The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019
RESEARCH ARTICLE

Bone Mineral Density and Bone Remodeling in Tunisian Patients with Inflammatory Bowel Disease



Samar Ben Jemaa1, *, Lassaad Chtourou2, Rim Akrout1, Khansa Chaabouni3, Tarek Chaabouni3, Hela Makni Fourati1, Ali Amouri2, Nabil Tahri2, Fatma Ayedi3, Sofien Baklouti1
1 Department of Rhumatology, Hedi Chaker University Hospital, Sfax, Tunisia
2 Department of Gastroenterology and Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
3 Laboratory of Biochemistry, Habib Bourguiba University Hospital, Sfax, Tunisia

Abstract

Background:

A high prevalence of osteopenia and osteoporosis is observed in patients with Inflammatory Bowel Disease (IBD).

Objective:

The aim of our study was to investigate the prevalence of bone loss, bone remodeling and risk factors in Tunisian patient with IBD.

Patients and Methods:

The study included 40 patients with IBD and 32 age- and sex-matched healthy controls subjects. All participants underwent bone densitometry by dual energy X-ray absorptiometry at the femoral neck and lumbar spine. Serum levels of 25-hydroxy vitamin D (25(OH)D), parathyroid hormone (PTH), osteocalcin(OC), and urinary degradation products of C-terminal telopeptide of type I collagen (CTXI) were measured in all participants to assess the bone metabolism status.

Results:

Twelve (30%) patients were normal, 32.5% were osteopenic and 37.5% were osteoporotic. Osteoporosis was more frequent in IBD patients than controls (p=0.0001). Age and inflammation were associated with low bone mineral density (BMD). Mean calcium, phosphorus and alkaline phosphatase levels were similar in both groups. Median 25(OH) D levels were significantly lower in IBD patients compared with controls (p=0.0001). Median urinary CTXI levels were significantly higher in IBD patients compared with healthy controls (p=0.007). No significant differences between IBD patients and controls concerning the median serum OC and PTH levels were found.

Conclusion:

In our study, there is a high prevalence of low BMD in IBD patients and an increase in bone resorption without a change of bone formation. Low BMI and hypovitaminoses D were identified as risk factors for low BMD.

Keywords: Inflammatory bowel disease, Osteopenia, Osteoporosis, Hypovitaminosis D, Bone mineral density, Bone remodeling.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 22
Last Page: 29
Publisher Id: TORJ-13-22
DOI: 10.2174/1874312901913010022

Article History:

Received Date: 30/11/2018
Revision Received Date: 31/01/2019
Acceptance Date: 18/02/2019
Electronic publication date: 28/02/2019
Collection year: 2019

Article Metrics:

CrossRef Citations:
0

Total Statistics:

Full-Text HTML Views: 316
Abstract HTML Views: 233
PDF Downloads: 143
ePub Downloads: 110
Total Views/Downloads: 802

Unique Statistics:

Full-Text HTML Views: 209
Abstract HTML Views: 125
PDF Downloads: 86
ePub Downloads: 70
Total Views/Downloads: 490
Geographical View

© 2019 Ben Jemaa et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Rhumatology, Hedi Chaker University Hospital, Sfax, PC: 3089, Tunisia; Tel: 23733004; E-mail: bendjmaa@gmail.com




1. INTRODUCTION

There is a growing body of evidence that patients with Inflammatory Bowel Disease (IBD) are at increased risk for osteopenia and osteoporosis. Osteopenia and osteoporosis are common extraintestinal complications in IBD that increase the

risk of vertebral and femoral neck fractures [1Robinson RJ, al-Azzawi F, Iqbal SJ, et al. Osteoporosis and determinants of bone density in patients with Crohn’s disease. Dig Dis Sci 1998; 43(11): 2500-6.[http://dx.doi.org/10.1023/A:1026650719552] [PMID: 9824142] , 2Ananthakrishnan AN, McGinley EL, Binion DG, Saeian K. Fracture-associated hospitalizations in patients with inflammatory bowel disease. Dig Dis Sci 2011; 56(1): 176-82.[http://dx.doi.org/10.1007/s10620-010-1433-9] [PMID: 20936351] ].

The prevalence of osteoporosis is changeable depending on the studied population and the technique of bone density measurement used [3Boubaker J, Feki M, Hsairi M, et al. Osteoporosis and inflammatory bowel disease: Prevalence and risk factors in Tunisian patients. Gastroenterol Clin Biol 2003; 27(10): 901-7.[PMID: 14631305] ]. Certain factors are related to the disease itself (intestinal inflammation, extent of lesions, disease duration), whereas others depend on the patient himself (age, body mass index, nutritional status, hormonal status) or the treatment (corticosteroids or surgical resection) [1Robinson RJ, al-Azzawi F, Iqbal SJ, et al. Osteoporosis and determinants of bone density in patients with Crohn’s disease. Dig Dis Sci 1998; 43(11): 2500-6.[http://dx.doi.org/10.1023/A:1026650719552] [PMID: 9824142] , 2Ananthakrishnan AN, McGinley EL, Binion DG, Saeian K. Fracture-associated hospitalizations in patients with inflammatory bowel disease. Dig Dis Sci 2011; 56(1): 176-82.[http://dx.doi.org/10.1007/s10620-010-1433-9] [PMID: 20936351] ].

Several studies have demonstrated a decrease in Bone Mineral Density (BMD) in patients with Crohn's Disease (CD), and to a less extent in Ulcerative Colitis (UC) [4Kotze LM, Costa CT, Cavassani MF, Nisihara RM. Alert for bone alterations and low serum concentrations of vitamin D in patients with intestinal inflammatory disease. Rev Assoc Med Bras (1992) 2017; 63(1): 13-7.[http://dx.doi.org/10.1590/1806-9282.63.01.13] [PMID: 28225873] ]. The higher prevalence of bone disease in CD patients is thought to be related to ileal and small intestine involvement of disease-causing vitamin D and calcium malabsorption, estrogen deficiency and malnutrition [1Robinson RJ, al-Azzawi F, Iqbal SJ, et al. Osteoporosis and determinants of bone density in patients with Crohn’s disease. Dig Dis Sci 1998; 43(11): 2500-6.[http://dx.doi.org/10.1023/A:1026650719552] [PMID: 9824142] , 5Jahnsen J, Falch JA, Aadland E, Mowinckel P. Bone mineral density is reduced in patients with Crohn’s disease but not in patients with ulcerative colitis: A population based study. Gut 1997; 40(3): 313-9.[http://dx.doi.org/10.1136/gut.40.3.313] [PMID: 9135518] ]. However, some recent studies have found no significant differences in the prevalence of osteoporosis between patients with UC and those with CD [6Bregenzer N, Erban P, Albrich H, et al. Screening for osteoporosis in patients with inflammatory bowel disease by using urinary N-telopeptides. Eur J Gastroenterol Hepatol 2002; 14(6): 599-605.[http://dx.doi.org/10.1097/00042737-200206000-00004] [PMID: 12072593] , 7Schoon EJ, Blok BM, Geerling BJ, Russel MG, Stockbrügger RW, Brummer RJ. Bone mineral density in patients with recently diagnosed inflammatory bowel disease. Gastroenterology 2000; 119(5): 1203-8.[http://dx.doi.org/10.1053/gast.2000.19280] [PMID: 11054377] ].

Bone tissue is constantly being renewed and repaired by a coupled process of resorption and formation called bone remodeling. In this study, we aimed to estimate the prevalence of bone loss and the rate of bone remodeling in Tunisian adults patients with IBD, and identify the potential risk factors of bone loss.

2. PATIENTS AND METHODS

2.1. Patients

This is a single-centre clinical cross-sectional and comparative study, conducted between October 2013 and June 2014. In this period, forty IBD patients who followed up at the Department of Gastroenterology and Rheumatology at Hedi Chaker University Hospital were included in this study. Our study received research ethics board approval from the “C.P.P. SUD” (0069/2018) committee. Thirty two age- and sex-matched healthy subjects were selected as controls. All participants, patients and controls, were of Tunisian origin.

The exclusion criteria of the study included diseases known to affect bone metabolism such as malignant diseases, celiac disease, short bowel disease, kidney failure, liver disease, thyroid disease, diabetes mellitus and the use of medications such as bisphosphonates, sodium fluoride, calcitonin and hormone substitution therapy.

The diagnosis of UC and CD was based on standard criteria including clinical criteria, endoscopy and histopathological biopsy [8Stange EF, Travis SPL, Vermeire S, et al. European Crohn’s and Colitis Organisation (ECCO). European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. J Crohn’s Colitis 2008; 2(1): 1-23.[http://dx.doi.org/10.1016/j.crohns.2007.11.001] [PMID: 21172194] , 9Stange EF, Travis SPL, Vermeire S, Beglinger C, Kupcinskas L. K Geboes and al. European crohn’s and colitis organisation. European evidence based consensus on the diagnosis and management of Crohn’s disease: Definitions and diagnosis. Gut 2006; 55: 1-15.[http://dx.doi.org/10.1136/gut.2005.081950a] [PMID: 16344569] ] and the Montreal classification was used for disease phenotyping [10Satsangi J, Silverberg MS, Vermeire S, Colombel J-F. The Montreal classification of inflammatory bowel disease: Controversies, consensus, and implications. Gut 2006; 55(6): 749-53.[http://dx.doi.org/10.1136/gut.2005.082909] [PMID: 16698746] ]. The activity and severity of diseases were evaluated based on the Crohn’s disease activity index (CDAI) for CD and the Truelove-Witts score for UC [11Truelove SC, Witts LJ. Cortisone in ulcerative colitis. BMJ 1955; 2(4947): 1041-8.[http://dx.doi.org/10.1136/bmj.2.4947.1041] [PMID: 13260656] , 12Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a crohn’s disease activity index. National cooperative crohn’s disease study. Gastroenterology 1976; 70(3): 439-44.[PMID: 1248701] ].

For each patient, the following data were collected: age, gender, menopausal status for females, smoking status, physical activity, solar index (number of hours of sun exposition X exposed part of the body (%)), body mass index (BMI) in Kg/m2, location, extent and duration of the disease, ongoing treatments, history of surgical resection, cumulative corticosteroid dose (expressed in g prednisone equivalent) and duration of corticosteroid treatment. Informed consent was obtained from all participants.

2.2. Methods

2.2.1. Biochemical Markers

Blood and urine samples were collected from all IBD patients and control subjects in the morning after an overnight fast. Then, they were stored at -80°C until assayed. Calcium, phosphorus, total serum alkaline phosphate and creatinine were determined with an optimized method using a CX9 Beckmann Coulter automate. Urinary CrossLaps were measured with an immunoenzymatic method.

Serum intact parathyroid hormone (PTH), 25 hydroxy vitamin D (25(OH) D) and serum osteocalcin were measured by an electro-chemiluminescence immunoassay ECLIA (Roche Elecsys2010).

Laboratory parameters such as albumin and Erythrocyte Sedimentation Rate (ESR) were also checked in all patients.

The serum calcium was corrected with albumin level using this formula:

Corrected calcium level = measured calcium level + 0,025 x (40-albumin).

Table 1 shows the biochemical markers which were measured in IBD patients and controls, their analytical method, their normal range and their unit.

Table 1
Biochemical markers measured in Inflammatory Bowel Disease patients and controls, their analytical Method, their normal range and their unit.


Table 2
Study population demographic and clinical parameters.


2.2.2. Bone Mineral Density Measurements

BMD was evaluated at the lumbar spine (L1 to L4) and the femoral neck using the Lunar Prodigy Dual-energy X-ray Absorptiometry (DXA) system.

BMD results were expressed as T-scores which is the number of Standard Deviations (SD) of the patients BMD from the mean peak value for a reference population with the same sex and race. Patients were classified according to the World Health Organisation (WHO) criteria [25World Health Organisation. Assessment of fracture risk and its application to sceening for post-menopausal osteoporosis. Report of a WHO study group. Tech Rep Ser (World Health Organ) 1994; 843: 1-129.] as normal (T-score > -1 SD at both lumbar spine and femoral neck), osteopenic (T-score from -1.0 SD to -2.5 SD at either lumbar spine or femoral neck or both) and osteoporotic (T-score ≤ -2.5 at either lumbar spine or femoral neck or both).

2.2.3. Statistical Analysis

Statistical analysis was carried out using the Statistical Package for Social Science (SPSS) program for Windows® version 20.0 software. Data were presented as the number (%) and mean ± Standard Deviation (SD) or median (range: min – max). Differences between groups were compared by Student test for continuous variables or Mann-Whitney test (nonparametric test) and by Chi-squared test for categorical variables. Correlations between continuous variables were assessed using Spearman rank correlation. A p value <0.05 was considered statistically significant.

All authors had access to the study data and reviewed and approved the final manuscript.

3. RESULTS

The main characteristics of the study subjects are shown in Table 2.

In all, 40 Tunisian IBD patients and 32 age- and sex-matched healthy controls were enrolled in the study. No participants had a History of drug use related to bone density such as bisphosphonate, vitamin D 3, SERM, denosumab and statin.

Nineteen (47.5%) patients were identified as having CD and 21 (52.5%) patients as having UC.

There were 17 men and 23 women in the total group. In patients with CD, male to female ratio was 0.72 and in UC patients, it was 0.75. Mean age was 43.53 ± 13.96 years (range 16 – 71) in all IBD patients whereas it was 45.14 ± 13.52 years (range 16 – 71) and 41.74 ± 14.59 years (range 19 – 62) in UC and CD patients, respectively.

There was no statistically significant difference in age, sex, smoking, solar index, physical activity and menopausal status between the IBD and the control groups. BMI was significantly lower in patients than controls subjects (p=0.001).

Median disease duration was 18 months (range 1 - 312 months) for CD and 31 months (range 1 – 168 months) for UC. CD was ileal in 15.8% of patients, ileocolonic in 68.4% and colonic in 15.8%. For UC, 33.3% of patients had left sided colitis, 42.9% had pancolitis and 23.8% proctitis. Mild and moderate activities of the disease were observed in 73.68% and in 80.9% of the CD and UC patients, respectively. Intestinal resection had been performed in 26.31% of patients with CD and one patient with UC had undergone coloproctectomy with ileoanal anastomosis.

Twenty-two (19 CD and 3 UC) patients had received corticosteroid treatments. The cumulative dose was 3770 ± 1081mg.

Ten patients had received 5-aminosalicylic acid (5-ASA), eight patients azathioprine, one cyclosporine and three infliximab. The results of biochemical markers measured in both groups of patients and controls, and the mean levels are summarized in Table 3.

Mean calcium, phosphorus and alkaline phosphatase levels were similar in both groups. Median 25-hydroxyvitamin D levels were significantly lower in IBD patients compared with controls (p=0.0001).

Median serum osteocalcin levels were lower and median parathyroid hormone levels were higher in IBD patients compared with the control group but the differences did not reach statistical significance (p = 0.34 and p = 0.187 respectively).

Median urinary Cross Laps levels were significantly higher in IBD patients compared with healthy controls (p = 0.007).

During the follow-up period, none of the patients reported a history or symptoms of bone fracture.

The Median SD of femoral neck and lumbar spine T-scores in IBD patients were -1 (-3.2; - 1.4) and -1.65 (-4; -1.5).

Using the WHO’s diagnostic criteria, 12 (30%) IBD patients were classified as normal, 13 (32.5%) were osteopenic and 15 (37.5%) were classified as osteoporotic.

Among controls, 20 subjects (62.5%) had normal BMD, 11 subjects (34.4%) had osteopenia and only one subject had osteoporosis.

Osteoporosis was more frequent in IBD patients than controls (p=0.0001).

No significant difference between UC and CD patients concerning the prevalence of osteopenia or osteoporosis was found (p = 0.828).

Mean age of patients with low BMD (46.42 ± 14.33 years) was significantly higher compared with those with normal BMD (39.75 ± 10.42) (p = 0.001). Fifteen patients had osteoporosis: ten men and five women. The prevalence of osteoporosis was significantly higher in men than women (p = 0.05).

There was no correlation between disease duration and disease clinical activity or disease localization and low BMD. Mean serum level of ESR was significantly higher in IBD patients with low BMD compared with IBD patients with normal BMD (p = 0.039). There was no significant correlation between low BMD and 25-OH vitamin D levels or urinary Cross Laps levels.

Among the twenty-eight patients who had low BMD, 16 had received corticosteroids and 12 did not. In the normal BMD group, 6 had received corticosteroid and 6 did not. The percentage of IBD patients who had received corticosteroid was numerically higher in the low BMD group compared with the normal BMD group but the difference was not statistically significant. The median cumulative dose of corticosteroid in patients with low BMD (515 mg (0 – 11200 mg)) was higher compared with those with normal BMD (250 mg (0 – 23900 mg) but the difference was not statistically significant (p = 0.642).

Table 4 shows the risk factors associated with low BMD in IBD patients.

Table 3
Bone biochemical markers and bone mineral density in the two groups of patients and controls.


Table 4
Risk factors associated with low BMD in the IBD patients.


4. DISCUSSION

In this study, we found that 70% of Tunisian patients with IBD have low BMD. The prevalence of osteopenia and osteoporosis was 32.5% and 37.5% respectively. We found a high prevalence of low BMD in our patients, which is considered to be one of the highest prevalence rates among previously-published articles. The prevalence of low BMD has been reported in the range of 22–77% in some earlier studies [26Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut 1997; 40(2): 228-33.[http://dx.doi.org/10.1136/gut.40.2.228] [PMID: 9071937] -32Dumitrescu G, Mihai C, Dranga M, Prelipcean CC. Bone mineral density in patients with inflammatory bowel disease from north-eastern Romania. Rev Med Chir Soc Med Nat Iasi 2013; 117(1): 23-8.[PMID: 24505888] ].

The prevalence of osteoporosis (37.5%) in our cohort of Tunisian IBD patients is comparable with that reported in other studies (12-57%) [14Reactive Brochures. Phosphorus Beckman Coulter. Chemistry Information Sheet 2008 MARCH; 389789 AF-20De jaeger C, Cherin P. Vitamine D: Effets sur la santé. Recommandations de bon usage. Médecine et Longévité 2010; 2: 182-99.]. Moreover, the proportion of IBD patients with osteopenia was 32.5% which is comparable with the corresponding value reported from other studies 23-67% [14Reactive Brochures. Phosphorus Beckman Coulter. Chemistry Information Sheet 2008 MARCH; 389789 AF-20De jaeger C, Cherin P. Vitamine D: Effets sur la santé. Recommandations de bon usage. Médecine et Longévité 2010; 2: 182-99.]. Osteoporosis is typically a multifactorial disease. The pathogenic mechanisms that might contribute to low BMD in IBD patients include advancing age, low BMI, smoking, alcohol abuse, immobilization or inactive lifestyle, the activation of inflammatory cytokines, hypogonadism, malnutrition, intestinal malabsorption of calcium and vitamin D, the use of corticosteroids, and genetic susceptibility [4Kotze LM, Costa CT, Cavassani MF, Nisihara RM. Alert for bone alterations and low serum concentrations of vitamin D in patients with intestinal inflammatory disease. Rev Assoc Med Bras (1992) 2017; 63(1): 13-7.[http://dx.doi.org/10.1590/1806-9282.63.01.13] [PMID: 28225873] , 33Abid H, Babakhouya F, Mellouki I, Aqodad N, Benajah D, El Abkari M. Prévalence de la perte osseuse au cours des maladies inflammatoires chroniques de l’intestin: Résultats préliminaires d’une étude mono-centrique marocaine. Revue marocaine des maladies de l’appareil digestif 2014; 17: 5-12.].

No significant difference between CD and UC was found. Several studies have failed to demonstrate any difference in the prevalence of bone loss between CD and UC [26Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut 1997; 40(2): 228-33.[http://dx.doi.org/10.1136/gut.40.2.228] [PMID: 9071937] , 28Pollak RD, Karmeli F, Eliakim R, Ackerman Z, Tabb K, Rachmilewitz D. Femoral neck osteopenia in patients with inflammatory bowel disease. Am J Gastroenterol 1998; 93(9): 1483-90.[http://dx.doi.org/10.1111/j.1572-0241.1998.468_q.x] [PMID: 9732930] , 34Tan B, Li P, Lv H, et al. Vitamin D levels and bone metabolism in Chinese adult patients with inflammatory bowel disease. J Dig Dis 2014; 15(3): 116-23.[http://dx.doi.org/10.1111/1751-2980.12118] [PMID: 24354597] , 35Silvennoinen JA, Karttunen TJ, Niemelä SE, Manelius JJ, Lehtola JK. A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut 1995; 37(1): 71-6.[http://dx.doi.org/10.1136/gut.37.1.71] [PMID: 7672685] ]. Other studies reported lower BMD in CD compared with UC [6Bregenzer N, Erban P, Albrich H, et al. Screening for osteoporosis in patients with inflammatory bowel disease by using urinary N-telopeptides. Eur J Gastroenterol Hepatol 2002; 14(6): 599-605.[http://dx.doi.org/10.1097/00042737-200206000-00004] [PMID: 12072593] , 27Ardizzone S, Bollani S, Bettica P, Bevilacqua M, Molteni P, Bianchi Porro G. Altered bone metabolism in inflammatory bowel disease: There is a difference between Crohn’s disease and ulcerative colitis. J Intern Med 2000; 247(1): 63-70.[http://dx.doi.org/10.1046/j.1365-2796.2000.00582.x] [PMID: 10672132] , 36Targownik LE, Bernstein CN, Nugent Z, Leslie WD. Inflammatory bowel disease has a small effect on bone mineral density and risk for osteoporosis. Clin Gastroenterol Hepatol 2013; 11(3): 278-85.[http://dx.doi.org/10.1016/j.cgh.2012.10.022] [PMID: 23103821] ].

Equally important is that this study the high prevalence of low BMD in male patients as compared with females. In agreement with some studies by Jahnsen et al., Robinson et al. and Shirazi et al. in the 2 patients groups studied (CD and UC), men had lower BMD than women [1Robinson RJ, al-Azzawi F, Iqbal SJ, et al. Osteoporosis and determinants of bone density in patients with Crohn’s disease. Dig Dis Sci 1998; 43(11): 2500-6.[http://dx.doi.org/10.1023/A:1026650719552] [PMID: 9824142] , 5Jahnsen J, Falch JA, Aadland E, Mowinckel P. Bone mineral density is reduced in patients with Crohn’s disease but not in patients with ulcerative colitis: A population based study. Gut 1997; 40(3): 313-9.[http://dx.doi.org/10.1136/gut.40.3.313] [PMID: 9135518] , 37Shirazi KM, Somi MH, Rezaeifar P, Fattahi I, Khoshbaten M, Ahmadzadeh M. Bone density and bone metabolism in patients with inflammatory bowel disease. Saudi J Gastroenterol 2012; 18(4): 241-7.[http://dx.doi.org/10.4103/1319-3767.98428] [PMID: 22824766] ].

There is evidence that body mass affects bone density in IBD. Several studies have shown that BMI is correlated with BMD [3Boubaker J, Feki M, Hsairi M, et al. Osteoporosis and inflammatory bowel disease: Prevalence and risk factors in Tunisian patients. Gastroenterol Clin Biol 2003; 27(10): 901-7.[PMID: 14631305] , 30Frei P, Fried M, Hungerbuhler V, Rammert C, Rousson V, Kullak-Ublick GA. Analysis of risk factors for low bone mineral density in inflammatory bowel disease. Digestion 2006; 73(1): 40-6.[http://dx.doi.org/10.1159/000092013] [PMID: 16543736] , 32Dumitrescu G, Mihai C, Dranga M, Prelipcean CC. Bone mineral density in patients with inflammatory bowel disease from north-eastern Romania. Rev Med Chir Soc Med Nat Iasi 2013; 117(1): 23-8.[PMID: 24505888] , 38Sakellariou GT, Moschos J, Berberidis C, Mpoumponaris A, Kadisc S. Molyvas E and al. Densité osseuse chez des hommes jeunes soufrant d’entérocolopathies inflammatoires récemment diagnostiquées. Rev Rhum 2006; 73: 1395-9.[http://dx.doi.org/10.1016/j.rhum.2006.04.010] , 39Jahnsen J, Falch JA, Mowinckel P, Aadland E. Body composition in patients with inflammatory bowel disease: A population-based study. Am J Gastroenterol 2003; 98(7): 1556-62.[http://dx.doi.org/10.1111/j.1572-0241.2003.07520.x] [PMID: 12873577] ]. Our present study did not found any correlation between BMI and low BMD.

Prior investigators have speculated controversies regarding the features of low BMD and corticosteroid use in IBD patients. In some of these studies, corticosteroid therapy appeared as a risk factor of bone loss [27Ardizzone S, Bollani S, Bettica P, Bevilacqua M, Molteni P, Bianchi Porro G. Altered bone metabolism in inflammatory bowel disease: There is a difference between Crohn’s disease and ulcerative colitis. J Intern Med 2000; 247(1): 63-70.[http://dx.doi.org/10.1046/j.1365-2796.2000.00582.x] [PMID: 10672132] , 29Sahli H, Meddeb N, Landolsi F. Fekih Monia, Boubaker Jalel, Filali Azza and al. Ostéoporose et maladie de crohn. Rev Rhum 2005; 72: 820-4., 30Frei P, Fried M, Hungerbuhler V, Rammert C, Rousson V, Kullak-Ublick GA. Analysis of risk factors for low bone mineral density in inflammatory bowel disease. Digestion 2006; 73(1): 40-6.[http://dx.doi.org/10.1159/000092013] [PMID: 16543736] , 40Zali M, Bahari A, Firouzi F, et al. Bone mineral density in Iranian patients with inflammatory bowel disease. Int J Colorectal Dis 2006; 21(8): 758-66.[http://dx.doi.org/10.1007/s00384-005-0084-3] [PMID: 16463035] , 41Siffledeen JS, Fedorak RN, Siminoski K, et al. Bones and Crohn’s: Risk factors associated with low bone mineral density in patients with Crohn’s disease. Inflamm Bowel Dis 2004; 10(3): 220-8.[http://dx.doi.org/10.1097/00054725-200405000-00007] [PMID: 15290915] ]. Frei et al. [30Frei P, Fried M, Hungerbuhler V, Rammert C, Rousson V, Kullak-Ublick GA. Analysis of risk factors for low bone mineral density in inflammatory bowel disease. Digestion 2006; 73(1): 40-6.[http://dx.doi.org/10.1159/000092013] [PMID: 16543736] ] demonstrated that bone loss is associated with cumulative steroid dose and duration of treatment. The main mechanism by which corticosteroids induce BMD loss is impairing osteoblast function, inducing osteoblast apoptosis, reducing intestinal calcium absorption and increasing renal calcium excretion [42van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and fracture risk: Relationship to daily and cumulative doses. Rheumatology (Oxford) 2000; 39(12): 1383-9.[http://dx.doi.org/10.1093/rheumatology/39.12.1383] [PMID: 11136882] , 43Ezzat Y, Hamdy K. The frequency of low bone mineral density and its associated risk factors in patients with inflammatory bowel diseases. Int J Rheum Dis 2010; 13(3): 259-65.[http://dx.doi.org/10.1111/j.1756-185X.2010.01542.x] [PMID: 20704624] ].

Unlike other studies, corticosteroid treatment is not associated with low BMD [3Boubaker J, Feki M, Hsairi M, et al. Osteoporosis and inflammatory bowel disease: Prevalence and risk factors in Tunisian patients. Gastroenterol Clin Biol 2003; 27(10): 901-7.[PMID: 14631305] , 44Habtezion A, Silverberg MS, Parkes R, Mikolainis S, Steinhart AH. Risk factors for low bone density in Crohn’s disease. Inflamm Bowel Dis 2002; 8(2): 87-92.[http://dx.doi.org/10.1097/00054725-200203000-00003] [PMID: 11854605] , 45Ghosh S, Cowen S, Hannan WJ, Ferguson A. Low bone mineral density in Crohn’s disease, but not in ulcerative colitis, at diagnosis. Gastroenterology 1994; 107(4): 1031-9.[http://dx.doi.org/10.1016/0016-5085(94)90227-5] [PMID: 7926456] ]. In the present study, we showed a significant association between duration of treatment and not with cumulative steroid dose.

There is controversial data in the literature regarding bowel resection as a risk factor of low BMD. Von Tirpitiz et al. found that history of bowel resection is a significant predictive factor of low BMD [46von Tirpitz C, Steder-Neukamm U, Glas K, et al. Osteoporosis in inflammatory bowel disease - Results of a survey among members of the German Crohn’s and Ulcerative Colitis Association. Z Gastroenterol 2003; 41(12): 1145-50.[PMID: 14661123] ]. In our present work, in accordance with Silvennoien et al. [35Silvennoinen JA, Karttunen TJ, Niemelä SE, Manelius JJ, Lehtola JK. A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut 1995; 37(1): 71-6.[http://dx.doi.org/10.1136/gut.37.1.71] [PMID: 7672685] ] and Stockbrugger et al. [47Stockbrügger RW, Schoon EJ, Bollani S, et al. Discordance between the degree of osteopenia and the prevalence of spontaneous vertebral fractures in Crohn’s disease. Aliment Pharmacol Ther 2002; 16(8): 1519-27.[http://dx.doi.org/10.1046/j.1365-2036.2002.01317.x] [PMID: 12182752] ], this correlation could not be found.

Vitamin D deficiency and disturbances of calcium metabolism would be a contributing factor to bone loss in IBD [48Jahnsen J, Falch JA, Mowinckel P, Aadland E. Vitamin D status, parathyroid hormone and bone mineral density in patients with inflammatory bowel disease. Scand J Gastroenterol 2002; 37(2): 192-9.[http://dx.doi.org/10.1080/003655202753416876] [PMID: 11843057] ]. A review on vitamin D status in IBD reported hypovitaminosis D in up to 65% of adult patients [49Pappa HM, Grand RJ, Gordon CM. Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease. Inflamm Bowel Dis 2006; 12(12): 1162-74.[http://dx.doi.org/10.1097/01.mib.0000236929.74040.b0] [PMID: 17119391] ]. Several reasons have been suggested for the low vitamin D status in patients with IBD including reduced intestinal absorption of vitamin D as a consequence of ileopathy, disrupted entero-hepatic circulation of this vitamin, renal insufficiency and reduced dietary intake and exposure to sunshine [50McCarthy D, Duggan P, O’Brien M, et al. Seasonality of vitamin D status and bone turnover in patients with Crohn’s disease. Aliment Pharmacol Ther 2005; 21(9): 1073-83.[http://dx.doi.org/10.1111/j.1365-2036.2005.02446.x] [PMID: 15854168] ]. In this study, 25 OHD levels were significantly low in IBD patients compared with controls but were not associated with osteoporosis. Thus, vitamin D deficiency is not the main cause of low BMD in most IBD patients. Moreover, PTH concentrations were higher compared with controls but didn’t reach a significant difference. These results are in accordance with those of Robinson [51Robinson RJ, Iqbal SJ, Abrams K, Al-Azzawi F, Mayberry JF. Increased bone resorption in patients with Crohn’s disease. Aliment Pharmacol Ther 1998; 12(8): 699-705.[http://dx.doi.org/10.1046/j.1365-2036.1998.00364.x] [PMID: 9726381] ], Silvennoinen [52Silvennoinen J. Relationships between vitamin D, parathyroid hormone and bone mineral density in inflammatory bowel disease. J Intern Med 1996; 239(2): 131-7.[http://dx.doi.org/10.1046/j.1365-2796.1996.420765000.x] [PMID: 8568480] ] and Haj Taeib [53Hadj Taieb S, Kallel L, Feki M, et al. Unbalanced bone remodeling in Tunisian patients with inflammatory bowel diseases. Tunis Med 2013; 91(4): 273-7.[PMID: 23673708] ].

Characterization of bone turnover is useful as previous data showed that biochemical markers of bone metabolism may help to estimate the risk of rapid bone loss, to choose and monitor therapeutic intervention, and to predict long-term osteodensitometric response to therapy [54Cashman KD. Altered bone metabolism in inflammatory disease: Role for nutrition. Proc Nutr Soc 2008; 67(2): 196-205.[http://dx.doi.org/10.1017/S0029665108007039] [PMID: 18412993] , 55Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem 1999; 45(8 Pt 2): 1359-68.[PMID: 10430819] ].

Previous studies using biochemical bone markers in IBD have produced conflicting results, showing either increased bone resorption without a compensatory increase in bone formation including our study [26Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut 1997; 40(2): 228-33.[http://dx.doi.org/10.1136/gut.40.2.228] [PMID: 9071937] , 35Silvennoinen JA, Karttunen TJ, Niemelä SE, Manelius JJ, Lehtola JK. A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut 1995; 37(1): 71-6.[http://dx.doi.org/10.1136/gut.37.1.71] [PMID: 7672685] , 56Gilman J, Shanahan F, Cashman KD. Altered levels of biochemical indices of bone turnover and bone-related vitamins in patients with Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther 2006; 23(7): 1007-16.[http://dx.doi.org/10.1111/j.1365-2036.2006.02835.x] [PMID: 16573803] ], decreased bone formation with no variation in resorptive markers [34Tan B, Li P, Lv H, et al. Vitamin D levels and bone metabolism in Chinese adult patients with inflammatory bowel disease. J Dig Dis 2014; 15(3): 116-23.[http://dx.doi.org/10.1111/1751-2980.12118] [PMID: 24354597] , 57Bischoff SC, Herrmann A, Göke M, Manns MP, von zur Mühlen A, Brabant G. Altered bone metabolism in inflammatory bowel disease. Am J Gastroenterol 1997; 92(7): 1157-63.[PMID: 9219790] , 58Schoon EJ, Geerling BG, Van Dooren IM, et al. Abnormal bone turnover in long-standing Crohn’s disease in remission. Aliment Pharmacol Ther 2001; 15(6): 783-92.[http://dx.doi.org/10.1046/j.1365-2036.2001.00997.x] [PMID: 11380316] ], decreased [59Schulte C, Dignass AU, Mann K, Goebell H. Reduced bone mineral density and unbalanced bone metabolism in patients with inflammatory bowel disease. Inflamm Bowel Dis 1998; 4(4): 268-75.[http://dx.doi.org/10.1097/00054725-199811000-00002] [PMID: 9836078] ] or increased [27Ardizzone S, Bollani S, Bettica P, Bevilacqua M, Molteni P, Bianchi Porro G. Altered bone metabolism in inflammatory bowel disease: There is a difference between Crohn’s disease and ulcerative colitis. J Intern Med 2000; 247(1): 63-70.[http://dx.doi.org/10.1046/j.1365-2796.2000.00582.x] [PMID: 10672132] , 50McCarthy D, Duggan P, O’Brien M, et al. Seasonality of vitamin D status and bone turnover in patients with Crohn’s disease. Aliment Pharmacol Ther 2005; 21(9): 1073-83.[http://dx.doi.org/10.1111/j.1365-2036.2005.02446.x] [PMID: 15854168] , 60Pollak RD, Karmeli F, Eliakim R, Acherman Z, Tabb K, Rachmilewitz D. Femoral neck osteopenia in patients with IBD. Am J Gastroenterol 1998; 93: 1483-90.[http://dx.doi.org/10.1111/j.1572-0241.1998.468_q.x] [PMID: 9732930] , 61] both bone formation and resorption markers. We showed an increase in bone resorption with no variation in bone formation as Haj Taeib and al [53Hadj Taieb S, Kallel L, Feki M, et al. Unbalanced bone remodeling in Tunisian patients with inflammatory bowel diseases. Tunis Med 2013; 91(4): 273-7.[PMID: 23673708] ] did.

In conclusion, this work can be considered as a warning about the importance of investigating bone changes in IBD patients. Our data set has demonstrated that patients with IBD have a high risk of osteoporosis. Major risk factors for low BMD values were age, inflammation biological marker and duration of corticosteroid treatment. Screening of these patients regularly and supplementation with vitamin D and/or Calcium could prevent osteoporotic process and its complications.

A limitation of our current study might be the restricted population of IBD patients, which needs to be further evaluated in a large cohort of patients. On the other hand, it is interesting to investigate the effect of substitution therapy in these patients by the monitoring of the BMD under treatment.

CONCLUSION

Bone alteration is more frequent in patients with IBD compared with healthy controls whereas there is no difference, concerning BMD, between CD and UC patients. In addition, we showed that serum levels of vitamin D were lower in the IBD group and urinary CrossLaps levels were higher. We also found that Low BMI and hypovitaminoses D in IBD patients due to malabsorption are risk factors for low BMD.

Finally, this study is a warning about the importance of monitoring of BMD by DEXA scan in patients with IBD in the clinical practice. Screening of these patients and starting initiating appropriate treatment could prevent bone loss and its complications especially among at-risk patients.

LIST OF ABBREVIATIONS

IBD  = Inflammatory Bowel Disease
25(OH) D  = 25-hydroxy vitamin D
PTH  = Parathyroid Hormone
OC  = Osteocalcin
CTX I  = C-terminal telopeptide of type I collagen
BMD  = Bone Mineral Density
CD  = Crohn's Disease
UC  = Ulcerative Colitis
CDAI  = Crohn’s Disease Activity Index
BMI  = Body Mass Index
ESR  = Erythrocyte Sedimentation Rate
DXA  = X-ray Absorptiometry
WHO  = World Health Organisation
SD  = Standard Deviations
5-ASA  = 5-Aminosalicylic Acid

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The study received research ethics board approval from the “C.P.P.SUD” (0069/2018) committee.

HUMAN AND ANIMAL RIGHTS

No Animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION

Informed consent was obtained from all participants.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Samar BEN JEMAA, Lassaad CHTOUROU, Rim AKROUT, Hela MAKNI FOURATI, Ali AMOURI, Nabil TAHRI and Sofien BAKLOUTI contributed to conception, design, acquisition, and interpretation of data. Khansa CHAABOUNI, Tarek CHAABOUNI and Fatma AYEDI contributed to data analysis.

REFERENCES

[1] Robinson RJ, al-Azzawi F, Iqbal SJ, et al. Osteoporosis and determinants of bone density in patients with Crohn’s disease. Dig Dis Sci 1998; 43(11): 2500-6.[http://dx.doi.org/10.1023/A:1026650719552] [PMID: 9824142]
[2] Ananthakrishnan AN, McGinley EL, Binion DG, Saeian K. Fracture-associated hospitalizations in patients with inflammatory bowel disease. Dig Dis Sci 2011; 56(1): 176-82.[http://dx.doi.org/10.1007/s10620-010-1433-9] [PMID: 20936351]
[3] Boubaker J, Feki M, Hsairi M, et al. Osteoporosis and inflammatory bowel disease: Prevalence and risk factors in Tunisian patients. Gastroenterol Clin Biol 2003; 27(10): 901-7.[PMID: 14631305]
[4] Kotze LM, Costa CT, Cavassani MF, Nisihara RM. Alert for bone alterations and low serum concentrations of vitamin D in patients with intestinal inflammatory disease. Rev Assoc Med Bras (1992) 2017; 63(1): 13-7.[http://dx.doi.org/10.1590/1806-9282.63.01.13] [PMID: 28225873]
[5] Jahnsen J, Falch JA, Aadland E, Mowinckel P. Bone mineral density is reduced in patients with Crohn’s disease but not in patients with ulcerative colitis: A population based study. Gut 1997; 40(3): 313-9.[http://dx.doi.org/10.1136/gut.40.3.313] [PMID: 9135518]
[6] Bregenzer N, Erban P, Albrich H, et al. Screening for osteoporosis in patients with inflammatory bowel disease by using urinary N-telopeptides. Eur J Gastroenterol Hepatol 2002; 14(6): 599-605.[http://dx.doi.org/10.1097/00042737-200206000-00004] [PMID: 12072593]
[7] Schoon EJ, Blok BM, Geerling BJ, Russel MG, Stockbrügger RW, Brummer RJ. Bone mineral density in patients with recently diagnosed inflammatory bowel disease. Gastroenterology 2000; 119(5): 1203-8.[http://dx.doi.org/10.1053/gast.2000.19280] [PMID: 11054377]
[8] Stange EF, Travis SPL, Vermeire S, et al. European Crohn’s and Colitis Organisation (ECCO). European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. J Crohn’s Colitis 2008; 2(1): 1-23.[http://dx.doi.org/10.1016/j.crohns.2007.11.001] [PMID: 21172194]
[9] Stange EF, Travis SPL, Vermeire S, Beglinger C, Kupcinskas L. K Geboes and al. European crohn’s and colitis organisation. European evidence based consensus on the diagnosis and management of Crohn’s disease: Definitions and diagnosis. Gut 2006; 55: 1-15.[http://dx.doi.org/10.1136/gut.2005.081950a] [PMID: 16344569]
[10] Satsangi J, Silverberg MS, Vermeire S, Colombel J-F. The Montreal classification of inflammatory bowel disease: Controversies, consensus, and implications. Gut 2006; 55(6): 749-53.[http://dx.doi.org/10.1136/gut.2005.082909] [PMID: 16698746]
[11] Truelove SC, Witts LJ. Cortisone in ulcerative colitis. BMJ 1955; 2(4947): 1041-8.[http://dx.doi.org/10.1136/bmj.2.4947.1041] [PMID: 13260656]
[12] Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a crohn’s disease activity index. National cooperative crohn’s disease study. Gastroenterology 1976; 70(3): 439-44.[PMID: 1248701]
[13] Reactive Brochures. Calcium Beckman Coulter. Mode d’emploi 2007 DECEMBRE; 389721 AD
[14] Reactive Brochures. Phosphorus Beckman Coulter. Chemistry Information Sheet 2008 MARCH; 389789 AF
[15] Reactive Brochures. Alkaline phosphatase Beckman Coulter. Chemistry Information Sheet 2015 DECEMBER; A18450 AN
[16] Reactive Brochures. Creatinine Beckman Coulter. Chemistry Information Sheet 2015 DECEMBER; A44573 AL
[17] Reactive Brochures. ELECSYS® vitamin D assay. Electrochemiluminescence binding assay (ECLIA) for the in-vitro determination of total 25-hydroxyvitamin D. Roche Diagnostics 2016.
[18] Souberbielle JC, Prié D, Courbebaisse M, et al. Actualité sur les effets de la vitamine D et l’évaluation du statut vitaminique D. Revue Francophone des laboratoires 2009; 414: 31-9.
[19] Haroon M, Regan MJ. Vitamin D deficiency: The time to ignore it has passed. Int J Rheu Dis 2010; 13 318Ŕ323
[20] De jaeger C, Cherin P. Vitamine D: Effets sur la santé. Recommandations de bon usage. Médecine et Longévité 2010; 2: 182-99.
[21] Reactive Brochures. PTH Ref 11972103 122.Roche Diagnostics GmbH. D-68298 Mannheim. 2015-03, V 24.0 English
[22] Reactive Brochures. N-MID Osteocalcin Ref 12149133 122. Elecsys 1010/2010 e MODULAR ANALYTICS E170.
[23] Reactive Brochures. Urine Cross Laps® EIA. For the quantification of degradation products of C-terminal telopeptides of Type l collagen in human urine. 2010; Doc: AC-03PL-A(4)
[24] Reactive Brochures. Albumin Beckman Coulter. Chemistry Information Sheet A18449AL 2015 APRIL;
[25] World Health Organisation. Assessment of fracture risk and its application to sceening for post-menopausal osteoporosis. Report of a WHO study group. Tech Rep Ser (World Health Organ) 1994; 843: 1-129.
[26] Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut 1997; 40(2): 228-33.[http://dx.doi.org/10.1136/gut.40.2.228] [PMID: 9071937]
[27] Ardizzone S, Bollani S, Bettica P, Bevilacqua M, Molteni P, Bianchi Porro G. Altered bone metabolism in inflammatory bowel disease: There is a difference between Crohn’s disease and ulcerative colitis. J Intern Med 2000; 247(1): 63-70.[http://dx.doi.org/10.1046/j.1365-2796.2000.00582.x] [PMID: 10672132]
[28] Pollak RD, Karmeli F, Eliakim R, Ackerman Z, Tabb K, Rachmilewitz D. Femoral neck osteopenia in patients with inflammatory bowel disease. Am J Gastroenterol 1998; 93(9): 1483-90.[http://dx.doi.org/10.1111/j.1572-0241.1998.468_q.x] [PMID: 9732930]
[29] Sahli H, Meddeb N, Landolsi F. Fekih Monia, Boubaker Jalel, Filali Azza and al. Ostéoporose et maladie de crohn. Rev Rhum 2005; 72: 820-4.
[30] Frei P, Fried M, Hungerbuhler V, Rammert C, Rousson V, Kullak-Ublick GA. Analysis of risk factors for low bone mineral density in inflammatory bowel disease. Digestion 2006; 73(1): 40-6.[http://dx.doi.org/10.1159/000092013] [PMID: 16543736]
[31] Koutroubakis IE, Zavos C, Damilakis J, et al. Low bone mineral density in Greek patients with inflammatory bowel disease: Prevalence and risk factors. Ann Gastroenterol 2011; 24(1): 41-6.[PMID: 24714255]
[32] Dumitrescu G, Mihai C, Dranga M, Prelipcean CC. Bone mineral density in patients with inflammatory bowel disease from north-eastern Romania. Rev Med Chir Soc Med Nat Iasi 2013; 117(1): 23-8.[PMID: 24505888]
[33] Abid H, Babakhouya F, Mellouki I, Aqodad N, Benajah D, El Abkari M. Prévalence de la perte osseuse au cours des maladies inflammatoires chroniques de l’intestin: Résultats préliminaires d’une étude mono-centrique marocaine. Revue marocaine des maladies de l’appareil digestif 2014; 17: 5-12.
[34] Tan B, Li P, Lv H, et al. Vitamin D levels and bone metabolism in Chinese adult patients with inflammatory bowel disease. J Dig Dis 2014; 15(3): 116-23.[http://dx.doi.org/10.1111/1751-2980.12118] [PMID: 24354597]
[35] Silvennoinen JA, Karttunen TJ, Niemelä SE, Manelius JJ, Lehtola JK. A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut 1995; 37(1): 71-6.[http://dx.doi.org/10.1136/gut.37.1.71] [PMID: 7672685]
[36] Targownik LE, Bernstein CN, Nugent Z, Leslie WD. Inflammatory bowel disease has a small effect on bone mineral density and risk for osteoporosis. Clin Gastroenterol Hepatol 2013; 11(3): 278-85.[http://dx.doi.org/10.1016/j.cgh.2012.10.022] [PMID: 23103821]
[37] Shirazi KM, Somi MH, Rezaeifar P, Fattahi I, Khoshbaten M, Ahmadzadeh M. Bone density and bone metabolism in patients with inflammatory bowel disease. Saudi J Gastroenterol 2012; 18(4): 241-7.[http://dx.doi.org/10.4103/1319-3767.98428] [PMID: 22824766]
[38] Sakellariou GT, Moschos J, Berberidis C, Mpoumponaris A, Kadisc S. Molyvas E and al. Densité osseuse chez des hommes jeunes soufrant d’entérocolopathies inflammatoires récemment diagnostiquées. Rev Rhum 2006; 73: 1395-9.[http://dx.doi.org/10.1016/j.rhum.2006.04.010]
[39] Jahnsen J, Falch JA, Mowinckel P, Aadland E. Body composition in patients with inflammatory bowel disease: A population-based study. Am J Gastroenterol 2003; 98(7): 1556-62.[http://dx.doi.org/10.1111/j.1572-0241.2003.07520.x] [PMID: 12873577]
[40] Zali M, Bahari A, Firouzi F, et al. Bone mineral density in Iranian patients with inflammatory bowel disease. Int J Colorectal Dis 2006; 21(8): 758-66.[http://dx.doi.org/10.1007/s00384-005-0084-3] [PMID: 16463035]
[41] Siffledeen JS, Fedorak RN, Siminoski K, et al. Bones and Crohn’s: Risk factors associated with low bone mineral density in patients with Crohn’s disease. Inflamm Bowel Dis 2004; 10(3): 220-8.[http://dx.doi.org/10.1097/00054725-200405000-00007] [PMID: 15290915]
[42] van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and fracture risk: Relationship to daily and cumulative doses. Rheumatology (Oxford) 2000; 39(12): 1383-9.[http://dx.doi.org/10.1093/rheumatology/39.12.1383] [PMID: 11136882]
[43] Ezzat Y, Hamdy K. The frequency of low bone mineral density and its associated risk factors in patients with inflammatory bowel diseases. Int J Rheum Dis 2010; 13(3): 259-65.[http://dx.doi.org/10.1111/j.1756-185X.2010.01542.x] [PMID: 20704624]
[44] Habtezion A, Silverberg MS, Parkes R, Mikolainis S, Steinhart AH. Risk factors for low bone density in Crohn’s disease. Inflamm Bowel Dis 2002; 8(2): 87-92.[http://dx.doi.org/10.1097/00054725-200203000-00003] [PMID: 11854605]
[45] Ghosh S, Cowen S, Hannan WJ, Ferguson A. Low bone mineral density in Crohn’s disease, but not in ulcerative colitis, at diagnosis. Gastroenterology 1994; 107(4): 1031-9.[http://dx.doi.org/10.1016/0016-5085(94)90227-5] [PMID: 7926456]
[46] von Tirpitz C, Steder-Neukamm U, Glas K, et al. Osteoporosis in inflammatory bowel disease - Results of a survey among members of the German Crohn’s and Ulcerative Colitis Association. Z Gastroenterol 2003; 41(12): 1145-50.[PMID: 14661123]
[47] Stockbrügger RW, Schoon EJ, Bollani S, et al. Discordance between the degree of osteopenia and the prevalence of spontaneous vertebral fractures in Crohn’s disease. Aliment Pharmacol Ther 2002; 16(8): 1519-27.[http://dx.doi.org/10.1046/j.1365-2036.2002.01317.x] [PMID: 12182752]
[48] Jahnsen J, Falch JA, Mowinckel P, Aadland E. Vitamin D status, parathyroid hormone and bone mineral density in patients with inflammatory bowel disease. Scand J Gastroenterol 2002; 37(2): 192-9.[http://dx.doi.org/10.1080/003655202753416876] [PMID: 11843057]
[49] Pappa HM, Grand RJ, Gordon CM. Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease. Inflamm Bowel Dis 2006; 12(12): 1162-74.[http://dx.doi.org/10.1097/01.mib.0000236929.74040.b0] [PMID: 17119391]
[50] McCarthy D, Duggan P, O’Brien M, et al. Seasonality of vitamin D status and bone turnover in patients with Crohn’s disease. Aliment Pharmacol Ther 2005; 21(9): 1073-83.[http://dx.doi.org/10.1111/j.1365-2036.2005.02446.x] [PMID: 15854168]
[51] Robinson RJ, Iqbal SJ, Abrams K, Al-Azzawi F, Mayberry JF. Increased bone resorption in patients with Crohn’s disease. Aliment Pharmacol Ther 1998; 12(8): 699-705.[http://dx.doi.org/10.1046/j.1365-2036.1998.00364.x] [PMID: 9726381]
[52] Silvennoinen J. Relationships between vitamin D, parathyroid hormone and bone mineral density in inflammatory bowel disease. J Intern Med 1996; 239(2): 131-7.[http://dx.doi.org/10.1046/j.1365-2796.1996.420765000.x] [PMID: 8568480]
[53] Hadj Taieb S, Kallel L, Feki M, et al. Unbalanced bone remodeling in Tunisian patients with inflammatory bowel diseases. Tunis Med 2013; 91(4): 273-7.[PMID: 23673708]
[54] Cashman KD. Altered bone metabolism in inflammatory disease: Role for nutrition. Proc Nutr Soc 2008; 67(2): 196-205.[http://dx.doi.org/10.1017/S0029665108007039] [PMID: 18412993]
[55] Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem 1999; 45(8 Pt 2): 1359-68.[PMID: 10430819]
[56] Gilman J, Shanahan F, Cashman KD. Altered levels of biochemical indices of bone turnover and bone-related vitamins in patients with Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther 2006; 23(7): 1007-16.[http://dx.doi.org/10.1111/j.1365-2036.2006.02835.x] [PMID: 16573803]
[57] Bischoff SC, Herrmann A, Göke M, Manns MP, von zur Mühlen A, Brabant G. Altered bone metabolism in inflammatory bowel disease. Am J Gastroenterol 1997; 92(7): 1157-63.[PMID: 9219790]
[58] Schoon EJ, Geerling BG, Van Dooren IM, et al. Abnormal bone turnover in long-standing Crohn’s disease in remission. Aliment Pharmacol Ther 2001; 15(6): 783-92.[http://dx.doi.org/10.1046/j.1365-2036.2001.00997.x] [PMID: 11380316]
[59] Schulte C, Dignass AU, Mann K, Goebell H. Reduced bone mineral density and unbalanced bone metabolism in patients with inflammatory bowel disease. Inflamm Bowel Dis 1998; 4(4): 268-75.[http://dx.doi.org/10.1097/00054725-199811000-00002] [PMID: 9836078]
[60] Pollak RD, Karmeli F, Eliakim R, Acherman Z, Tabb K, Rachmilewitz D. Femoral neck osteopenia in patients with IBD. Am J Gastroenterol 1998; 93: 1483-90.[http://dx.doi.org/10.1111/j.1572-0241.1998.468_q.x] [PMID: 9732930]
[61] Miheller P, Toth M, Molnar E, Zágoni T, Rácz K, Tulassay Z. Serum bone marker measurements in bone metabolism disorders associated with inflammatory bowel diseases. Orv Hetil 2001; 142: 1557-60.

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


SCImago Journal Ranking

SCImago Journal & Country Rank

Browse Contents



Webmaster Contact: info@benthamopen.net
Copyright © 2019 Bentham Open