BioMed Research International
Volume 2018 (2018), Article ID 8928174, 6 pages
https://doi.org/10.1155/2018/8928174

Research Article

Increased Risk for Hip Fractures among Patients with Cholangitis: A Nationwide Population-Based Study

Chieh-Cheng Hsu,¹ Horng-Chaung Hsu,2,3 Che-Chen Lin,⁴ Yu-Chiao Wang,⁴ Hsuan-Ju Chen,⁴ Yung-Cheng Chiu,2,3 Chien-Chun Chang,² and Shu-Jui Kuo²

¹Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
²Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
³College of Medicine, China Medical University, Taichung, Taiwan
⁴Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan

Correspondence should be addressed to Shu-Jui Kuo; b90401073@gmail.com

Received 16 November 2017; Revised 2 March 2018; Accepted 10 April 2018; Published 5 June 2018

Academic Editor: Joao Eurico Fonseca

Copyright © 2018 Chieh-Cheng Hsu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background. Cholangitis is the infectious disease involving the biliary tract, which may induce systemic inflammation. Bone loss is a well-known sequelae after systemic inflammatory disease, and one grave complication after osteoporosis is hip fracture. We want to know whether cholangitis can contribute to increased risk of hip fracture. Methods. All the patients diagnosed with cholangitis since January 1, 2001, to December 31, 2009, were assessed. All the subjects with cancer history, traumatic accident, and previous fracture were excluded. We selected the controls without cholangitis and matched the controls to cholangitis patients by age, sex, osteoporosis, and the use of steroid for more than 30 days by approximately 1:4 ratio. Results. There were 2735 subjects in the cholangitis cohort and 10915 in the noncholangitis cohort. There were 101 hip fractures in the cholangitis cohort with the incidence density of 7.58 per 1000 person-years. As for the noncholangitis cohort, 366 individuals suffered from hip fracture with the incidence density of 5.86 per 1000 person-years. The risk of hip fracture was higher in the cholangitis cohort with a 1.29-fold increased risk than the noncholangitis cohort (hazard ratio = 1.29, 95% confidence interval = 1.03-1.61). The association between cholangitis and the hip fracture was more prominent among subjects less than 65 years (hazard ratio = 2.65, 95% confidence interval =1.30-5.39) and the subjects without comorbidities (hazard ratio = 3.01, 95% confidence interval = 1.42-6.41). Conclusions. Cholangitis is associated with higher risk for hip fracture, especially among young subjects free from medical comorbidities.

1. Introduction

Cholangitis is the infectious disease affecting the biliary tract [1]. It is mainly caused by the obstruction of biliary tract, mostly by the stone [2]. Cholangitis has been considered as a risk factor for subsequent gastrointestinal cancer because of the systemic inflammation triggered by the disease [3]. However, the detrimental consequences of systemic inflammation after cholangitis other than cancer have not been completely delineated at present.

Bone loss is a well-known sequelae after systemic inflammatory disease, which can be explained by the perspective of evolutionary medicine, altered energy expenditure and storage, and neuroendocrine as well as immunologic factors [4]. One grave complication after osteoporosis is hip fracture [5]. Hip fractures account for one-fourth of geriatric fractures necessitating hospitalization with substantial morbidity and mortality [6].

Bone complications are prevalent among patients with liver dysfunction. The known liver diseases associated with bone loss included chronic hepatitis C infection, primary biliary cirrhosis, primary sclerosing cholangitis, or liver transplant. The incidences of osteoporosis and fracture risk are high among these liver diseases [7]. However, the bone disease after cholangitis has not been discussed before. Based on the observations mentioned above, we hypothesize that cholangitis could lead to increased risk for hip fractures. We thus performed a nationwide population-based study to ascertain our hypothesis.

2. Materials and Methods

The Taiwanese government established the nationwide and single-payer based National Health Insurance (NHI) program for all Taiwanese citizens. The National Health Research Institute (NHRI) constructed the National Health Insurance Research Database (NHIRD) comprising the claim data, registry of beneficiary, and clinic and hospital files of the insured individuals. In our study, we set up the study cohort by the Longitudinal Health Insurance Database (LHID), which was a subset of NHIRD. The ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) system was utilized as the disease coding system in NHIRD. The NHRI removed the original identification number to safeguard the privacy of all the insured individuals and provided a scrambled identification number to link the claim data to each insured citizen before releasing the data for researchers.

The study was approved by the Ethics Review Board of China Medical University (CMUH104-REC2-115).

We constructed a population-based cohort study to determine whether the patients with cholangitis are more susceptible to hip fractures. All of the patients who had the admission episode because of the de novo diagnosis of cholangitis (ICD-9-CM 576.1) since January 1, 2001, to December 31, 2009, were all assessed. The subjects with cancer history (ICD-9-CM 140-208), accident indicative of high energy trauma (presence of E coding), and previous hip fracture history (ICD-9-CM 820) were all excluded.

The index date was defined as the date when the diagnosis of cholangitis was initially coded.

We selected the control subjects without the coding of cholangitis from the LHID and matched the controls to cholangitis patients by age (per 5 year), sex, the coding of osteoporosis (ICD-9-CM 733.0 and 733.1) at index date, the continuous use of oral steroid over 30 days before the index date, and year of index date by approximately 1:4 ratio. The diagnosis of osteoporosis would only be coded by the Taiwanese physician if the patient had the T score value of less than -2.5. The control subjects fulfilling the matching criteria were enrolled on the same date as the matched cholangitis patients.

The two sample t-test for continuous variables and chi-square test for categorical variables were utilized for between-group comparisons. The incidence density of the hip fracture was expressed as case per 1000 person-years. The Kaplan-Meier method was utilized to measure the cumulative incidence of hip fractures, and the log rank test was utilized to determine the significance of between-group differences. To interpret the risk of hip fracture for both cohorts, the crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated by utilizing the single-variable and multivariable Cox proportional hazard models. The SAS 9.4 software (SAS Institute, Cary, NC, USA) was utilized for data analysis and the R software (R Foundation for Statistical computing, Vienna, Austria) was applied to plot the incidence curves.

3. Results

There were 2735 patients in the cholangitis cohort and 10915 subjects in the noncholangitis cohort (Table 1). The distribution of age, sex, history of osteoporosis, and oral steroid use were similar between the two groups. The enlisted comorbidities, including hypertension, diabetes, epilepsy, ischemic heart disease, chronic obstructive pulmonary disease, anxiety, sleep disorder, stroke, liver cirrhosis, and end stage renal disease were all higher in the cholangitis cohort than in the control cohort (all p < 0.05). The flow diagram for subject recruitment was shown in Figure 1. There were 101 hip fractures in the cholangitis cohort with the incidence density of 7.58 per 1000 person-years. As for the noncholangitis cohort, 366 individuals suffered from hip fracture with the incidence density of 5.86 per 1000 person-years (Table 2). The cholangitis cohort had higher hip fracture incidence than in the noncholangitis cohort (Figure 2, p = 0.02). After adjustment for age, sex, and comorbidities, the cholangitis patients had 1.29-fold increased risk of hip fracture than the noncholangitis subjects (hazard ratio = 1.29, 95% confidence interval = 1.03-1.61). Age, female gender, diabetes, stroke, and end stage renal disease were also associated with higher incidence of hip fracture in our model.

Table 1: Comparison of demographic profiles and history of comorbidities in cholangitis and noncholangitis cohorts.

Cholangitis
p value

No (N=10915)
Yes (N=2735)

n
%
n
%

Sex

0.99

    Women
5163
47.3
1294
47.3

    Men
5752
52.7
1441
52.7

Age, year

0.99

    <35
580
5.31
145
5.30

    35–65
4560
41.8
1140
41.7

    ≥65
5775
52.9
1450
53.0

    Mean (SD) #
63.7 (16.5)

63.9 (16.5)

0.58

Comorbidities

    Hypertension
5411
49.6
1524
55.7
<.0001

    Diabetes
2285
20.9
811
29.7
<.0001

    Epilepsy
110
1.01
48
1.76
0.0011

    IHD
2983
27.3
936
34.2
<.0001

    COPD
2174
19.9
663
24.2
<.0001

    Stroke
2127
19.5
689
25.2
<.0001

    Live cirrhosis
172
1.58
235
8.59
<.0001

    Osteoporosis
1650
15.1
417
15.2
0.8653

    ESRD
82
0.75
31
1.13
0.0485

Drug used

    Steroid
3308
30.3
831
30.4
0.9376

Chi-square test; #Student’s t-test.

IHD: ischemic heart disease; COPD: chronic obstructive pulmonary disease.

ESRD: end-stage renal disease; SD: standard deviation.

Table 2: The adjusted hazard ratio of hip fracture in different risk factors.

Variables
N
Event
Crude HR (95%CI)
Adjusted HR† (95% CI)

Cholangitis

    No
10915
366
1.00
1.00

    Yes
2735
101
1.28 (1.03-1.61)
1.29 (1.03-1.61)

Sex

    Women
6457
279
1.00
1.00

    Men
7193
188
0.63 (0.53-0.76)
0.64 (0.53-0.79)

Age
13650
467
1.12 (1.11-1.13)
1.11 (1.10-1.12)

Comorbidities

    Hypertension

        No
6715
120
1.00
1.00

        Yes
6935
347
3.26 (2.65-4.01)
1.07 (0.84-1.34)

    Diabetes

        No
10554
316
1.00
1.00

        Yes
3096
151
1.87 (1.54-2.27)
1.23 (1.00-1.5)

    Epilepsy

        No
13492
462
1.00
1.00

        Yes
158
5
1.25 (0.52-3.01)
0.83 (0.34-2.01)

    IHD

        No
9731
251
1.00
1.00

        Yes
3919
216
2.47 (2.06-2.97)
0.98 (0.80-1.21)

    COPD

        No
10813
307
1.00
1.00

        Yes
2837
160
2.39 (1.98-2.90)
1.13 (0.92-1.40)

    Stroke

        No
10834
287
1.00
1.00

        Yes
2816
180
2.96 (2.45-3.56)
1.26 (1.03-1.55)

    Live cirrhosis

        No
13243
452
1.00
1.00

        Yes
407
15
1.53 (0.92-2.56)
1.43 (0.85-2.40)

    Osteoporosis

        No
11583
331

        Yes
2067
136
2.56 (2.09-3.12)
1.06 (0.85-1.33)

    ESRD

        No
13537
460
1.00
1.00

        Yes
113
7
2.89 (1.37-6.11)
3.07 (1.45-6.52)

Steroid

    No
9511
303
1.00
1.00

    Yes
4139
164
1.51 (1.25-1.83)
1.10 (0.9-1.35)

IHD: ischemic heart disease; COPD: chronic obstructive pulmonary disease.

ESRD: end-stage renal disease.

HR, hazard ratio; adjusted HR†: multiple analysis including age, sex, each comorbidity, and oral steroid used.

Figure 1: The flow diagram of the recruitment process.

Figure 2: The incidence of hip fracture among cholangitis and control cohorts. The dashed line indicates the cholangitis cohort, and the solid line indicates the matched control cohort. The log rank test was utilized to assess the significance of difference between the curves.

Table 3 showed that the association between cholangitis and the increased risk of hip fracture was more prominent among subjects aged less than 65 years (hazard ratio = 2.65, 95% confidence interval =1.30-5.39) and the subjects without comorbidities (hazard ratio = 3.01, 95% confidence interval = 1.42-6.41).

Table 3: Incidence and adjusted hazard ratio of hip fracture stratified by sex, age, and comorbidities between the two cohorts.

Variables
Cholangitis
Compared to noncholangitis cohort

No

Yes

Event
PY
Rate
Event
PY
Rate
Crude HR (95% CI)
Adjusted HR†(95% CI)

Overall
366
62466
5.86
101
13332
7.58
1.29 (1.03-1.61)
1.29 (1.03-1.61)

Sex

    Women
218
30211
7.22
61
6619
9.22
1.27 (0.96-1.69)
1.27 (0.96-1.70)

    Men
148
32255
4.59
40
6713
5.96
1.29 (0.91-1.83)
1.27 (0.89-1.82)

Age, year

    <65
19
32802
0.58
15
7298
2.06
3.53 (1.80-6.96)
2.65 (1.30-5.39)

    ≥65
347
29664
11.7
86
6034
14.3
1.22 (0.96-1.54)
1.15 (0.90-1.45)

Comorbidity

    No
29
21929
1.32
9
3348
2.69
2.04 (0.97-4.31)
3.01 (1.42-6.41)

    Yes
337
40536
8.31
92
9984
9.21
1.11 (0.88-1.39)
1.26 (1.00-1.59)

PY, person-year; rate, incidence density (per 1,000 person-years); HR, hazard ratio; adjusted HR†: multiple analysis including age, sex, each comorbidity, and oral steroid used; CI: confidence interval

4. Discussion

In our study, we demonstrated that the admission episode for more than seven days due to de novo cholangitis is associated with higher risk for hip fracture. We also showed that the association between cholangitis and the increased risk of hip fracture was more prominent among subjects aged less than 65 years and the subjects without comorbidities. These results have not been reported before.

Rainer et al. have proposed the “three-pillar theory” to explain the bone loss due to chronic systemic inflammation, including evolutionary medicine, altered energy expenditure and storage, and neuroendocrine as well as immunologic factors [4]. Among the immunologic factors related to chronic systemic inflammation, the receptor activator of nuclear factor-κB (RANK) is well known for its role on the osteoclastic activation and the pathogenesis of osteoporosis [4]. One of the most devastating complications of osteoporosis is hip fracture, which is associated with significant morbidity and mortality [8]. It is thus prudent to speculate the correlation between the disease entity triggering systemic inflammation, such as cholangitis, and the occurrence of hip fracture.

The fever component of Charcot triad (jaundice, right upper quadrant abdominal pain, and fever) highlights the fact that cholangitis can initiate systemic inflammatory response. It is intriguing that whether the magnitude and duration of systemic inflammation of cholangitis can contribute to bone loss, or even hip fracture.

Angulo et al. performed 10-year longitudinal bone mineral density assay for patients with primary sclerosing cholangitis (PSC) for 237 patients. They demonstrated that osteoporosis was found in 15% patients and occurred 23.8-fold more frequently than the matched controls. Patients with PSC lost 1% of bone mass per year [9]. These results suggested that the inflammation of biliary tract correlates with bone loss, and the inflammation of biliary tract can exert the detrimental effect on bone mass in a time-dependent manner. In our study, we showed that the patients with cholangitis had 1.29 times the risk for hip fracture when compared with the matched control subjects.

Age (more than 65-year-old), female gender, stroke, and ESRD were also associated with higher incidence of hip fracture in our model. The findings derived from our model were consistent with previous studies [10, 11]. These consistent results not only supplement the published observations but also consolidate the validity and internal consistency of our model.

There are limitations to the study. First, not all the risk factors for the hip fracture can be obtained from the NHIRD for analysis, such as vitamin D insufficiency. The diagnosis of osteoporosis would only be coded by the Taiwanese physician if the patient had the T score less than -2.5. The true value of the T score cannot be obtained from the database. We cannot exclude the possibility that some subjects can have low-grade systemic inflammation triggered by subclinical stone disease, which was designated into the control group. However, the presence of subclinical cholangitis will contribute to the underestimation of the significance of difference. The best way to evaluate the pure impact of cholangitis on the risk of hip fracture was propensity score matching for all medical comorbidities. The lack of propensity score matching may raise the concern that the observed higher facture rate in the cholangitis cohort may be secondary to some other concomitant medical comorbidities associated with cholangitis. However, propensity score matching will jeopardize the generalizability of our results, so we just match the coding of osteoporosis and the history of steroid use only.

It is interesting that the effect of cholangitis on the occurrence of hip fracture was more prominent among subjects aged less than 65 years and the subjects without baseline comorbidities. We assume that the systemic inflammatory burden was higher among the elderly subjects and the subjects with medical comorbidities. The process of cholangitis would only exert mild increments on the systemic inflammatory burden. However, among the subjects with lower baseline systemic inflammation, the inflammatory effects following cholangitis will be more prominent.

5. Conclusions

In conclusion, we showed that cholangitis is associated with higher risk for hip fracture, especially among the subjects without baseline medical comorbidities and aged less than 65 years. Preventive measures for hip fracture, such as antiosteoporotic regimen, may be warranted for the young cholangitis patients without medical comorbidities.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This study is supported by the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005), Tseng-Lien Lin Foundation (Taiwan), Brain Disease Foundation (Taiwan), and Katsuzo and Kiyo Aoshima Memorial Funds, Japan.

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