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Journal of Clinical Neuroscience 59 (2019) 224–228

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Journal of Clinical Neuroscience

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Clinical study

Risk factors for ischemic stroke post bone fracture

Qi An a,b, Zhe Chen a, Kang Huo a, Hua Su c, Qiu-Min Qu a,⇑
Department of Neurology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
Department of Rheumatology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Stroke is one of the most devastating complications after bone fracture. However, due to the rarity of the
Received 17 March 2018 complication, the risk factor for post fracture stroke remains unknown. We retrospectively reviewed
Accepted 24 September 2018 2914 fractured adults referred to the first affiliated hospital of Xi’an Jiaotong University, a regional refer-
ral 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
Keywords: prevalence of post fracture stroke was 0.446%. The post fracture stroke prevalence in patients older than
Ischemic stroke
68 years old was 3.542%. Compared to patients with vertebral (0.124%) and femur (0.619%) fractures,
Post fracture stroke
Risk factor
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.
Ó 2018 Elsevier Ltd. All rights reserved.

1. Introduction ment of acute ischemic stroke [8,9]. However, fracture is a con-

traindication for thrombolysis. For these who have not received
Bone fracture is a common health problem that can cause long- thrombolysis, either antiplatelet or anticoagulation therapy is rec-
term disability. After adjusting for competing risks of death, the ommended to decrease the prevalence of recurrent stroke
residual life time risk of fracture for women and men from age of [8,10,11]. Meanwhile, all these therapies might increase the risk
60 was 44% and 25%, respectively [1]. Some types of fractures, such of hemorrhage after fractures. Thus, it is a better alternative med-
as vertebral fractures, hip fractures, wrist-forearm fractures, are ical strategy to prevent post fracture stroke through identifying
osteoporosis-related and increasing with age [2,3]. Worldwide, and interfering with related risk factors. However, to the best of
the disability adjusted life years (DALYs) lost due to osteoporotic our knowledge, there was rare research on risk factors of post frac-
fracture is 5.8 million, accounting for 0.83% of the global burden ture stroke. The aim of this study was to identify these risk factors
of noncommunicable diseases [4]. for post fracture stroke.
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 2. Methods
bone fractures is rare. Bone fractured patients with post fracture
stroke have poorer functional recovery and require more care dur- This was a retrospective study and included patients hospital-
ing the 1st year than those without [7]. In addition, the treatments ized for fracture in the First Affiliated Hospital of Xi’an Jiaotong
for post fracture stroke are challenging. Currently, intravenous University, a regional referral center in China, from January 1st,
thrombolysis is widely accepted and is still the leading therapy 2008, to May 31st, 2013. All fractures were confirmed by radiology
approved by the US Food and Drug Administration for the manage- (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
⇑ Corresponding author at: 277 West Yanta Road, Xi’an, Shaanxi, China. excessive trauma (e.g., motor vehicle accident) were also excluded.
E-mail address: (Q.-M. Qu). This study was approved by the Ethics Committee of The First
0967-5868/Ó 2018 Elsevier Ltd. All rights reserved.
Q. An et al. / Journal of Clinical Neuroscience 59 (2019) 224–228 225

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 medi-
cal records, and were further classified as Group 0–1 and Group 2–
6 for clinical purposes, respectively.
Statistical analyses were conducted by SPSSÒ software (version
13.0). Numerical data was expressed as mean ± SD (standard devi-
ation) or median (range min–max), while categorical data was
expressed as percentages or numbers. Numerical data was com-
pared 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
Fig. 1. Study flow diagram. and removal levels were 0.05 and 0.10, respectively. For the Logis-
tic Regression analysis, continuous neutrophil cell counts were
Affiliated Hospital of Xi’an Jiaotong University. Written informed transformed into Dichotomous variables based on the cutoff point
consent was signed by each patient before entering into this study. of 75th percentile (i.e. 7.34  109/L) for clinical purposes. P < 0.05
We searched the hospital information system in our center. In was deemed to indicate a significant difference.
the study period, a total of 3605 patients were diagnosed as ‘‘frac-
ture” and admitted. After eliminating 691 patients according to the
exclusion criteria, 2914 patients were enrolled in the present study 3. Results
ultimately, including 806, 323 and 431 patients who fractured
their vertebral, femur and hip, respectively (Fig. 1). The median A total of 13 patients had post fracture stroke during our study
following-up time was 20 days (ranging from 4 to 90 days). We period. And all strokes were ischemic. The prevalence of stroke
extracted demographic and medical records in the hospital infor- after fracture was 0.446%. Table 2 shows the clinical characteristics
mation system, including age, gender and fracture type etc. History of the 13 patients. Compared to patients with vertebral (0.124%)
of hypertension, diabetes mellitus, hyperlipidemia, stroke, fracture and femur (shaft/ distal, 0.619%) fractures, patients with hip frac-
and routine examination and biochemistry results were also tures had a higher prevalence of stroke (2.320%) (P < 0.001). The
recorded. The results of routine examination and biochemistry, median time between fracture and the onset of stroke was 4 days
including levels of white blood cell (WBC), neutrophile, hemoglo- (ranging from 1 to 25 days). LACI was the most common stroke
bin, platelet, albumin, fibrinogen, D-dimer, etc., were tested within type (7 out of 13 patients), no TACI was observed. Concerning
24 h after admission. about the test validity, the following study was focused on patients
Brain computed tomography (CT) or magnetic resonance imag- with hip fractures only.
ing (MRI) was conducted among patients who were suspected to Among these 431 hip-fractured patients, the median age were
have post fracture stroke based on symptoms and physical exam- 76 years old (ranging from 34 to 101 years old). The demographic
inations. And all these patients satisfied the World Health Organi- characteristics and comorbidities of hip fractured patients at
zation criteria for acute stroke [12]. All the ischemic strokes were admission are shown in Table 3. There were more females (59%)
further classified based on the Oxford shire Community Stroke Pro- than males. About 25% (1 0 9) patients had a history of prior stroke,
ject (OCSP) criteria: total anterior circulation infarction (TACI), par- 89 were ischemic stroke, 16 were haemorrhagic stroke, and 4 had
tial anterior circulation infarction (PACI), posterior circulation both. Most patients had fractures on left hips (54.52%). However,
infarction (POCI), and lacunar infarction (LACI) [13]. The diagnostic the stroke prevalence was not correlated with gender and the loca-
criteria of the complications are demonstrated in Table 1. tion of hip fractures (P = 0.95 and P = 0.76, respectively). Hyperlipi-
CHADS2 and its derived scales were first designed to predict the demia, previous fracture and comorbidities were more common in
risk of ischemic stroke among patients with chronic atrial fibrilla- patients with post fracture stroke compared to those without
tion and to guide the antithrombotic treatment [14,15]. Recently, (P = 0.027, P = 0.004, P = 0.036, respectively, Table 3). Most of the

Table 1
The diagnostic criteria of the complications.

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 drugs
Hyperlipidemia TC >5.18 mmol/L or use of lipid-lowering agents
Coronary Heart Disease a history of myocardial infarction or angina pectoris, or cardiac bypass 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 Failure a history of congestive heart failure, or with symptoms of heart failure and at least one echocardiographic abnormality in
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.

Patients with post fracture IS Patients without post fracture IS

(n = 10) (n = 421)
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 score  2 7.98 ± 2.79  109/L, P = 0.074; 221.20 ± 83.74  109/L VS
(P = 0.049, Table 4). 177.77 ± 75.41  10 /L, P = 0.073). Patients with and without post
Patients with post fracture ischemic stroke had significantly fracture stroke had similar levels on hemoglobin, albumin, fibrino-
higher neutrophile counts than those without (7.76 ± 3.59  109/ gen and D-dimer.
L VS 6.04 ± 2.54  109/L, P = 0.037). Meanwhile, the hip-fractured In multiple logistic regression analysis, the only independent
patients had higher WBC and platelet levels. However, no statisti- predictor of ischemic stroke was history of prior fracture
cal difference was observed (9.59 ± 3.85  109/L VS (OR = 6.417, 95% CI = 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 as a modifiable risk factor for primary ischemic stroke [35]. In the
vertebral or hip fractured patients, ambulation is markedly limited
In our study, the prevalence of post fracture stroke was 0.446%, because of pain and disability. Further studies are needed to deter-
which is higher than 0.104% of the general population [18]. mine whether the incidence of ischemic stroke after fractures
Patients with advanced age and hip fractures were more likely to would decrease by improving the mobility.
have post fracture stroke. In multiple logistic regression analysis, Third, hip has unique anatomical and histological structures.
we found that history of prior fracture was an independent risk Compared with vertebral and femur shaft and radius, hip has rich
factor for post fracture stroke. To the best of our knowledge, this hematopoietic cells in bone marrow cavity [36]. As mentioned pre-
is the first study analyzed the prevalence and risk factors of post viously, fractures could stimulate hematopoietic marrow resulting
fracture stroke among Chinese populations. in augmented inflammation [25]. Thus, it seems rational to predict
The etiology of post fracture ischemic stroke is largely unclear. more severe inflammatory reactions after hip fractures.
Fat embolism could be one of the causative factors, especially in In our study, we noted that prior fracture was an independent
long bone and pelvic fractures [19]. The general prevalence of fat risk factor for post hip fracture ischemic stroke. It was an intriguing
embolism after hip fractures varies from 0.7 to 3.3% [20]. The risk result and had never been mentioned before. The relationship
of fat embolism is highest with the first 3–4 days after trauma [21]. between previous fracture and subsequent post fracture ischemic
In our study, the results that patients with post hip fracture stroke remains unclear. Further studies are needed to verify the
ischemic stroke had higher lipid levels than those without implied relationship between prior fracture and post fracture ischemic
fat embolism might be a latent etiology. However, only about half stroke.
of our patients (7 out of 13) developed ischemic stroke within Our study had some limitations. First, our study only included
4 days, suggesting existence of other mechanisms. Paradoxical patients in the First Affiliated Hospital of Xi’an Jiaotong University,
embolism of vein thrombosis is an underlying etiology for ischemic where patients are likely to have more severe and complex condi-
stroke [22]. We reviewed the transthoracic echocardiography of tions. The incidence of post fracture ischemic stroke might be over-
our 10 patients with post hip fracture ischemic stroke, however, estimated. Second, due to the retrospective nature of the study, we
no proof of intracardiac right-to-left shunts were recorded. Thus, may have missed some mild strokes if they were not recognized
paradox embolism might not be the etiology for post fracture and recorded, which would lead to underestimation. Third, we only
ischemic stroke among our patients. recorded the stroke during in hospital period. Patients who had
As suspected, older patients had higher risks for post bone frac- stroke after discharging were not included. Fourth, the patient
ture ischemic stroke. After long bone or proximal femur fractures, sample is small due to the low events incidence. Further studies
interleukin 6 (IL-6) was significantly increased only in older with larger patients in multiple hospitals are needed to verify the
patients [23]. Fornage et al found that IL-6 was associated with result obtained in this study.
white matter leisions (WML) and brain infarcts among elderly par-
ticipants of the Cardiovascular Health Study [24]. Furthermore, 5. Conclusions
fractures could stimulate hematopoietic marrow resulting in aug-
mented inflammation through HMGB1 (high mobility group box Hip fractured patients with advanced age are prone to post frac-
1) and macrophage/microglia infiltration in brain tissue [25]. It’s ture ischemic stroke. Hyperlipidemia, history of prior fracture,
worth noting that WML and lacunar infarction are correlated more comorbidities, higher CHADS2 score and neutrophil counts
tightly with each other and both are associated with cerebral small are related to post fracture ischemic stroke. History of prior frac-
vessel disease [26,27]. These intriguing results could partially ture is an independent risk factor for ischemic stroke. These find-
explain why elderly patients were more vulnerable to post fracture ings could help doctors identify fractured patients who are at
ischemic stroke and lacunar infarction was the most common high risks for post fracture ischemic stroke and provide them with
ischemic stroke type among our patients. prompt therapies in order to prevent the complex clinical entity.
The prevalence of post hip fracture stroke in our study is
2.320%, which is comparable to previous reports (ranging from Conflict of interest statement
0.2% to 4.1%) [28–30]. Similar to the published studies, we
observed that hip fractured patients were more likely to have post All the authors declare that they have no conflict of interest.
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
This work was supported by grants to Hua Su from the National
younger than 68 years old. Advanced age is an important risk fac-
Institutes of Health (R01 NS027713 and R21 NS083788) and from
tor for ischemic stroke [31,32]. It has also been shown that
the Michael Ryan Zodda Foundation and UCSF Research Evaluation
advanced age (older than 75 years) was associated with increased
and Allocation Committee (REAC).
risk of ischemic stroke after hip surgery [29]. Elder patients are
more likely to combine with other diseases and their general con-
ditions are likely to be poorer. Our study showed that patients with Acknowledgements
post fracture ischemic stroke had more comorbidities and higher
CHADS2 scores than those without. We should thank Professor Yu-sheng Qiu in the Orthopedic
Second, immobility and life style change after hip fracture. Epi- department and Mrs. Rong Peng in the Archive department of
demiology shows that fractures in the thoracolumbar spine, hip the First Affiliated Hospital of Xi’an Jiaotong University for their
and distal radius are the top three causes of fracture types in the helps in data collection.
elder [33]. It was reported that both vertebral and hip fractures
increased the risk of ischemic stroke [28,34]. As far as we know, Appendix A. Supplementary material
there is no research suggesting that distal radius fracture increases
the risk of ischemic stroke. The American Heart Association (AHA) Supplementary data to this article can be found online at
and American Stroke Association (ASA) have listed physical activity
228 Q. An et al. / Journal of Clinical Neuroscience 59 (2019) 224–228

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