemic stroke and lacunar infarction was the most common ischemic stroke
type among our patients.
The prevalence of post hip fracture stroke in our study is
2.320%, which is comparable to previous reports (ranging from 0.2% to 4.1%) [28–
30]. Similar to the published studies, we observed that hip fractured patients were
more likely to have post fracture ischemic stroke as well [28]. The following three
factors might be responsible for this result.
First, hip fracture occurs mostly in patients with advanced age. In our research, all
post hip fracture stroke patients were no younger than 68 years old. Advanced age is
an important risk factor for ischemic stroke [31,32]. It has also been shown that
advanced age (older than 75 years) was associated with increased risk of ischemic
stroke after hip surgery [29]. Elder patients are more likely to combine with other
diseases and their general conditions are likely to be poorer. Our study showed that
patients with post fracture ischemic stroke had more comorbidities and higher
CHADS2 scores than those without.
Second, immobility and life style change after hip fracture. Epidemiology shows
that fractures in the thoracolumbar spine, hip and distal radius are the top three causes
of fracture types in the elder [33]. It was reported that both vertebral and hip fractures
increased the risk of ischemic stroke [28,34]. As far as we know, there is no research
suggesting that distal radius fracture increases the risk of ischemic stroke. The
American Heart Association (AHA) and American Stroke Association (ASA) have
listed physical activity as a modifiable risk factor for primary ischemic stroke [35]. In
the vertebral or hip fractured patients, ambulation is markedly limited because of pain
and disability. Further studies are needed to determine whether the incidence of
ischemic stroke after fractures would decrease by improving the mobility.
Third, hip has unique anatomical and histological structures. Compared with vertebral
and femur shaft and radius, hip has rich hematopoietic cells in bone marrow cavity [36].
As mentioned previously, fractures could stimulate hematopoietic marrow resulting in
augmented inflammation [25]. Thus, it seems rational to predict more severe
inflammatory reactions after hip fractures.
 In our study, we noted that prior fracture was an independent risk factor for post hip
fracture ischemic stroke. It was an intriguing result and had never been mentioned
before. The relationship between previous fracture and subsequent post fracture
ischemic stroke remains unclear. Further studies are needed to verify the relationship
between prior fracture and post fracture ischemic stroke.
Our study had some limitations. First, our study only included patients in the First
Affiliated Hospital of Xi’an Jiaotong University, where patients are likely to have more
severe and complex conditions. The incidence of post fracture ischemic stroke might be
overestimated. Second, due to the retrospective nature of the study, we may have missed
some mild strokes if they were not recognized and recorded, which would lead to
underestimation. Third, we only recorded the stroke during in hospital period. Patients
who had stroke after discharging were not included. Fourth, the patient sample is small
due to the low events incidence. Further studies with larger patients in multiple hospitals
are needed to verify the result obtained in this study.
5. Conclusions
Hip fractured patients with advanced age are prone to post fracture ischemic stroke.
Hyperlipidemia, history of prior fracture, more comorbidities, higher CHADS2 score
and neutrophil counts are related to post fracture ischemic stroke. History of prior
fracture is an independent risk factor for ischemic stroke. These findings could help
doctors identify fractured patients who are at high risks for post fracture ischemic stroke
and provide them with prompt therapies in order to prevent the complex clinical entity.