|Year : 2014 | Volume
| Issue : 4 | Page : 138-145
High prevalence of hypovitaminosis D and osteoporosis in inflammatory bowel disease patients
Alaauldin M Habib1, Mona G Balata2
1 Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Physical Medicine, Rheumatology and Rehabilitation Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||19-Apr-2014|
|Date of Acceptance||19-Apr-2014|
|Date of Web Publication||21-Nov-2014|
Alaauldin M Habib
Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 11461
Inflammatory bowel disease (IBD) is a group of immune-mediated diseases affecting the gastrointestinal tract. There is a high prevalence of vitamin D deficiency and osteoporosis in patients of IBD. It is not known whether vitamin D deficiency is a predisposing factor or a consequence of IBD. The aim of this study was to evaluate the association between serum vitamin D status and osteoporosis in IBD patients.
Materials and methods
A total of 34 patients of IBD, 22 ulcerative colitis (UC) and 12 Crohn's disease (CD), were recruited in a retrospective cross-sectional study. Serum 25-hydroxy vitamin D was assessed by the chemiluminescent assay. Bone mineral density was assessed using dual-energy X-ray absorptiometry scan of the lumbar spine and left hip joint.
There is a high prevalence of hypovitaminosis D (deficiency and insufficiency) in patients of IBD (94.2%). There are no significant differences in vitamin D deficiency with respect to IBD subtype (UC or CD), patient sex, or disease activity. Bone mineral density is reduced in IBD patients irrespective of the disease subtype (UC or CD) or steroid therapy.
Vitamin D deficiency is prevalent in IBD patients. Vitamin D deficiency is not associated with patient sex, disease subtype, or activity. Osteoporosis is prevalent in IBD patients irrespective of steroid therapy or IBD subtype.
Keywords: hypovitaminosis D, inflammatory bowel disease, osteoporosis
|How to cite this article:|
Habib AM, Balata MG. High prevalence of hypovitaminosis D and osteoporosis in inflammatory bowel disease patients. Tanta Med J 2014;42:138-45
|How to cite this URL:|
Habib AM, Balata MG. High prevalence of hypovitaminosis D and osteoporosis in inflammatory bowel disease patients. Tanta Med J [serial online] 2014 [cited 2020 Dec 1];42:138-45. Available from: http://www.tdj.eg.net/text.asp?2014/42/4/138/145277
| Introduction|| |
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a group of debilitating conditions associated with a mucosal dysregulated immune response to intestinal microorganisms in a genetically susceptible host. These conditions affect up to 0.5% of the population in developed countries and an increasing proportion in developing nations [1-3]. Although not completely defined, the pathogenesis of IBD involves a complex interplay between genetic, environmental, and immunologic factors. Although patients with IBD, including both CD and UC, are known to have an increased incidence of vitamin D deficiency [4-14], it is not known whether a low vitamin D is a status contributing factor and/or a consequence of IBD. Vitamin D, signaling through the vitamin D receptors (VDR), has been shown in murine models to dictate the outcome of experimental IBD [15,16]. Vitamin D appears to regulate T-cell development and function, which may influence the outcome of the immune response by either promoting or preventing autoimmunity.
IBD has been associated with low bone mass and a high prevalence of osteopenia and densitometric osteoporosis [17-21]. The etiopathogenesis and risk factors leading to this complication remain controversial [22-24]. An increased risk of developing an osteoporotic fracture because of low bone mass is predictable. Several studies have demonstrated a decrease in bone mineral density (BMD) in patients with CD and to a lesser extent in UC. 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, malnutrition, and so on [25,26]. However, most recent studies found no significant differences in the prevalence of osteoporosis between patients with UC and those with CD [27-29].
Our aim was to study the correlations between IBD and serum vitamin D and BMD in patients of IBD.
| Materials and methods|| |
A total of 34 patients were diagnosed as IBD according to clinical history, endoscopic, histological, and radiological findings. They were recruited over a 2-year period in Riyadh National Hospital from February 2010 to March 2012. Patients gave informed consent for any research interventions before their enrollment for this study that had been approved from the Local Research Ethics Committee. Exclusion criteria of the patients included coexisting renal failure, hepatic disease, pregnancy, children, lactation, chronic inflammatory joint disease, medications such as anticonvulsants, vitamin D supplementations, and significant malabsorptions. 25-hydroxy vitamin D [25(OH) D] serum concentrations were assessed using chemiluminescent immunoassay (CLIA) technology for the quantitative determination of 25(OH) D (LIAISON R 25 OH Vitamin D Total Assay (310600), Dia Sorin Inc, 1951 Northwestern Ave - Stillwater, MN 55082, USA).
Plasma 25 (OH) D concentration was used to determine the vitamin D status of our patients. The lowest recorded value of 25 (OH) D for each patient, measured in nanograms per deciliter, was used in the analysis. The date when each lowest value was obtained was also recorded. Vitamin D deficiency was defined as a concentration less than 20 ng/dl and severe deficiency as a concentration less than 10 ng/dl. Sufficiency was designated as a concentration more than 30 ng/dl, with 20-30 ng/dl considered relatively insufficient. All patients had their lumbar spine BMD measured using dual-energy X-ray absorptiometry (DEXA).
Posterior-anterior scans of the lumbar spine (L2-L4) and left hip (femoral neck) were taken using a Hologic QDR 4500 W (Hologic Inc., Bedford, Massachusetts, USA) scanner. Lumbar T-score and Z-score were calculated using locally validated manufacturer's reference ranges, whereas femoral scores were calculated using published data . Lumbar spine scans were inspected for evidence of degenerative changes. Osteopenia was defined as a value for BMD between -1.0 and -2.5 SD below the young adult mean (i.e. T-score between -1.0 and -2.5) . Osteoporosis was defined as a value for BMD that was 2.5 SD or more below the young adult mean (i.e. T-score <− 2.5). Fasting blood samples were collected for Ca, parathyroid hormone, C-reactive protein (CRP), erythrocyte sedimentation rate, albumin, hematocrit, alkaline phosphatase, Mg, and phosphate.
Demographic data, disease location, and behavior (classified according to the Montreal classification for both CD and UC ) were obtained from our previously described IBD clinical database . Current and past medication use and smoking status were included. Medication use was classified as ever having used 5-aminosalicylic acid compounds, immunomodulators (i.e. azathioprine, 6-mercaptopurine, methotrexate), and antitumor necrosis factor biologic agents (i.e. infliximab, adalimumab).
Patients were compared against an age-matched (P = 0.50) control group with irritable bowel syndrome, defined according to the Rome criteria .
Data were entered into a Microsoft Excel spreadsheet (Microsoft Corp., Redmond, Washington, USA) and analyzed using Stata 9.2 (StataCorp., College Station, Texas, USA). Continuous variables were summarized using mean and SDs, whereas categorical variables were described using proportions. The χ2 -test and the t-test were used to perform between-group comparison for categorical and continuous variables, respectively. Univariate logistic and linear regressions were used to examine the initial association of the variables with the outcomes of interest. Multivariate models were constructed using variables from the univariate analysis that were significant at P value less than 0.1. Variables were considered to be independent predictors in the multivariate model at P value less than 0.05.
| Results|| |
The demographic data of the studied patients and the control individuals are presented in [Table 1]. There were 34 patients with IBD; the number of male patients was 21 (61.8%) and of female patients was 13 (38.2%), with mean age of 36.2 ± 17 years and the mean duration of the disease of 33 ± 30 months. About 65% (n = 22) of the patients were UC, whereas about 35% (n = 12) of them were CD. Four patients (about 12%) underwent surgical resection (partial, subtotal, or total); three of them were UC and one was CD. Eight (about 24%) patients were smokers. In all, 16 (47%) patients were active (10 were UC and six were CD), whereas 18 (53%) were inactive (11 were UC and seven were CD).
Biochemical data of our studied patients (IBD) in comparison with the control group irritable bowel syndrome (IBS) individuals are presented in [Table 2], which showed no significant differences between both groups of IBD with respect to serum Ca, corrected Ca, serum parathyroid hormone, serum phosphate, serum Mg, and serum alkaline phosphatase (all P > 0.05); however, erythrocyte sedimentation rate and CRP were significantly higher, whereas serum 25 (OH) D, serum albumin, and hematocrit were significantly lower in our patients of IBD compared with the control group (P < 0.05) ([Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]).
The mean value of serum 25 (OH) D of our patients was 16.0 ± 9.2, which was significantly lower than that of the control group (31 ± 11.9; (P = 0.000). Vitamin D of our patients showed deficiency (≤20 ng/ml) in about 61.8% (21 patients), insufficiency (21-30 ng/ml) in about 32.4% (11 patients), and sufficiency (≥30 ng/ml) in about 5.9% (two) patients. No significant differences were observed in vitamin D deficiency in our studied patient group with respect to the following variants: sex, activity of the disease, and subtype of IBD (UC or CD; P > 0.05).
BMD of the femoral neck (T-score and Z-score) of our IBD patients was significantly lower than that of the control group (IBS); lumbar spine BMD (T-score and Z-score) was significantly lower in our patients of IBD compared with IBS patient (the control group). No significant differences were observed in femoral and lumbar BMD when the UC group was compared with the CD group of patients. Femoral and lumbar BMD (both T-score and Z-score) were significantly lower in the UC group and the CD group when each group was compared with the IBS (control) group separately. BMD of our IBD patients on steroid therapy (for both femoral neck and lumbar spine by both T-score and Z-score) showed values (mean ± SD) lower than that of the IBD patients without steroid therapy but were statistically insignificant (P > 0.05).
| Discussion|| |
Our study identified high rates of vitamin D deficiency in IBD patients; serum levels less than 30 ng/dl have been detected in 94.2% of our IBD patients. Deficiencies of vitamin D in our IBD patients were not affected by the patient sex, disease subtype, or activity.
Early studies demonstrated a high prevalence of vitamin D deficiency [12, 13, 35] and secondary hyperparathyroidism  among patients with CD. Subsequent authors have generally concluded that concentrations of 25 (OH) D (and calcium, phosphate, alkaline phosphatase, and parathyroid hormone) are normal [18,36-40].
Although one might predict that vitamin D deficiency would be more likely in small bowel disease, vitamin D concentrations did not differ between patients with CD and those with UC. In addition, patients with small bowel CD did not have the lowest vitamin D concentrations. The observation of low vitamin D concentrations in UC is not unique; Schoon et al.  also observed reduced vitamin D concentrations in recently diagnosed CD and UC patients. Andreassen et al.  have suggested that vitamin D deficiency in IBD patients is related to inadequate intake. Compston and Creamer  observed that vitamin D intake in CD patients who had undergone small bowel resection was below the recommended daily allowance.
However, in health, the majority of vitamin D is derived from endogenous synthesis following exposure to sunlight. Although all of our patients were outpatients, one cannot exclude the possibility that IBD results in the modification of personal habits or living conditions. Alternatively, the systemic inflammatory response may affect the endogenous synthesis of vitamin D.
These findings of low serum levels of vitamin D were in agreement with many previous reports [12,43-47].
Hassan et al.  found no association between vitamin D deficiency and the IBD activity in their patients. El-Matary et al.  reported in their study that serum values of vitamin D were significantly lower in 60 children with newly diagnosed IBD compared with healthy controls, but the activity of IBD for both CD and UC did not correlate with vitamin D values in these children.
Blanck and Aberra  reported in their study on 34 patients of UC that vitamin D deficiency is common among patients of UC, and this deficiency is related to disease activity. In addition, Ulitsky et al. , in their study on 504 IBD patients (403 CD and 101 UC patients), reported a correlation between vitamin D concentrations and disease activity only in CD patients according to the Harvey-Bradshaw index. In another study, which compared 34 patients with CD and 34 age-matched and sex-matched controls, vitamin D levels were significantly lower in CD patients. In addition, severity of disease, which was assessed by the Harvey-Bradshaw score, correlated with serum 25(OH) D levels . In the aforementioned study, Crohn's severity was evaluated by Bradshaw score, which consists of clinical parameters . Tajika et al.  demonstrated that 25(OH) D levels were correlated with CD duration and activity (with CDAI) in 33 CD patients in Japan.
These variations may be due to variations in the disease duration, genetic susceptibilities, differences in nutritional habits, the size of the study population, and differences in the scoring systems of the evaluation of the disease activity.
Possible mechanisms of vitamin D deficiency in IBD are decreased exposure to sunlight, decreased oral intake of vitamin D in patients with IBD versus healthy individuals, ileal resection and diminished fat-soluble vitamin absorption, decreased intestinal absorption of vitamin D, disturbed enterohepatic circulation of vitamin D metabolites, or increased loss of vitamin D through the gastrointestinal system as a result of a protein-losing enteropathy.
We collected all the samples of our patients in one season (summer) to avoid seasonal variations in the onset and exacerbation of IBD that have been reported [35, 54, 55), with high incidence in the winter, although suboptimal vitamin D status was observed even in the summer [4, 9, 12], which may lead to a persistently elevated level of parathyroid hormone and increased rates of bone turnover.
On the basis of provocative interventions assessing the impact of vitamin D supplementation on both parathyroid hormone levels  and intestinal calcium absorption , the lower limit of the normal range for 25 (OH) D was defined, and as a result the currently accepted definition of vitamin D deficiency was reached as 25 (OH) D less than 20 ng/dl [56-59], vitamin D insufficiency as 25 (OH) D between 21 and 30 ng/dl, and sufficient vitamin D as 25 (OH) D greater than 30 ng/dl . Therefore, we used these parameters in interpreting plasma 25 (OH) D in our study.
We reported higher rates of vitamin D deficiency than other reports, between 22 and 70% in CD [4-14] and up to 45% in UC .
Decreased vitamin D levels have also been detected in patients with newly diagnosed IBD [28, 60, 61]. In our cohort of IBD patients, the prevalence of vitamin D deficiency was 61.8% for patients with vitamin D levels less than 20 ng/dl and 32.4% for patients with vitamin D levels ranging between 21 and 29 ng/dl; hence, levels less than 30 ng/dl composed 94.2% of the cohort population. These high rates of vitamin deficiency may be related to some causes of IBD, such as higher CD activity scores, CRP, and ferritin and low cholesterol , severity, duration, surgical small bowel resection , and small bowel involvement in CD ; however, other factors related to the involved patients may be also incriminated, such as genetic susceptibilities of the Asian patients, which constituted most of our cohort patients; dark complexion of most of the patients; worse nutritional status; smoking [4, 5, 12, 62]; and lack of appropriate sun exposure, which may be related to avoidance of sun exposure in the very hot summer or the dressing habits of the Muslim women .
Our IBD patients showed significant reduction in BMD when compared with the IBS control group, not affected by the disease subtype. Corticosteroid therapy negatively affected BMD but was statistically insignificant.
Compston et al.  studied the forearm with single-photon absorptiometry and the lumbar spine with quantitative tomography [computed tomography (CT)] scanning in 17 patients with UC, 51 with CD (46 with small bowel involvement and 38 with resections), and four with indeterminate IBD. They found osteoporosis (defined as a BMD > 2 SD below the age-matched control mean) in 14% of patients with UC and 41% of those with CD. All except eight in each group had taken steroids. The BMD correlated negatively with lifetime steroid use and positively with BMI. A higher percentage of men than women had osteoporosis, which might reflect the use of hormone replacement therapy in women, whereas the men were unlikely to have been offered testosterone.
Motley et al.  studied the lumbar spine using CT scanning repeated at 1 year in 54 patients with IBD and found a rapid rate of trabecular bone loss in 20%. No significant correlation with steroid use was found. There was a negative correlation with BMI. Clements et al.  studied 50 patients with IBD at intervals over a mean of 8 years using single-photon absorptiometry and found increased rates of cortical bone loss in some. Silvennoinen et al. , using DEXA of the lumbar spine and femoral neck, studied 67 patients with UC, 78 with CD, and seven with indeterminate IBD. Of these, 30% had a Z-score of −1 or below compared with 16% of controls. The BMD correlated negatively (slightly) with lifetime steroid use. There was no significant reduction in those who had never received steroids.
In another study , forearm CT scanning was studied in 61 patients with CD, 22 patients with UC, and seven with indeterminate IBD. Of these, 30% had a Z-score of −1 or below compared with 16% of controls. In another abstract  of a study on 38 patients with UC, DEXA showed no significant difference in BMD between patients and controls, but on repeat testing at 1 year there was a significant decrease in BMD in the group of six men who had received steroids. A DEXA study from Norway  confirmed reduced BMD in 60 patients with CD but not in 60 with UC, whereas a DEXA study from the UK , which found osteoporosis in 27% of 79 patients with IBD (44 with CD and 35 with UC), stated that there was no significant difference between CD and UC.
Steroids have a number of adverse effects on bone. They suppress circulating estrogen and interleukin-6, which is a stimulator of osteoclastic activity . In men, steroids reduce blood testosterone concentrations [72,73], resulting in a similar effect on bone . Steroids also inhibit osteoblast maturation, synthetic ability, and calcium absorption and increase urinary loss, thus causing secondary hyperparathyroidism, which increases bone remodeling. However, in CD the relationship between steroids and reduced BMD could also be partly explained by the associated increased activity of the disease necessitating the steroids. Preliminary data  suggest that circulating interleukin-6 is both increased in active disease and associated with low BMD.
There were some limitations to our study; the number of the studied patients is the first limitation, which did not allow a strong calculation of the relationship between vitamin D status and IBD activity. The retrospective nature of the study is another limitation; additional factors that may influence vitamin D status had not been considered in our study. Seasonal variation and sunlight exposure were not studied. The racial and geographic variations and their effects on vitamin D status were not studied. Dietary vitamin D supplementations were not studied. In intestinal forms of IBD, we did not study whether vitamin D deficiency is a predisposing factor or consequence of the disease due to malabsorption. Endoscopic severity and inflammatory markers of the disease were not performed as disease activity indices rather than the objective markers.
| Conclusion|| |
We found a high prevalence of hypovitaminosis D in IBD patients, both UC and CD. No associations were found between vitamin D deficiency and disease activity, subtype, or patient sex. Further studies are recommended to study the mechanism of vitamin D deficiency in IBD patients and whether vitamin D deficiency is a predisposing factor and/or consequence of malabsorption in IBD. Further studies are also recommended to study the value of vitamin D supplementation in IBD patients. We found a high prevalence of osteoporosis in IBD patients regardless of steroid therapy or disease subtype in these patients. We recommend further studies searching the different mechanisms and treatment modalities of osteoporosis in IBD.
| Acknowledgements|| |
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]