European Journal of Internal Medicine 25 (2014) 87–91
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
A nationwide population cohort study: Irritable bowel syndrome is a risk factor of osteoporosis Chia-Ming Yen a,1, Chih-Hsin Muo b, Ming-Chia Lin c,1, Shih-Ni Chang b, Yen-Jung Chang b,f,1, Chia-Hung Kao d,e,⁎,1 a
Department of Anesthesiology, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan Department of Nuclear Medicine, E-DA Hospital, Kaohsiung, Taiwan d Department of Nuclear Medicine PET Center, China Medical University Hospital, Taichung, Taiwan e Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan f Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 14 August 2013 Received in revised form 14 October 2013 Accepted 17 October 2013 Available online 30 October 2013 Keywords: Cohort study Irritable bowel syndrome Osteoporosis National Health Insurance
a b s t r a c t Background: The goal of the study is to determine the relationship between irritable bowel syndrome (IBS) and osteoporosis in Taiwan. Materials and methods: We collected data from the National Health Insurance (NHI) program in Taiwan. The sample in this study consisted of 31,892 patients enrolled from 2000 to 2009 and diagnosed by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). We divided the sample into 2 cohorts based on whether they had IBS, and formed subgroups based on age, sex, enrolment year, and enrolment month. Results: Age and gender did not differ statistically among the 2 cohorts. Results show that IBS is more correlated with urbanization and the occupation of business. The IBS cohort had a higher incidence of osteoporosis than the non-IBS cohort (6.90 vs 4.15 per 1000 person-years; HR = 1.65, 955 CI = 1.54–1.77). Female patients aged 40–59 years had the highest risk of developing osteoporosis (HR = 4.42, 95% CI = 3.37–5.79 in the IBS cohort; HR = 4.41, 95% CI = 3.67–5.29 in the non-IBS cohort, respectively). In IBS patients less than 40 years of age, female patients had a significant 2.18-fold greater risk of developing osteoporosis than male patients (HR = 2.18, 95% CI = 1.09–4.38). Conclusions: IBS is a risk factor for osteoporosis in Taiwan. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by chronic abdominal pain or discomfort and altered GI function in the absence of alarm or over-inflammation [1]. IBS pathogenesis can involve altered intestinal motility, visceral hypersensitivity, altered compliance of the gut wall, psychological disturbance, or any combination of these conditions [2]. The etiology of IBS remains unknown, but it seems that stressors, such as life events and chronic stress, and the patient's individual and genetic background can modulate intestinal disease activity through complex psychoimmunologic mechanisms, both on a systemic level and on a gut mucosal level [3]. The development of symptom-based criteria, such as Rome criteria or GI
⁎ Corresponding author at: Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x7412; fax: +886 4 22336174. E-mail address: [email protected] (C.-H. Kao). 1 Ming-Chia Lin and Chia-Ming Yen contributed equally to this work, as well as Yen-Jung Chang and Chia-Hung Kao contributed equally to this work.
symptom questionnaire has made it more convenient and effective for research [4]. Osteoporosis is a condition characterized by a reduction in bone mass, disruption of bone micro-architecture, and skeletal fragility, with a resulting increase in fracture risk [5]. Osteoporosis has traditionally been viewed as a physiological process associated with aging, but today it is recognized as a multifactorial systemic polygenic disease in which hormonal, environmental, and nutritional factors modulate genetic determinants [6,7]. Traditional risk factors for osteoporosis include aging, hypertension, antihypertensive medication [8], primary hyperparathyroidism [9], menopause [10], type 2 diabetes mellitus [11], corticosteroid abuse [12], Parkinson's disease [13], social disadvantage [14], low calcium intake [15], and vitamin D deficiency [15]. Disorders of the liver and the gastrointestinal tract, particularly chronic inflammatory processes such as inflammatory bowel disease (IBD) and coeliac disease, are commonly associated with osteopenia and osteoporosis [16]. The increased prevalence of osteopenia and osteoporosis is a significant complication in both children and adults [17]. Therefore, this study adopts the large database of the National Health Insurance (NHI) to confirm whether IBS is a risk factor for osteoporosis in Taiwan.
0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.10.009
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2. Methods
2.3. Statistical analysis
2.1. Data sources
All data were expressed as frequency (with percent) or mean with standard deviation. We used the chi-square test to compare the distributions of categorical sociodemographic variables between the 2 cohorts. We also calculated the incidence density with person-years by these variables in the study cohort and comparison cohort. We calculated the incidence rate ratio (IRR) of osteoporosis for each variable. To estimate the osteoporosis-free risk of developing osteoporosis in IBS patients and non-IBS patients, we performed survival analysis by using the Kaplan–Meier method, with significance based on the logrank test. We used multivariate Cox's proportional-hazards regression analysis to assess the effects of IBS on the risk of osteoporosis. We also calculated the hazard ratio (HR) and 95% confidence interval (CI) by using the model. We defined statistical significance as a two-tailed P value of less than .05.
The National Health Insurance (NHI) in Taiwan is a mandatory universal health insurance program implemented in 1995 that offers comprehensive medical care to all residents (up to 99% of the population). Claims data are collected in the National Health Insurance Research Database (NHIRD) and managed by the National Health Research Institutes (NHRI). For research purposes, this study uses a sub-data set of 1 million randomly selected patients from 23 million insured people registered from 1996 to 2000. This database contained all medical records of each insurant from 1996 to 2010. Diagnoses in the database were coded using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).
2.2. Study groups 3. Results We identified an exposed study cohort from the database consisting of newly diagnosed patients with IBS (n = 31,892, ICD-9-CM 564.1) from 2000 to 2009. We excluded patients with osteoporosis and hip fracture history (n = 6913, ICD-9-CM 733.0 and 820) before enrolment. Fig. 1 shows the flow of patient selection. For each IBS case identified in the study, we randomly selected a comparison non-IBS cohort (i.e., insurants without IBS) from the database at a 1:4 ratio. We frequency matched the controls with IBS patients on the bases of sex, age (every 5 years), enrolment year, and enrolment month. We followed both the IBS patient cohort and the comparison cohort from the enrolment date to December 31, 2010 or diagnosis of osteoporosis, whichever came first. We calculated the person-years of follow-up time for each person until osteoporosis diagnosis (ICD-9CM 733.0) or censored. The date of censoring was defined as the date the study patients died in the follow-up period, the date of last withdrawal from NHI, or the date of termination of follow-up. Sociodemographic characteristic included urbanization and occupation. Urbanization was grouped into five levels based on Liu's report. The highest urban was defined as level “1” and the lowest was defined as level “5”. According to attribute of insurant's institution, we classified occupation into five types: public, labor, business, low income, and retired and others.
The demographic data in this study show that 49.7% of the IBS patients were male. Age and sex among the 2 cohorts did not differ statistically (Table 1). The IBS patients had a higher proportion of living in urban areas (30.6% vs 28.7%, Pb .0001) and with business occupations (42.2% vs 39.2%, P b .0001). Table 2 presents the incident densities and rate ratio of IBS-associated osteoporosis based on sociodemographic status. Overall, the follow-up results show a higher osteoporosis incidence in the IBS cohort than in the non-IBS cohort (6.90 vs 4.15 per 1000 person-years). Kaplan–Meier survival analysis shows that the osteoporosis-free rate was 2% lower in the IBS patients than in the controls, but significant in the follow-up period (Log-rank P b .0001). Multivariate analysis for Cox's proportionalhazards regression model shows that the risk of osteoporosis was significantly higher in the IBS cohort than in the non-IBS cohort (HR = 1.65, 95% CI = 1.54–1.77) (Table 2). Compared to males without IBS and females without IBS, the risks of osteoporosis in male and female IBS patients were 1.70 (95% CI = 1.49– 1.94) and 1.63 (95% CI = 1.50–1.77), respectively. In both cohorts, the incidence densities of osteoporosis increased from b 40 to ≥60 years (0.60 to 19.74 and 0.16 to 12.55 per 10 000 person-years in nonIBS and IBS groups, respectively) (Table 2). However, compared
Fig. 1. Flow chart for selecting study subjects.
C.-M. Yen et al. / European Journal of Internal Medicine 25 (2014) 87–91 Table 1 Demographics between patients with and without IRS.
Table 3 Incidence and hazard ratio for osteoporosis stratified in female by age group.
IRS
P-value
Yes N = 24,979
Male Age, year b40 40–59 ≥60 Mean (SD) Urbanization 1 (highest) 2 3 4 5 (lowest) Occupation Public Labor Business Low income Retired and others
89
IBS
No N = 99,911
n
%
n
%
12,422
49.7
49,686
49.7
9169 9498 6312 46.4
36.7 38.0 25.3 (18.7)
36,676 37,992 25,243 46.1
36.7 38.0 25.3 (18.7)
7168 7320 4584 3513 2392
28.7 29.3 18.4 14.1 9.58
30,520 28,887 17,876 13,232 9393
30.6 28.9 17.9 13.2 9.40
2755 9002 9790 144 3288
11.0 36.0 39.2 0.58 13.2
10,015 33,765 42,138 515 13,478
10.0 33.8 42.2 0.52 13.5
Age, year b40 40–59 ≥60
N0.99 N0.99
Non-IBS
N
Case
IR
N
Case
IR
4938 5028 2591
28 307 463
0.80 9.49 31.79
19,752 20,112 10,361
24 683 1182
0.18 5.42 20.63
IRR
(95% CI)
4.45 1.75 1.54
(2.58–7.67)*** (1.53–2.00)*** (1.38–1.72)***
Incidence, per 1000 person-years. IRR, incidence rate ratio, IBS compared to non-IBS. ⁎⁎⁎ p b 0.0001. b0.0001
b0.0001
Chi-square test.
with the non-IBS cohort in patients b 40 years of age, the HR of osteoporosis in b 40 years IBS cohort was the highest (HR = 3.74, 95% CI = 2.40–5.84). Table 3 shows the age-stratification analysis of the risk of IBSassociated osteoporosis in female. Compared with non-IBS patients in IBS cohort, female patients had the highest risk of developing osteoporosis at b40 years of age (IRR = 4.45, 95% CI = 2.58–7.67 and followed by 40–59 and ≥60 years (IRR = 1.75 and 1.54, 95% CI = 1.53–2.00 and 1.38–1.72, respectively). 4. Discussion The relationship between IBS and osteoporosis is not well discussed in Taiwan. We hypothesized that IBS increases the risk of osteoporosis. For this study, we used the NHRI-released sub-data set for 1million randomly
selected patients from 23 million insured people registered from 1996 to 2010. The diagnoses in the database were coded using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). We identified an exposed study cohort from the database consisting of newly diagnosed patients with IBS (n = 31,892, ICD-9-CM 564.1) from 2000 to 2009. The patients with osteoporosis and hip fracture history (n = 6913, ICD-9-CM 733.0 and 820) before enrolment were excluded. We calculated the person-years of follow-up time for each person until osteoporosis diagnosis (ICD-9-CM 733.0) or censored. Several statistical analysis methods were adopted for differential purpose. To compare the distributions of categorical sociodemographic variables between the 2 cohorts, we used chi-square test. We performed survival analysis by using the Kaplan–Meier method, with significance based on the log-rank test. We used multivariate Cox's proportionalhazards regression analysis to assess the effects of IBS on the risk of osteoporosis. The demographic data show that 49.7% of the IBS patients were men. Age and sex among the 2 cohorts did not differ statistically (Table 1). Epidemiological studies have shown that the prevalence of IBS in the female population differs from that in the male population, with IBS being more common in female [18]. This study shows that different races may exhibit a varying prevalence of IBS, along with sex differences in various races [19]. However, this study shows that a high proportion of IBS patients lived in urban areas, and they were involved in business occupations. Psychological and social factors can influence digestive functions [19].
Table 2 Incidence and hazard ratio for osteoporosis stratified by demographics. IBS
Overall Sex Male Female Age, year b40 40–59 ≥60 Urbanization 1 (highest) 2 3 4 5 (lowest) Occupation Public Labor Business Low income Retired and others
Non-IBS Incidence
IRR
(95% CI)
Adjusted HR
(95% CI)
Case
Person-years
Case
Person-years
1120
162,408
6.90
2586
622,542
4.15
1.66
(1.55–1.78)⁎⁎⁎
1.65
(1.54–1.77)⁎⁎⁎
322 798
80,652 81,755
3.99 9.76
698 1888
306,440 316,102
2.28 5.97
1.75 1.63
(1.54–2.00)⁎⁎⁎ (1.50–1.78)⁎⁎⁎
1.70 1.63
(1.49–1.94)⁎⁎⁎ (1.50–1.77)⁎⁎⁎
39 370 711
64,680 61,706 36,022
0.60 6.00 19.74
39 821 1726
346,709 238,316 137,517
0.16 3.45 12.55
3.81 1.74 1.57
(2.45–6.95)⁎⁎⁎ (1.54–1.97)⁎⁎⁎ (1.44–1.72)⁎⁎⁎
3.74 1.73 1.59
(2.40–5.84)⁎⁎⁎ (1.53–1.96)⁎⁎⁎ (1.46–1.74)⁎⁎⁎
285 289 186 214 146
45,492 47,678 30,342 23,064 15,821
6.26 6.06 6.13 9.28 9.23
629 697 403 441 416
191,556 180,324 11,725 81,375 57,546
3.28 3.87 3.61 5.42 7.23
1.91 1.58 1.72 1.74 1.29
(1.66–2.20)⁎⁎⁎ (1.38–1.81)⁎⁎⁎ (1.45–2.05)⁎⁎⁎ (1.48–2.05)⁎⁎⁎ (1.07–1.56)⁎⁎
1.89 1.50 1.73 1.73 1.38
(1.64–2.17)⁎⁎⁎ (1.31–1.73)⁎⁎⁎ (1.45–2.06)⁎⁎⁎ (1.47–2.04)⁎⁎⁎ (1.15–1.67)⁎⁎⁎
126 498 270 11 215
17,907 58,943 63,953 889 20,716
7.04 8.45 4.22 12.37 10.38
286 1252 616 13 419
62,283 209,925 265,450 3048 81,836
4.59 5.96 2.32 4.26 5.12
1.54 1.43 1.83 2.98 2.05
(1.25–1.90)⁎⁎⁎ (1.29–1.59)⁎⁎⁎ (1.59–2.11)⁎⁎⁎ (1.33–6.64)⁎⁎ (1.74–2.41)⁎⁎⁎
1.69 1.49 1.79 3.13 1.83
(1.37–2.09)⁎⁎⁎ (1.34–1.65)⁎⁎⁎ (1.55–2.07)⁎⁎⁎ (1.38–7.10)⁎⁎ (1.55–2.16)⁎⁎⁎
Incidence, per 1000 person-years. IRR, incidence rate ratio, compared to non-IBS. Adjusted model, adjusted for age, sex, urbanization, depression and cancer. ⁎⁎ P b 0.01. ⁎⁎⁎ P b 0.001.
Incidence
90
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Anxiety related to GI sensations, symptoms, or the context in which these may occur is called gastrointestinal specific anxiety (GSA), and GSA can influence symptom severity and quality of life in patients with IBS [20]. From our study, we found that some results were similar to the Stobaugh et al. We found that age and sex did not differ statistically among 2 groups. The females who are under 40 years old and the males who are between 40 to 60 years old with IBS had the highest risk of developing osteoporosis [21]. Although the pathogenesis of osteoporosis remains unclear, research in the Western context has demonstrated that IBS is a risk factor for osteoporosis [22]. In Taiwan, Kaplan–Meier survival analysis shows that the osteoporosis-free rate was 2% lower in IBS patients than in controls. However significant in the follow-up period (Log-rank Pb.0001), and the risk of osteoporosis was significantly higher in the IBS cohort than in the non-IBS cohort. The cases were diagnosed of IBS, which we gathered from NHI is through ICD-9. We cannot know exactly if they were diagnosed by Rome II or Rome III, because Rome III criteria have a lower detection rate than Rome II criteria [23]. The severity of osteoporosis is diagnosed from the degree of bone marrow density loss [22]. Malabsorption and inflammation are 2 major causes of bone loss in inflammatory bowel disease and IBD [24]. Mucosal inflammation plays an important role in the initiation of functional abnormalities, resulting in the clinical manifestation of IBS [25]. Previous studies have shown that patients with IBS exhibited an altered production of mast cells, T lymphocytes, B lymphocytes, and mucosal cytokine. The relative inflammatory factors, such as the Mast cell, are located near nerve fibers, leading to the development of chronic visceral hyperalgesia. This increases the severity of abdominal pain [25,26]. The ratio of intestinal absorption depends on the normal, fully functional intestinal mucosa, especially in the acute phase of the disease. This in turn leads to a decreased absorption of vitamin D and calcium [24]. Patients with IBS suffer from lower consumption of milk and milk products, which are important sources of calcium. Some IBS patients consume replacement foods such as soy and rice. However, low calcium intake is still apparent in these patients [27]. Vitamin D plays an important role in the regulation of calcium. A lack of vitamin D effectively increases serum PTH, leading to a high bone turnover and increased bone absorption and subsequent bone loss and the release of calcium ions into the bloodstream. This ultimately leads to osteoporosis and fractures [8]. This study shows that the incidence of osteoporosis was highest in the oldest group. Some studies have confirmed age-related osteoporosis in humans and mice [28,29]. This phenomenon seems to occur through the gene expression of the RAS component in the bone tissue [29]. Estrogen plays an important role in the regulation of bone metabolism. Estrogen can prevent osteoporosis by inhibiting osteoblast apoptosis, increasing osteoblast lifespan, and regulating bone formation [30,31]. The decrease in bone mineral density (BMD) that occurs postmenopause often leads to osteoporosis. However, the decreasing rate of BMD is faster in the early post-menopausal period, and the onset of menopause is typically 50 years [28,31,32]. This study shows that women aged 40–59years had the highest risk of developing osteoporosis. The sex difference in IBS prevalence is significant, with IBS predominantly occurring in women [4]. The absorption ability of gastrointestinal tract depends upon the amount of normal mucosa. Chronic and psychological stress increases the activity of IBS, and it affects the normal gastrointestinal absorption through mucosal inflammation [3]. In young female patients, those diagnosed with osteoporosis may present gastrointestinal or endocrine disorders induced by stress or other psychological factors. Anorexia and other GI tract disorders can induce malnutrition, leading to a decrease in BMD. Ovary dysfunction reduces the production of estrogen, leading to post-menopausal-like osteoporosis [33–35]. Thus, malabsorption and ovary dysfunction induced by stress may be caused by significant differences in patients less than 40 years old.
The identification of IBS in this study was based on an ICD-9 code, but this study still has some limitations. First, the NHIRD does not provide detailed information regarding patients such as their smoking habits, alcohol consumption, BMI, physical activity, socioeconomic status, and family history of cancer. All of these variables are possible risk factors for IBS or osteoporosis. Second, the evidence derived from a cohort study is generally of a lower methodological quality than that from randomized trials. This is because a cohort study design is subject to many biases related to adjustment for confounding factors. Despite our meticulous study design with adequate control for confounding factors, a key limitation of this study is that bias can still remain because of possible unmeasured or unknown confounders. Third, the diagnoses in NHI claims primarily serve the purpose of administrative billing, and cannot be verified for scientific purposes. We were unable to contact the patients directly to obtain more information because of the anonymity ensured by the identification numbers. Although the data that we obtained regarding IBS and osteoporosis diagnoses were highly reliable, underlying mechanisms must still be explored and identified. Additional large population-based unbiased studies are required to confirm our current findings before drawing any firm conclusions. 5. Conclusion This study shows that IBS is a risk factor for predicting osteoporosis in Taiwan, especially in middle-aged female patients. Osteoporosisinduced fracture is also a well-known severe complication. If IBS can be diagnosed early and treated, it may reduce the prevalence of the fracture. Learning points • Irritable bowel syndrome, osteoporosis. Contributors Conception/design: Chia-Ming Yen, Ming-Chia Lin, Chia-Hung Kao. Provision of study materials: Chih-Hsin Muo, Shih-Ni Chang, YenJung Chang. Collection and/or assembly of data: Chia-Ming Yen, Ming-Chia Lin, Chia-Hung Kao. Data analysis and interpretation: Chia-Ming Yen, Chih-Hsin Muo, Ming-Chia Lin, Chia-Hung Kao. Manuscript writing: All authors. Final approval of manuscript: All authors. Funding The study was supported by grants from the study hospital (DMR-102-014 and DMR-102-023); Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH102-TDB-111-004), Taiwan Department of Health Cancer Research Center for Excellence (DOH102-TD-C-111-005); and International ResearchIntensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I002-303). Conflict of interests The authors declare that they have no conflicts of interest. References [1] Hoffman JM. Irritable bowel syndrome: is the colonicmucosa to blame? Neurogastroenterol Motil 2012;24:1051–3. [2] Callahan MJ. Irritable bowel syndrome neuropharmacology a review of approved and investigational compounds. J Clin Gastroenterol 2002;35: s58–67 (Suppl.). [3] Bengtsson M, Sjöberg K, Candamio M, Lerman A, Ohlsson B. Anxiety in close relationships is higher and self-esteem lower in patients with irritable bowel
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Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
A nationwide population cohort study: Irritable bowel syndrome is a risk factor of osteoporosis Chia-Ming Yen a,1, Chih-Hsin Muo b, Ming-Chia Lin c,1, Shih-Ni Chang b, Yen-Jung Chang b,f,1, Chia-Hung Kao d,e,⁎,1 a
Department of Anesthesiology, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan Department of Nuclear Medicine, E-DA Hospital, Kaohsiung, Taiwan d Department of Nuclear Medicine PET Center, China Medical University Hospital, Taichung, Taiwan e Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan f Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 14 August 2013 Received in revised form 14 October 2013 Accepted 17 October 2013 Available online 30 October 2013 Keywords: Cohort study Irritable bowel syndrome Osteoporosis National Health Insurance
a b s t r a c t Background: The goal of the study is to determine the relationship between irritable bowel syndrome (IBS) and osteoporosis in Taiwan. Materials and methods: We collected data from the National Health Insurance (NHI) program in Taiwan. The sample in this study consisted of 31,892 patients enrolled from 2000 to 2009 and diagnosed by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). We divided the sample into 2 cohorts based on whether they had IBS, and formed subgroups based on age, sex, enrolment year, and enrolment month. Results: Age and gender did not differ statistically among the 2 cohorts. Results show that IBS is more correlated with urbanization and the occupation of business. The IBS cohort had a higher incidence of osteoporosis than the non-IBS cohort (6.90 vs 4.15 per 1000 person-years; HR = 1.65, 955 CI = 1.54–1.77). Female patients aged 40–59 years had the highest risk of developing osteoporosis (HR = 4.42, 95% CI = 3.37–5.79 in the IBS cohort; HR = 4.41, 95% CI = 3.67–5.29 in the non-IBS cohort, respectively). In IBS patients less than 40 years of age, female patients had a significant 2.18-fold greater risk of developing osteoporosis than male patients (HR = 2.18, 95% CI = 1.09–4.38). Conclusions: IBS is a risk factor for osteoporosis in Taiwan. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by chronic abdominal pain or discomfort and altered GI function in the absence of alarm or over-inflammation [1]. IBS pathogenesis can involve altered intestinal motility, visceral hypersensitivity, altered compliance of the gut wall, psychological disturbance, or any combination of these conditions [2]. The etiology of IBS remains unknown, but it seems that stressors, such as life events and chronic stress, and the patient's individual and genetic background can modulate intestinal disease activity through complex psychoimmunologic mechanisms, both on a systemic level and on a gut mucosal level [3]. The development of symptom-based criteria, such as Rome criteria or GI
⁎ Corresponding author at: Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x7412; fax: +886 4 22336174. E-mail address: [email protected] (C.-H. Kao). 1 Ming-Chia Lin and Chia-Ming Yen contributed equally to this work, as well as Yen-Jung Chang and Chia-Hung Kao contributed equally to this work.
symptom questionnaire has made it more convenient and effective for research [4]. Osteoporosis is a condition characterized by a reduction in bone mass, disruption of bone micro-architecture, and skeletal fragility, with a resulting increase in fracture risk [5]. Osteoporosis has traditionally been viewed as a physiological process associated with aging, but today it is recognized as a multifactorial systemic polygenic disease in which hormonal, environmental, and nutritional factors modulate genetic determinants [6,7]. Traditional risk factors for osteoporosis include aging, hypertension, antihypertensive medication [8], primary hyperparathyroidism [9], menopause [10], type 2 diabetes mellitus [11], corticosteroid abuse [12], Parkinson's disease [13], social disadvantage [14], low calcium intake [15], and vitamin D deficiency [15]. Disorders of the liver and the gastrointestinal tract, particularly chronic inflammatory processes such as inflammatory bowel disease (IBD) and coeliac disease, are commonly associated with osteopenia and osteoporosis [16]. The increased prevalence of osteopenia and osteoporosis is a significant complication in both children and adults [17]. Therefore, this study adopts the large database of the National Health Insurance (NHI) to confirm whether IBS is a risk factor for osteoporosis in Taiwan.
0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.10.009
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2. Methods
2.3. Statistical analysis
2.1. Data sources
All data were expressed as frequency (with percent) or mean with standard deviation. We used the chi-square test to compare the distributions of categorical sociodemographic variables between the 2 cohorts. We also calculated the incidence density with person-years by these variables in the study cohort and comparison cohort. We calculated the incidence rate ratio (IRR) of osteoporosis for each variable. To estimate the osteoporosis-free risk of developing osteoporosis in IBS patients and non-IBS patients, we performed survival analysis by using the Kaplan–Meier method, with significance based on the logrank test. We used multivariate Cox's proportional-hazards regression analysis to assess the effects of IBS on the risk of osteoporosis. We also calculated the hazard ratio (HR) and 95% confidence interval (CI) by using the model. We defined statistical significance as a two-tailed P value of less than .05.
The National Health Insurance (NHI) in Taiwan is a mandatory universal health insurance program implemented in 1995 that offers comprehensive medical care to all residents (up to 99% of the population). Claims data are collected in the National Health Insurance Research Database (NHIRD) and managed by the National Health Research Institutes (NHRI). For research purposes, this study uses a sub-data set of 1 million randomly selected patients from 23 million insured people registered from 1996 to 2000. This database contained all medical records of each insurant from 1996 to 2010. Diagnoses in the database were coded using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).
2.2. Study groups 3. Results We identified an exposed study cohort from the database consisting of newly diagnosed patients with IBS (n = 31,892, ICD-9-CM 564.1) from 2000 to 2009. We excluded patients with osteoporosis and hip fracture history (n = 6913, ICD-9-CM 733.0 and 820) before enrolment. Fig. 1 shows the flow of patient selection. For each IBS case identified in the study, we randomly selected a comparison non-IBS cohort (i.e., insurants without IBS) from the database at a 1:4 ratio. We frequency matched the controls with IBS patients on the bases of sex, age (every 5 years), enrolment year, and enrolment month. We followed both the IBS patient cohort and the comparison cohort from the enrolment date to December 31, 2010 or diagnosis of osteoporosis, whichever came first. We calculated the person-years of follow-up time for each person until osteoporosis diagnosis (ICD-9CM 733.0) or censored. The date of censoring was defined as the date the study patients died in the follow-up period, the date of last withdrawal from NHI, or the date of termination of follow-up. Sociodemographic characteristic included urbanization and occupation. Urbanization was grouped into five levels based on Liu's report. The highest urban was defined as level “1” and the lowest was defined as level “5”. According to attribute of insurant's institution, we classified occupation into five types: public, labor, business, low income, and retired and others.
The demographic data in this study show that 49.7% of the IBS patients were male. Age and sex among the 2 cohorts did not differ statistically (Table 1). The IBS patients had a higher proportion of living in urban areas (30.6% vs 28.7%, Pb .0001) and with business occupations (42.2% vs 39.2%, P b .0001). Table 2 presents the incident densities and rate ratio of IBS-associated osteoporosis based on sociodemographic status. Overall, the follow-up results show a higher osteoporosis incidence in the IBS cohort than in the non-IBS cohort (6.90 vs 4.15 per 1000 person-years). Kaplan–Meier survival analysis shows that the osteoporosis-free rate was 2% lower in the IBS patients than in the controls, but significant in the follow-up period (Log-rank P b .0001). Multivariate analysis for Cox's proportionalhazards regression model shows that the risk of osteoporosis was significantly higher in the IBS cohort than in the non-IBS cohort (HR = 1.65, 95% CI = 1.54–1.77) (Table 2). Compared to males without IBS and females without IBS, the risks of osteoporosis in male and female IBS patients were 1.70 (95% CI = 1.49– 1.94) and 1.63 (95% CI = 1.50–1.77), respectively. In both cohorts, the incidence densities of osteoporosis increased from b 40 to ≥60 years (0.60 to 19.74 and 0.16 to 12.55 per 10 000 person-years in nonIBS and IBS groups, respectively) (Table 2). However, compared
Fig. 1. Flow chart for selecting study subjects.
C.-M. Yen et al. / European Journal of Internal Medicine 25 (2014) 87–91 Table 1 Demographics between patients with and without IRS.
Table 3 Incidence and hazard ratio for osteoporosis stratified in female by age group.
IRS
P-value
Yes N = 24,979
Male Age, year b40 40–59 ≥60 Mean (SD) Urbanization 1 (highest) 2 3 4 5 (lowest) Occupation Public Labor Business Low income Retired and others
89
IBS
No N = 99,911
n
%
n
%
12,422
49.7
49,686
49.7
9169 9498 6312 46.4
36.7 38.0 25.3 (18.7)
36,676 37,992 25,243 46.1
36.7 38.0 25.3 (18.7)
7168 7320 4584 3513 2392
28.7 29.3 18.4 14.1 9.58
30,520 28,887 17,876 13,232 9393
30.6 28.9 17.9 13.2 9.40
2755 9002 9790 144 3288
11.0 36.0 39.2 0.58 13.2
10,015 33,765 42,138 515 13,478
10.0 33.8 42.2 0.52 13.5
Age, year b40 40–59 ≥60
N0.99 N0.99
Non-IBS
N
Case
IR
N
Case
IR
4938 5028 2591
28 307 463
0.80 9.49 31.79
19,752 20,112 10,361
24 683 1182
0.18 5.42 20.63
IRR
(95% CI)
4.45 1.75 1.54
(2.58–7.67)*** (1.53–2.00)*** (1.38–1.72)***
Incidence, per 1000 person-years. IRR, incidence rate ratio, IBS compared to non-IBS. ⁎⁎⁎ p b 0.0001. b0.0001
b0.0001
Chi-square test.
with the non-IBS cohort in patients b 40 years of age, the HR of osteoporosis in b 40 years IBS cohort was the highest (HR = 3.74, 95% CI = 2.40–5.84). Table 3 shows the age-stratification analysis of the risk of IBSassociated osteoporosis in female. Compared with non-IBS patients in IBS cohort, female patients had the highest risk of developing osteoporosis at b40 years of age (IRR = 4.45, 95% CI = 2.58–7.67 and followed by 40–59 and ≥60 years (IRR = 1.75 and 1.54, 95% CI = 1.53–2.00 and 1.38–1.72, respectively). 4. Discussion The relationship between IBS and osteoporosis is not well discussed in Taiwan. We hypothesized that IBS increases the risk of osteoporosis. For this study, we used the NHRI-released sub-data set for 1million randomly
selected patients from 23 million insured people registered from 1996 to 2010. The diagnoses in the database were coded using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). We identified an exposed study cohort from the database consisting of newly diagnosed patients with IBS (n = 31,892, ICD-9-CM 564.1) from 2000 to 2009. The patients with osteoporosis and hip fracture history (n = 6913, ICD-9-CM 733.0 and 820) before enrolment were excluded. We calculated the person-years of follow-up time for each person until osteoporosis diagnosis (ICD-9-CM 733.0) or censored. Several statistical analysis methods were adopted for differential purpose. To compare the distributions of categorical sociodemographic variables between the 2 cohorts, we used chi-square test. We performed survival analysis by using the Kaplan–Meier method, with significance based on the log-rank test. We used multivariate Cox's proportionalhazards regression analysis to assess the effects of IBS on the risk of osteoporosis. The demographic data show that 49.7% of the IBS patients were men. Age and sex among the 2 cohorts did not differ statistically (Table 1). Epidemiological studies have shown that the prevalence of IBS in the female population differs from that in the male population, with IBS being more common in female [18]. This study shows that different races may exhibit a varying prevalence of IBS, along with sex differences in various races [19]. However, this study shows that a high proportion of IBS patients lived in urban areas, and they were involved in business occupations. Psychological and social factors can influence digestive functions [19].
Table 2 Incidence and hazard ratio for osteoporosis stratified by demographics. IBS
Overall Sex Male Female Age, year b40 40–59 ≥60 Urbanization 1 (highest) 2 3 4 5 (lowest) Occupation Public Labor Business Low income Retired and others
Non-IBS Incidence
IRR
(95% CI)
Adjusted HR
(95% CI)
Case
Person-years
Case
Person-years
1120
162,408
6.90
2586
622,542
4.15
1.66
(1.55–1.78)⁎⁎⁎
1.65
(1.54–1.77)⁎⁎⁎
322 798
80,652 81,755
3.99 9.76
698 1888
306,440 316,102
2.28 5.97
1.75 1.63
(1.54–2.00)⁎⁎⁎ (1.50–1.78)⁎⁎⁎
1.70 1.63
(1.49–1.94)⁎⁎⁎ (1.50–1.77)⁎⁎⁎
39 370 711
64,680 61,706 36,022
0.60 6.00 19.74
39 821 1726
346,709 238,316 137,517
0.16 3.45 12.55
3.81 1.74 1.57
(2.45–6.95)⁎⁎⁎ (1.54–1.97)⁎⁎⁎ (1.44–1.72)⁎⁎⁎
3.74 1.73 1.59
(2.40–5.84)⁎⁎⁎ (1.53–1.96)⁎⁎⁎ (1.46–1.74)⁎⁎⁎
285 289 186 214 146
45,492 47,678 30,342 23,064 15,821
6.26 6.06 6.13 9.28 9.23
629 697 403 441 416
191,556 180,324 11,725 81,375 57,546
3.28 3.87 3.61 5.42 7.23
1.91 1.58 1.72 1.74 1.29
(1.66–2.20)⁎⁎⁎ (1.38–1.81)⁎⁎⁎ (1.45–2.05)⁎⁎⁎ (1.48–2.05)⁎⁎⁎ (1.07–1.56)⁎⁎
1.89 1.50 1.73 1.73 1.38
(1.64–2.17)⁎⁎⁎ (1.31–1.73)⁎⁎⁎ (1.45–2.06)⁎⁎⁎ (1.47–2.04)⁎⁎⁎ (1.15–1.67)⁎⁎⁎
126 498 270 11 215
17,907 58,943 63,953 889 20,716
7.04 8.45 4.22 12.37 10.38
286 1252 616 13 419
62,283 209,925 265,450 3048 81,836
4.59 5.96 2.32 4.26 5.12
1.54 1.43 1.83 2.98 2.05
(1.25–1.90)⁎⁎⁎ (1.29–1.59)⁎⁎⁎ (1.59–2.11)⁎⁎⁎ (1.33–6.64)⁎⁎ (1.74–2.41)⁎⁎⁎
1.69 1.49 1.79 3.13 1.83
(1.37–2.09)⁎⁎⁎ (1.34–1.65)⁎⁎⁎ (1.55–2.07)⁎⁎⁎ (1.38–7.10)⁎⁎ (1.55–2.16)⁎⁎⁎
Incidence, per 1000 person-years. IRR, incidence rate ratio, compared to non-IBS. Adjusted model, adjusted for age, sex, urbanization, depression and cancer. ⁎⁎ P b 0.01. ⁎⁎⁎ P b 0.001.
Incidence
90
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Anxiety related to GI sensations, symptoms, or the context in which these may occur is called gastrointestinal specific anxiety (GSA), and GSA can influence symptom severity and quality of life in patients with IBS [20]. From our study, we found that some results were similar to the Stobaugh et al. We found that age and sex did not differ statistically among 2 groups. The females who are under 40 years old and the males who are between 40 to 60 years old with IBS had the highest risk of developing osteoporosis [21]. Although the pathogenesis of osteoporosis remains unclear, research in the Western context has demonstrated that IBS is a risk factor for osteoporosis [22]. In Taiwan, Kaplan–Meier survival analysis shows that the osteoporosis-free rate was 2% lower in IBS patients than in controls. However significant in the follow-up period (Log-rank Pb.0001), and the risk of osteoporosis was significantly higher in the IBS cohort than in the non-IBS cohort. The cases were diagnosed of IBS, which we gathered from NHI is through ICD-9. We cannot know exactly if they were diagnosed by Rome II or Rome III, because Rome III criteria have a lower detection rate than Rome II criteria [23]. The severity of osteoporosis is diagnosed from the degree of bone marrow density loss [22]. Malabsorption and inflammation are 2 major causes of bone loss in inflammatory bowel disease and IBD [24]. Mucosal inflammation plays an important role in the initiation of functional abnormalities, resulting in the clinical manifestation of IBS [25]. Previous studies have shown that patients with IBS exhibited an altered production of mast cells, T lymphocytes, B lymphocytes, and mucosal cytokine. The relative inflammatory factors, such as the Mast cell, are located near nerve fibers, leading to the development of chronic visceral hyperalgesia. This increases the severity of abdominal pain [25,26]. The ratio of intestinal absorption depends on the normal, fully functional intestinal mucosa, especially in the acute phase of the disease. This in turn leads to a decreased absorption of vitamin D and calcium [24]. Patients with IBS suffer from lower consumption of milk and milk products, which are important sources of calcium. Some IBS patients consume replacement foods such as soy and rice. However, low calcium intake is still apparent in these patients [27]. Vitamin D plays an important role in the regulation of calcium. A lack of vitamin D effectively increases serum PTH, leading to a high bone turnover and increased bone absorption and subsequent bone loss and the release of calcium ions into the bloodstream. This ultimately leads to osteoporosis and fractures [8]. This study shows that the incidence of osteoporosis was highest in the oldest group. Some studies have confirmed age-related osteoporosis in humans and mice [28,29]. This phenomenon seems to occur through the gene expression of the RAS component in the bone tissue [29]. Estrogen plays an important role in the regulation of bone metabolism. Estrogen can prevent osteoporosis by inhibiting osteoblast apoptosis, increasing osteoblast lifespan, and regulating bone formation [30,31]. The decrease in bone mineral density (BMD) that occurs postmenopause often leads to osteoporosis. However, the decreasing rate of BMD is faster in the early post-menopausal period, and the onset of menopause is typically 50 years [28,31,32]. This study shows that women aged 40–59years had the highest risk of developing osteoporosis. The sex difference in IBS prevalence is significant, with IBS predominantly occurring in women [4]. The absorption ability of gastrointestinal tract depends upon the amount of normal mucosa. Chronic and psychological stress increases the activity of IBS, and it affects the normal gastrointestinal absorption through mucosal inflammation [3]. In young female patients, those diagnosed with osteoporosis may present gastrointestinal or endocrine disorders induced by stress or other psychological factors. Anorexia and other GI tract disorders can induce malnutrition, leading to a decrease in BMD. Ovary dysfunction reduces the production of estrogen, leading to post-menopausal-like osteoporosis [33–35]. Thus, malabsorption and ovary dysfunction induced by stress may be caused by significant differences in patients less than 40 years old.
The identification of IBS in this study was based on an ICD-9 code, but this study still has some limitations. First, the NHIRD does not provide detailed information regarding patients such as their smoking habits, alcohol consumption, BMI, physical activity, socioeconomic status, and family history of cancer. All of these variables are possible risk factors for IBS or osteoporosis. Second, the evidence derived from a cohort study is generally of a lower methodological quality than that from randomized trials. This is because a cohort study design is subject to many biases related to adjustment for confounding factors. Despite our meticulous study design with adequate control for confounding factors, a key limitation of this study is that bias can still remain because of possible unmeasured or unknown confounders. Third, the diagnoses in NHI claims primarily serve the purpose of administrative billing, and cannot be verified for scientific purposes. We were unable to contact the patients directly to obtain more information because of the anonymity ensured by the identification numbers. Although the data that we obtained regarding IBS and osteoporosis diagnoses were highly reliable, underlying mechanisms must still be explored and identified. Additional large population-based unbiased studies are required to confirm our current findings before drawing any firm conclusions. 5. Conclusion This study shows that IBS is a risk factor for predicting osteoporosis in Taiwan, especially in middle-aged female patients. Osteoporosisinduced fracture is also a well-known severe complication. If IBS can be diagnosed early and treated, it may reduce the prevalence of the fracture. Learning points • Irritable bowel syndrome, osteoporosis. Contributors Conception/design: Chia-Ming Yen, Ming-Chia Lin, Chia-Hung Kao. Provision of study materials: Chih-Hsin Muo, Shih-Ni Chang, YenJung Chang. Collection and/or assembly of data: Chia-Ming Yen, Ming-Chia Lin, Chia-Hung Kao. Data analysis and interpretation: Chia-Ming Yen, Chih-Hsin Muo, Ming-Chia Lin, Chia-Hung Kao. Manuscript writing: All authors. Final approval of manuscript: All authors. Funding The study was supported by grants from the study hospital (DMR-102-014 and DMR-102-023); Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH102-TDB-111-004), Taiwan Department of Health Cancer Research Center for Excellence (DOH102-TD-C-111-005); and International ResearchIntensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I002-303). Conflict of interests The authors declare that they have no conflicts of interest. References [1] Hoffman JM. Irritable bowel syndrome: is the colonicmucosa to blame? Neurogastroenterol Motil 2012;24:1051–3. [2] Callahan MJ. Irritable bowel syndrome neuropharmacology a review of approved and investigational compounds. J Clin Gastroenterol 2002;35: s58–67 (Suppl.). [3] Bengtsson M, Sjöberg K, Candamio M, Lerman A, Ohlsson B. Anxiety in close relationships is higher and self-esteem lower in patients with irritable bowel
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