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Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease
Nutrition 27 (2011) 1023–1028
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Applied nutritional investigation
Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease Sachiko Nakajima M.D. a, Hideki Iijima M.D., Ph.D. a, *, Satoshi Egawa M.D., Ph.D. a, Shinichiro Shinzaki M.D., Ph.D. a, Jumpei Kondo M.D. a, Takahiro Inoue M.D. a, Yoshito Hayashi M.D. a, Jin Ying M.D. a, Akira Mukai M.D. a, Tomofumi Akasaka M.D. a, Tsutomu Nishida M.D., Ph.D. a, Tatsuya Kanto M.D., Ph.D. a, b, Masahiko Tsujii M.D., Ph.D. a, Norio Hayashi M.D., Ph.D. a a b
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Department of Dendritic Cell Biology and Clinical Application, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 January 2010 Accepted 28 October 2010
Objective: Inflammatory bowel disease (IBD) is a chronic inflammatory process in the digestive tract and patients with IBD develop osteopenia. Although vitamins K and D are important for maintaining bone health and inhibiting inflammation, their roles in patients with IBD are not clear. We investigated the roles of vitamins K and D in the bone health and inflammation in patients with IBD. Methods: Bone mineral density (BMD) of patients with IBD (Crohn’s disease [CD], n ¼ 47, and ulcerative colitis [UC], n ¼ 40) was measured with dual-energy X-ray absorptiometry. Vitamin K and D levels of patients with IBD and healthy volunteers (n ¼ 41) were evaluated by measuring serum undercarboxylated osteocalcin and 1,25 dihydroxyvitamin D, respectively. Clinical activity index was evaluated in patients with CD and UC. Results: BMD was low in patients with CD and UC. Serum undercarboxylated osteocalcin levels were significantly higher in patients with CD, but not with UC, compared with healthy subjects, indicating that bone vitamin K is insufficient in patients with CD. The levels of undercarboxylated osteocalcin were significantly correlated with the clinical activity index of CD, although they were not correlated with BMD. The levels of 1,25 dihydroxyvitamin D were significantly lower in patients with CD and UC than in healthy subjects. The levels of 1,25 dihydroxyvitamin D were inversely correlated with BMD in patients with UC and were not correlated with the clinical activity index of CD. Conclusion: Vitamins K and D are insufficient in patients with IBD. Insufficiency of vitamin K is suggested to be associated with inflammatory processes of CD. Ó 2011 Elsevier Inc. All rights reserved.
Keywords: Vitamin K Vitamin D Inflammatory bowel disease Osteopenia Clinical disease activity
Introduction Crohn’s disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are characterized as a chronic relapsing and remitting process in the digestive tract and are associated with decrease of bone mineral density (BMD) [1–4]. The causes of decreased BMD in patients with IBD have been suggested to be multifactorial, including the inflammatory
This study was supported by Grant in Aid from the Japan Society for the Promotion of Science (grant 19590721). * Corresponding author. Tel.: þ81-6-6879-3621; fax: þ81-6-6879-3629. E-mail address: [email protected] (H. Iijima). 0899-9007/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2010.10.021
bowel process, low body weight, glucocorticoid use, and hypocalcemia [5,6]. In general, vitamins K and D are considered important for the maintenance of bone metabolism [7,8]. In addition, vitamins K and D have been suggested to be involved in inflammatory processes [9–12]. When the supply of vitamin K is insufficient or abnormal, functionally defective vitamin K–dependent protein molecules are produced at their site of synthesis and are released into the bloodstream. Vitamin K acts as a cofactor for the posttranslational g-carboxylation of glutamate residues in vitamin K–dependent proteins, such as coagulation factors and osteocalcin (OC) [13,14]. OC, synthesized by osteoblasts during bone matrix formation, is carboxylated at the g-carboxyglutamate
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residues and carboxylated OC binds to the hydroxyapatite molecules for bone formation [15]. Undercarboxylated OC (ucOC) is a fraction of OC that is not subjected to the carboxylation process and serum ucOC concentration has been shown to be a sensitive biomarker of vitamin K deficiency [16,17]. The measurement of ucOC is widely used as a surrogate marker of vitamin K reserves in the bone [18]. In addition to its function in bone metabolism, vitamin K has been shown to suppress inflammation in vitro and in vivo [9–11]. Ohsaki et al. [9] reported that vitamin K suppresses the production of interleukin-6 in human macrophagic THP-1 cells and dietary supplementation of vitamin K1 suppresses lipopolysaccharide-induced inflammatory process in rats [9]. A community-based epidemiologic study has also reported that high vitamin K levels are associated with lower concentrations of circulating inflammatory markers, such as interleukin-6 [19]. Vitamin D also serves for optimal calcium homeostasis and bone metabolism [20]. In addition, the biologically active form of vitamin D has immunomodulatory functions, including suppression of proinflammatory cytokine expression and regulation of immune cell activity [12]. To date, only a few reports have shown the association between vitamin K and BMD in patients with IBD [21,22]. An inverse correlation between BMD and serum ucOC has been reported in patients with CD [21]. The patients described in that report had longstanding CD in remission, with a mean disease duration of 16 years. The correlation between BMD and precise clinical conditions, such as disease activity and diseased area, was not examined. Although lower plasma vitamin K (phylloquinone or menaquinone-7) levels have been reported to be correlated with lower BMD in patients with CD and those with UC [22], the correlation between vitamin K and BMD in CD and UC has not been separately examined in detail. The role of vitamin D insufficiency in IBD-related bone disease is also still uncertain. Serum 25-hydroxy vitamin D levels have been shown to correlate with BMD in patients with recently diagnosed IBD [23]. In contrast, 1,25 dihydroxyvitamin D (1,25-[OH]2D), which is an active form of vitamin D and has a more prominent short-term beneficial effect than 25-hydroxy vitamin D on bone metabolism [24], has been shown to be negatively correlated with BMD in patients with CD [25]. In that report, the correlation of 1,25(OH)2D and BMD in patients with UC was not shown. Therefore, the roles of vitamins K and D in the maintenance of bone health in IBD are not yet fully clarified. Moreover, it is not clear whether vitamin K and D levels are associated with inflammation in IBD, although the anti-inflammatory effects of vitamins K and D have been reported in animals and humans [9,12,19]. In this study, we investigated the roles of vitamins K and D in relation to bone metabolism and the clinical activity of IBD. Materials and methods Subjects Serum samples were collected from 47 patients with CD, 40 patients with UC, and 41 age-/sex-matched healthy volunteers (HVs). Detailed patient characteristics are listed in Table 1. All patients were Japanese, consecutively recruited at the Department of Gastroenterology and Hepatology, Osaka University Hospital (Suita, Osaka, Japan). The study protocol was approved by the ethics committee of the Osaka University Graduate School of Medicine, and written informed consent was obtained from each participant. Patients were diagnosed with UC or CD according to endoscopic, radiologic, histologic, and clinical criteria provided by the Council for International Organizations of Medical Sciences in the World Health Organization and the International Organization for the Study of Inflammatory Bowel Disease [26,27]. Disease activity was measured using Lightiger’s clinical activity index (CAI) for UC [28]
Table 1 Clinical characteristics and results of blood tests*
Sex Male Female Premenopausal Postmenopausal Age (y) Lifetime corticosteroid dose (g) Cumulative corticosteroid dose (mg) Disease duration (mo) Medication Corticosteroid 5-Aminosalicylic acid Azathioprine Activity indexy PTH (pg/mL) NTX (nmol BCE/L) BAP (U/L)
CD (n ¼ 47)
UC (n ¼ 40)
HVs (n ¼ 41)
31 16 11 5
21 (52.0) 19 (48.0) 13 (33.0) 6 (15.0) 44 16 3.5 7.1 1.6 4.4 103 105.5
25 16 13 3 38 d d d
5 (12.8) 45 (97.8) 19 (40.4) 107.6 88.0 49.3 19.4 15.1 5.3 26.4 8.0
9 (22.5) 38 (95.0) 6 (15.0)z 0.7 1.3 46.8 19.3 12.6 3.7 22.4 6.7
d d d d d d d
(66.0) (34.0) (23.0) (11.0) 40 3.0 2.2 6.7 1.5 6.3 148 106.2
(61.0) (39.0) (32.0) (7.0) 11
BAP, bone-specific alkaline phosphatase; BCE, bone collagen equivalent; CD, Crohn’s disease; HV, healthy volunteer; NTX, N-telopeptide of type I collagen; PTH, intact parathyroid hormone; UC, ulcerative colitis * Data are presented as number of subjects (percentage) or mean SD. y Activity index is shown with Crohn’s disease activity index in CD or Lightiger’s clinical activity index in UC. z Patients who were treated with azathioprine were significantly different between UC and CD (P < 0.05).
or the Crohn’s disease activity index (CDAI) for CD [29]. Patients who were already being treated with bisphosphonates, calcium, vitamin K, or vitamin D supplementation were excluded from the study. None of the patients had a history of fragility fractures. Patients with UC included those with total colitis in 13 patients, left-sided colitis in 20 patients, and rectal-type colitis in 6 patients; and 1 patient had undergone a total colectomy. Patients with CD included those with disease involving the ileum in 21 patients, the colon in 4 patients, and the ileum and colon in 22 patients; and 28 of these patients had a history of bowel surgery related to CD.
Evaluation of BMD BMD was measured at the lumbar spine (L2–L4) and femoral neck with dualenergy X-ray absorptiometry (Discovery A, Hologic, Bedford, MA, USA). BMD values obtained were expressed as T- or Z-scores.
Biochemical measurements Each participant was invited to provide a fasting blood sample. Blood was collected by venepuncture into a Vacutainer tube and processed to serum, which was immediately stored at 80 C until used for analysis. Serum ucOC was measured by an electrochemiluminescence immunoassay (Sanko Junyaku, Co. Ltd., Tokyo, Japan). Serum OC was measured by an immunoradiometric assay (Mitsubishi Chemical Medicine, Tokyo, Japan). Serum 1,25-(OH)2D concentrations were measured by a radioimmunoassay (Immunodiagnostic Systems, Boldon, UK). Serum intact parathyroid hormone was measured by electrochemiluminescence immunoassay (Roche Diagnostics, Basel, Switzerland). Serum crosslinked N-telopeptide of type I collagen, a marker of bone resorption, was measured by an enzyme-linked immunosorbent assay (Ostex International, Inc., Seattle, WA, USA). Bone-specific alkaline phosphatase, a marker of bone formation, was measured by an enzyme immunoassay (Quidel Corporation, San Diego, CA, USA).
Statistical analysis All statistical analyses were performed using StatView 5.0 (SAS Institute, Cary, NC, USA). The Mann-Whitney U test and the Kruskal-Wallis test followed by the Mann-Whitney U test with Bonferroni’s correction for multiple comparisons were used for the statistical analysis. Correlations between two independent measurements were assessed using Pearson’s correlation coefficient. P < 0.05 was considered statistically significant.
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Results Characteristics and BMD in patients with IBD The baseline characteristics and laboratory data of subjects with CD and UC and of HVs are listed in Table 1. There were no significant differences in the characteristics of patients with CD and UC and of HVs, except that the proportion of subjects treated with azathioprine was significantly higher in patients with CD than in those with UC (Table 1). When we analyzed BMD in patients with CD and UC, the T- and Z-scores of CD and UC in the lumbar spine and the femoral neck were lower than zero. In addition, the mean T-scores of the femoral neck were lower than 1.0 (1.08 and 1.09 in CD and UC, respectively), indicating a high prevalence of osteopenia in patients with IBD (Table 2). The mean T-score at the femoral neck was significantly lower than that at the lumbar spine in patients with CD (P < 0.05; Table 2). Corticosteroid use has been reported to decrease BMD in patients with IBD [1]. Although there was a trend toward a lower BMD at the lumbar spine in patients treated with corticosteroids compared with untreated patients, BMD was not significantly different by corticosteroid use in our cohort (Table 2).
Deficiency of vitamins K and D in patients with IBD We next assessed vitamin K and D levels by analyzing serum ucOC and 1,25-(OH)2D. Serum ucOC concentrations were significantly higher in patients with CD compared with HVs (P < 0.05; Fig. 1A). In addition, serum ucOC levels were significantly higher in patients with CD than in those with UC (P < 0.05; Fig. 1A), suggesting that patients with CD but not with UC have a vitamin K deficiency. The increase of ucOC levels was not associated with bowel resection or disease location in patients with CD (data not shown). We next investigated the levels of serum 1,25-(OH)2D in patients with IBD. Serum 1,25-(OH)2D concentrations were significantly lower in patients with CD compared with HVs (P < 0.05; Fig. 1B). The levels of 1,25-(OH)2D were also significantly decreased in patients with UC than in HVs (Fig. 1B).
Table 2 Bone mineral density in patients with CD and UC in the presence or absence of treatment with corticosteroid* CD (n ¼ 47) Lumbar spine T-score Total Corticosteroid present Corticosteroid absent Z-score Total Corticosteroid present Corticosteroid absent
UC (n ¼ 40) Femoral neck
Lumbar spine
Femoral neck
0.63 0.98 1.08 1.13y 0.73 1.23 1.09 1.39 1.28 1.07 1.02 1.57 0.92 1.05 1.17 0.87 0.55 0.95 1.08 1.10y 0.74 1.23 1.09 1.39
0.28 0.95 0.67 1.07y 0.13 0.82 0.52 1.05 0.80 1.48 0.44 1.79 0.34 0.85 0.55 0.44 0.22 0.86 0.70 0.99 0.13 0.82 0.52 1.05
CD, Crohn’s disease; UC, ulcerative colitis * Results are presented as mean SD. y T- and Z-scores were significantly lower at the femoral neck compared with the lumbar spine (P < 0.05). The numbers of patients treated with corticosteroid were 5 in CD and 9 in UC, respectively.
Fig. 1. Serum ucOC and 1,25-(OH)2D levels in patients with UC, patients with CD, and HVs. (A) Serum ucOC concentration in patients with CD was significantly higher than in patients with UC and in HVs. (B) Serum 1,25-(OH)2D concentration in patients with CD and those with UC was significantly lower than in HVs. * P < 0.05 by Kruskal-Wallis test followed by the Mann-Whitney U test with Bonferroni’s correction. 1,25-[OH]2D, 1,25 dihydroxyvitamin D; CD, Crohn’s disease; HV, healthy volunteer; UC, ulcerative colitis; ucOC, undercarboxylated osteocalcin.
Relation between vitamin status and BMD in patients with IBD We then analyzed whether deficiency of vitamins K and D is correlated with BMD in patients with IBD. There was no significant correlation between ucOC and T-score at the lumbar spine or the femoral neck in patients with CD and those with UC (Fig. 2A). In contrast to our speculation that lower vitamin D levels would be associated with decreased BMD, serum 1,25(OH)2D levels were inversely correlated with BMD in the lumbar spine and the femoral neck of patients with UC (P < 0.05; Fig. 2B). There was no significant correlation between 1,25-(OH)2D and T-score in patients with CD (Fig. 2B). We next tested if the level of soluble receptor activator of nuclear factor-kB ligand (sRANKL), which promotes osteoclastogenesis [30,31], is associated with osteopenia in IBD. There were no significant differences in serum sRANKL levels in patients with CD, patients with UC, and HVs (data not shown). The sRANKL expression levels were, however, negatively correlated with T-score at the lumbar spine and the femoral neck in patients with CD (P < 0.05; Fig. 3). There were no correlations between sRANKL and T-score in patients with UC.
Relation between vitamin status and disease activity in patients with IBD Vitamin K has been shown to inhibit the inflammatory process [9]. When we analyzed the association between ucOC and CAI in patients with UC, no correlation was observed between serum ucOC or ucOC/OC, which determines the undercarboxylation ratio in total OC, and CAI in patients with UC (data not shown). Next, we evaluated the correlation between ucOC and CDAI, which is generally accepted as an index to evaluate the clinical disease activity of CD [29]. Serum ucOC was significantly correlated with CDAI in patients with CD (r ¼ 0.32, P < 0.05; Fig. 4A). In addition, the ratio of ucOC to OC was more significantly correlated with CDAI (r ¼ 0.36, P < 0.0001; Fig. 4B). Other inflammatory or nutritional factors (e.g., C-reactive protein, body mass index, and albumin) were not associated with increases in ucOC in patients with UC and those with CD (data not shown). We also investigated the relation between vitamin D level and CAI in UC or CDAI in CD, but there was no significant correlation between serum 1,25-(OH)2D levels and CAI or CDAI in patients with UC or CD (data not shown).
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Fig. 2. Correlation between bone mineral density and serum ucOC or 1,25-(OH)2D in patients with CD and UC. (A) There were no significant correlations between T-scores and ucOC in CD and UC. (B) Negative correlations were found between 1,25-(OH)2D and T-score at the lumbar spine and femoral neck in patients with UC (r ¼ 0.40, P < 0.05, at the lumbar spine; r ¼ 0.47, P < 0.01, at the femoral neck), whereas there were no significant correlations between 1,25-(OH)2D and T-score in patients with CD. 1,25[OH]2D, 1,25 dihydroxyvitamin D; CD, Crohn’s disease; UC, ulcerative colitis; ucOC, undercarboxylated osteocalcin.
Discussion We showed in this study that vitamins K and D are insufficient in patients with CD, as determined by an increase in serum ucOC and a decrease in 1,25-(OH)2D. The levels of 1,25-(OH)2D were decreased in patients with UC, whereas ucOC levels were not significantly different between patients with UC and HVs. Although we did not directly measure serum vitamin K because the measurement requires a special method such as highperformance liquid chromatography, ucOC is widely used as a surrogate marker of vitamin K reserves of bone [18]. The levels of ucOC and 1,25-(OH)2D can be affected by several factors. A previous study (in Kyoto, Japan) reported that vitamin K and D intakes in patients with IBD exceeded the Japanese minimum daily requirement [22]. Thus, an insufficient intake of vitamins K
and D may not be the main reason for the vitamin K and D deficiencies. The second possibility is that absorption of the vitamins by the inflamed intestine is disrupted. The levels of ucOC and 1,25-(OH)2D did not differ, however, among disease locations or between patients with and without a history of bowel resection in patients with CD. The third possible reason can be decreased fat intake, which would affect the absorption of fat-soluble vitamins such as vitamins K and D. Because patients with CD, but not with UC, in Japan are usually treated by a fatdecreased diet with/without elemental nutrition therapy with a severe decrease of fat, the difference in the levels of ucOC between patients with CD and those with UC might be caused by the changes in dietary fat. In addition to the changes in dietary fat, production of vitamin K by intestinal bacteria species may have caused the difference in ucOC levels between patients with
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Fig. 3. The sRANKL was negatively correlated with T-scores at the lumbar spine and the femoral neck in patients with Crohn’s disease. The correlation was significant at the lumbar spine (r ¼ 0.35, P < 0.05) and the femoral neck (r ¼ 0.34, P < 0.05). sRANKL, soluble receptor activator of nuclear factor-kB ligand.
CD and those with UC because the bacterial flora composition of patients with CD is significantly altered from that of healthy controls and patients with UC [32,33]. Further investigation is required to determine the mechanisms for the vitamin K and D deficiencies in IBD. In the present study, vitamin K and D deficiencies were not significantly associated with decreased BMD. Previous reports have shown that vitamin K alters the bone microarchitecture and structural properties and that vitamin K deficiency is a risk for bone fracture independent of an decrease in BMD [34–36]. Therefore, decreased BMD and vitamin K deficiency can be the independent risks of bone fragility in patients with IBD. The active form of vitamin D, 1,25-(OH)2D, has been shown to have a prominent beneficial effect on bone metabolism and disease activity in CD compared with plain vitamin D [24], but we did not find any correlation between 1,25-(OH)2D levels and BMD in patients with CD. Furthermore, we found an inverse correlation between 1,25-(OH)2D levels and BMD in patients with UC. Abreu et al. [25] showed that vitamin D production is increased in the inflamed intestinal tissue of patients with IBD by the local activation of vitamin D–converting enzyme 1a-hydroxylase [25]. According to their findings, we speculate that the active form of vitamin D production is upregulated by the local production of vitamin D–converting enzyme in the inflamed intestine of patients with UC and low BMD. In addition, an increase of serum
sRANKL was significantly correlated with a decrease of BMD in our patients with CD (unpublished observation). Soluble RANKL, which is increased by activated macrophages and T cells, has been shown to be an important trigger of osteoclastogenesis by binding with its receptor RANK in the bone tissue [31,37–39]. The complex relation between immune status and bone homeostasis in IBD requires further investigation. In the present study, we demonstrated a positive correlation between serum ucOC and CDAI in patients with CD. Because ucOC levels are affected by total OC levels that reflect bone turnover [18], we also analyzed the correlation between ucOC/ OC and CDAI. The correlation of ucOC/OC and CDAI was found to be prominent (Fig. 3B). Considering that vitamin K has inhibited inflammation in animal and epidemiologic studies [9,19], vitamin K status may be closely associated with the inflammation of CD. Recent reports have demonstrated that vitamin K serves as a transcriptional regulator by the pregnane X receptor/steroid and the xenobiotic receptor [40]. The role of vitamin K as an inflammatory mediator in intestinal inflammation, such as in IBD, requires further investigation. A vitamin K supplementation study is ongoing in our laboratory. Similarly to vitamin K, 1, 25-(OH)2D has been shown to have immunosuppressive properties [12,41]. In contrast to the correlation between ucOC and CDAI, there was no correlation between 1,25-(OH)2D and CDAI. A decrease of 1,25-(OH)2D may not be observed in patients with
Fig. 4. (A) Serum ucOC (r ¼ 0.32, P < 0.05) and (B) ucOC/OC (r ¼ 0.36, P < 0.0001) correlated significantly with the CDAI in patients with Crohn’s disease. CDAI, Crohn’s disease activity index; ucOC, undercarboxylated osteocalcin.
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a high CDAI, probably because of the local induction of vitamin D–converting enzyme in the inflamed intestine, as discussed earlier. In conclusion, BMD is decreased in patients with IBD. The status of vitamins K and D is different between patients with CD and those with UC. A significant correlation of vitamin K deficiency and clinical disease activity was observed in patients with CD. Further prospective study is needed to clarify the role of vitamin K in patients with IBD.
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[18] Vermeer C, Shearer MJ, Zittermann A, Bolton-Smith C, Szulc P, Hodges S, et al. Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health. Eur J Nutr 2004;43:325–35. [19] Shea MK, Booth SL, Massaro JM, Jacques PF, D’Agostino RB Sr, DawsonHughes B, et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol 2008;167:313–20. [20] Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B. Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med 2004;116:634–9. [21] Schoon EJ, Muller MC, Vermeer C, Schurgers LJ, Brummer RJ, Stockbrugger RW. Low serum and bone vitamin K status in patients with longstanding Crohn’s disease: another pathogenetic factor of osteoporosis in Crohn’s disease? Gut 2001;48:473–7. [22] Kuwabara A, Tanaka K, Tsugawa N, Nakase H, Tsuji H, Shide K, et al. High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. Osteoporos Int 2009;20:935–42. [23] Leslie WD, Miller N, Rogala L, Bernstein CN. Vitamin D status and bone density in recently diagnosed inflammatory bowel disease: the Manitoba IBD Cohort Study. Am J Gastroenterol 2008;103:1451–9. [24] Miheller P, Muzes G, Hritz I, Lakatos G, Pregun I, Lakatos PL, et al. Comparison of the effects of 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D on bone pathology and disease activity in Crohn’s disease patients. Inflamm Bowel Dis 2009;15:1656–62. [25] Abreu MT, Kantorovich V, Vasiliauskas EA, Gruntmanis U, Matuk R, Daigle K, et al. Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn’s disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut 2004;53:1129–36. [26] Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol 1989;170(suppl):2–6, discussion 16–9. [27] Podolsky DK. Inflammatory bowel disease (1). N Engl J Med 1991;325: 928–37. [28] Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990;336:16–9. [29] 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;70:439–44. [30] Takayanagi H. Novel signaling pathways and therapeutic targets in osteoclasts. Adv Exp Med Biol 2007;602:93–6. [31] Theill LE, Boyle WJ, Penninger JMRANK-L. Rank: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 2002;20:795–823. [32] Ramotar K, Conly JM, Chubb H, Louie TJ. Production of menaquinones by intestinal anaerobes. J Infect Dis 1984;150:213–8. [33] Gophna U, Sommerfeld K, Gophna S, Doolittle WF, Veldhuyzen van Zanten SJ. Differences between tissue-associated intestinal microfloras of patients with Crohn’s disease and ulcerative colitis. J Clin Microbiol 2006;44:4136–41. [34] Tsugawa N, Shiraki M, Suhara Y, Kamao M, Ozaki R, Tanaka K, et al. Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. J Bone Miner Metab 2008;26:79–85. [35] Xin F, Takemitsu M, Atsuta Y. Effect of vitamin K(2) on lumbar vertebral bone: histomorphometric analyses in experimental osteoporotic rats. J Orthop Sci 2001;6:535–9. [36] Mawatari T, Miura H, Higaki H, Moro-Oka T, Kurata K, Murakami T, et al. Effect of vitamin K2 on three-dimensional trabecular microarchitecture in ovariectomized rats. J Bone Miner Res 2000;15:1810–7. [37] Vega D, Maalouf NM, Sakhaee K. CLINICAL Review: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab 2007;92:4514–21. [38] Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999;402:304–9. [39] Komine M, Kukita A, Kukita T, Ogata Y, Hotokebuchi T, Kohashi O. Tumor necrosis factor-alpha cooperates with receptor activator of nuclear factor kappaB ligand in generation of osteoclasts in stromal cell–depleted rat bone marrow cell culture. Bone 2001;28:474–83. [40] Ichikawa T, Horie-Inoue K, Ikeda K, Blumberg B, Inoue S. Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells. J Biol Chem 2006;281:16927–34. [41] Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579–85.
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Applied nutritional investigation
Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease Sachiko Nakajima M.D. a, Hideki Iijima M.D., Ph.D. a, *, Satoshi Egawa M.D., Ph.D. a, Shinichiro Shinzaki M.D., Ph.D. a, Jumpei Kondo M.D. a, Takahiro Inoue M.D. a, Yoshito Hayashi M.D. a, Jin Ying M.D. a, Akira Mukai M.D. a, Tomofumi Akasaka M.D. a, Tsutomu Nishida M.D., Ph.D. a, Tatsuya Kanto M.D., Ph.D. a, b, Masahiko Tsujii M.D., Ph.D. a, Norio Hayashi M.D., Ph.D. a a b
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Department of Dendritic Cell Biology and Clinical Application, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 January 2010 Accepted 28 October 2010
Objective: Inflammatory bowel disease (IBD) is a chronic inflammatory process in the digestive tract and patients with IBD develop osteopenia. Although vitamins K and D are important for maintaining bone health and inhibiting inflammation, their roles in patients with IBD are not clear. We investigated the roles of vitamins K and D in the bone health and inflammation in patients with IBD. Methods: Bone mineral density (BMD) of patients with IBD (Crohn’s disease [CD], n ¼ 47, and ulcerative colitis [UC], n ¼ 40) was measured with dual-energy X-ray absorptiometry. Vitamin K and D levels of patients with IBD and healthy volunteers (n ¼ 41) were evaluated by measuring serum undercarboxylated osteocalcin and 1,25 dihydroxyvitamin D, respectively. Clinical activity index was evaluated in patients with CD and UC. Results: BMD was low in patients with CD and UC. Serum undercarboxylated osteocalcin levels were significantly higher in patients with CD, but not with UC, compared with healthy subjects, indicating that bone vitamin K is insufficient in patients with CD. The levels of undercarboxylated osteocalcin were significantly correlated with the clinical activity index of CD, although they were not correlated with BMD. The levels of 1,25 dihydroxyvitamin D were significantly lower in patients with CD and UC than in healthy subjects. The levels of 1,25 dihydroxyvitamin D were inversely correlated with BMD in patients with UC and were not correlated with the clinical activity index of CD. Conclusion: Vitamins K and D are insufficient in patients with IBD. Insufficiency of vitamin K is suggested to be associated with inflammatory processes of CD. Ó 2011 Elsevier Inc. All rights reserved.
Keywords: Vitamin K Vitamin D Inflammatory bowel disease Osteopenia Clinical disease activity
Introduction Crohn’s disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are characterized as a chronic relapsing and remitting process in the digestive tract and are associated with decrease of bone mineral density (BMD) [1–4]. The causes of decreased BMD in patients with IBD have been suggested to be multifactorial, including the inflammatory
This study was supported by Grant in Aid from the Japan Society for the Promotion of Science (grant 19590721). * Corresponding author. Tel.: þ81-6-6879-3621; fax: þ81-6-6879-3629. E-mail address: [email protected] (H. Iijima). 0899-9007/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2010.10.021
bowel process, low body weight, glucocorticoid use, and hypocalcemia [5,6]. In general, vitamins K and D are considered important for the maintenance of bone metabolism [7,8]. In addition, vitamins K and D have been suggested to be involved in inflammatory processes [9–12]. When the supply of vitamin K is insufficient or abnormal, functionally defective vitamin K–dependent protein molecules are produced at their site of synthesis and are released into the bloodstream. Vitamin K acts as a cofactor for the posttranslational g-carboxylation of glutamate residues in vitamin K–dependent proteins, such as coagulation factors and osteocalcin (OC) [13,14]. OC, synthesized by osteoblasts during bone matrix formation, is carboxylated at the g-carboxyglutamate
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residues and carboxylated OC binds to the hydroxyapatite molecules for bone formation [15]. Undercarboxylated OC (ucOC) is a fraction of OC that is not subjected to the carboxylation process and serum ucOC concentration has been shown to be a sensitive biomarker of vitamin K deficiency [16,17]. The measurement of ucOC is widely used as a surrogate marker of vitamin K reserves in the bone [18]. In addition to its function in bone metabolism, vitamin K has been shown to suppress inflammation in vitro and in vivo [9–11]. Ohsaki et al. [9] reported that vitamin K suppresses the production of interleukin-6 in human macrophagic THP-1 cells and dietary supplementation of vitamin K1 suppresses lipopolysaccharide-induced inflammatory process in rats [9]. A community-based epidemiologic study has also reported that high vitamin K levels are associated with lower concentrations of circulating inflammatory markers, such as interleukin-6 [19]. Vitamin D also serves for optimal calcium homeostasis and bone metabolism [20]. In addition, the biologically active form of vitamin D has immunomodulatory functions, including suppression of proinflammatory cytokine expression and regulation of immune cell activity [12]. To date, only a few reports have shown the association between vitamin K and BMD in patients with IBD [21,22]. An inverse correlation between BMD and serum ucOC has been reported in patients with CD [21]. The patients described in that report had longstanding CD in remission, with a mean disease duration of 16 years. The correlation between BMD and precise clinical conditions, such as disease activity and diseased area, was not examined. Although lower plasma vitamin K (phylloquinone or menaquinone-7) levels have been reported to be correlated with lower BMD in patients with CD and those with UC [22], the correlation between vitamin K and BMD in CD and UC has not been separately examined in detail. The role of vitamin D insufficiency in IBD-related bone disease is also still uncertain. Serum 25-hydroxy vitamin D levels have been shown to correlate with BMD in patients with recently diagnosed IBD [23]. In contrast, 1,25 dihydroxyvitamin D (1,25-[OH]2D), which is an active form of vitamin D and has a more prominent short-term beneficial effect than 25-hydroxy vitamin D on bone metabolism [24], has been shown to be negatively correlated with BMD in patients with CD [25]. In that report, the correlation of 1,25(OH)2D and BMD in patients with UC was not shown. Therefore, the roles of vitamins K and D in the maintenance of bone health in IBD are not yet fully clarified. Moreover, it is not clear whether vitamin K and D levels are associated with inflammation in IBD, although the anti-inflammatory effects of vitamins K and D have been reported in animals and humans [9,12,19]. In this study, we investigated the roles of vitamins K and D in relation to bone metabolism and the clinical activity of IBD. Materials and methods Subjects Serum samples were collected from 47 patients with CD, 40 patients with UC, and 41 age-/sex-matched healthy volunteers (HVs). Detailed patient characteristics are listed in Table 1. All patients were Japanese, consecutively recruited at the Department of Gastroenterology and Hepatology, Osaka University Hospital (Suita, Osaka, Japan). The study protocol was approved by the ethics committee of the Osaka University Graduate School of Medicine, and written informed consent was obtained from each participant. Patients were diagnosed with UC or CD according to endoscopic, radiologic, histologic, and clinical criteria provided by the Council for International Organizations of Medical Sciences in the World Health Organization and the International Organization for the Study of Inflammatory Bowel Disease [26,27]. Disease activity was measured using Lightiger’s clinical activity index (CAI) for UC [28]
Table 1 Clinical characteristics and results of blood tests*
Sex Male Female Premenopausal Postmenopausal Age (y) Lifetime corticosteroid dose (g) Cumulative corticosteroid dose (mg) Disease duration (mo) Medication Corticosteroid 5-Aminosalicylic acid Azathioprine Activity indexy PTH (pg/mL) NTX (nmol BCE/L) BAP (U/L)
CD (n ¼ 47)
UC (n ¼ 40)
HVs (n ¼ 41)
31 16 11 5
21 (52.0) 19 (48.0) 13 (33.0) 6 (15.0) 44 16 3.5 7.1 1.6 4.4 103 105.5
25 16 13 3 38 d d d
5 (12.8) 45 (97.8) 19 (40.4) 107.6 88.0 49.3 19.4 15.1 5.3 26.4 8.0
9 (22.5) 38 (95.0) 6 (15.0)z 0.7 1.3 46.8 19.3 12.6 3.7 22.4 6.7
d d d d d d d
(66.0) (34.0) (23.0) (11.0) 40 3.0 2.2 6.7 1.5 6.3 148 106.2
(61.0) (39.0) (32.0) (7.0) 11
BAP, bone-specific alkaline phosphatase; BCE, bone collagen equivalent; CD, Crohn’s disease; HV, healthy volunteer; NTX, N-telopeptide of type I collagen; PTH, intact parathyroid hormone; UC, ulcerative colitis * Data are presented as number of subjects (percentage) or mean SD. y Activity index is shown with Crohn’s disease activity index in CD or Lightiger’s clinical activity index in UC. z Patients who were treated with azathioprine were significantly different between UC and CD (P < 0.05).
or the Crohn’s disease activity index (CDAI) for CD [29]. Patients who were already being treated with bisphosphonates, calcium, vitamin K, or vitamin D supplementation were excluded from the study. None of the patients had a history of fragility fractures. Patients with UC included those with total colitis in 13 patients, left-sided colitis in 20 patients, and rectal-type colitis in 6 patients; and 1 patient had undergone a total colectomy. Patients with CD included those with disease involving the ileum in 21 patients, the colon in 4 patients, and the ileum and colon in 22 patients; and 28 of these patients had a history of bowel surgery related to CD.
Evaluation of BMD BMD was measured at the lumbar spine (L2–L4) and femoral neck with dualenergy X-ray absorptiometry (Discovery A, Hologic, Bedford, MA, USA). BMD values obtained were expressed as T- or Z-scores.
Biochemical measurements Each participant was invited to provide a fasting blood sample. Blood was collected by venepuncture into a Vacutainer tube and processed to serum, which was immediately stored at 80 C until used for analysis. Serum ucOC was measured by an electrochemiluminescence immunoassay (Sanko Junyaku, Co. Ltd., Tokyo, Japan). Serum OC was measured by an immunoradiometric assay (Mitsubishi Chemical Medicine, Tokyo, Japan). Serum 1,25-(OH)2D concentrations were measured by a radioimmunoassay (Immunodiagnostic Systems, Boldon, UK). Serum intact parathyroid hormone was measured by electrochemiluminescence immunoassay (Roche Diagnostics, Basel, Switzerland). Serum crosslinked N-telopeptide of type I collagen, a marker of bone resorption, was measured by an enzyme-linked immunosorbent assay (Ostex International, Inc., Seattle, WA, USA). Bone-specific alkaline phosphatase, a marker of bone formation, was measured by an enzyme immunoassay (Quidel Corporation, San Diego, CA, USA).
Statistical analysis All statistical analyses were performed using StatView 5.0 (SAS Institute, Cary, NC, USA). The Mann-Whitney U test and the Kruskal-Wallis test followed by the Mann-Whitney U test with Bonferroni’s correction for multiple comparisons were used for the statistical analysis. Correlations between two independent measurements were assessed using Pearson’s correlation coefficient. P < 0.05 was considered statistically significant.
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Results Characteristics and BMD in patients with IBD The baseline characteristics and laboratory data of subjects with CD and UC and of HVs are listed in Table 1. There were no significant differences in the characteristics of patients with CD and UC and of HVs, except that the proportion of subjects treated with azathioprine was significantly higher in patients with CD than in those with UC (Table 1). When we analyzed BMD in patients with CD and UC, the T- and Z-scores of CD and UC in the lumbar spine and the femoral neck were lower than zero. In addition, the mean T-scores of the femoral neck were lower than 1.0 (1.08 and 1.09 in CD and UC, respectively), indicating a high prevalence of osteopenia in patients with IBD (Table 2). The mean T-score at the femoral neck was significantly lower than that at the lumbar spine in patients with CD (P < 0.05; Table 2). Corticosteroid use has been reported to decrease BMD in patients with IBD [1]. Although there was a trend toward a lower BMD at the lumbar spine in patients treated with corticosteroids compared with untreated patients, BMD was not significantly different by corticosteroid use in our cohort (Table 2).
Deficiency of vitamins K and D in patients with IBD We next assessed vitamin K and D levels by analyzing serum ucOC and 1,25-(OH)2D. Serum ucOC concentrations were significantly higher in patients with CD compared with HVs (P < 0.05; Fig. 1A). In addition, serum ucOC levels were significantly higher in patients with CD than in those with UC (P < 0.05; Fig. 1A), suggesting that patients with CD but not with UC have a vitamin K deficiency. The increase of ucOC levels was not associated with bowel resection or disease location in patients with CD (data not shown). We next investigated the levels of serum 1,25-(OH)2D in patients with IBD. Serum 1,25-(OH)2D concentrations were significantly lower in patients with CD compared with HVs (P < 0.05; Fig. 1B). The levels of 1,25-(OH)2D were also significantly decreased in patients with UC than in HVs (Fig. 1B).
Table 2 Bone mineral density in patients with CD and UC in the presence or absence of treatment with corticosteroid* CD (n ¼ 47) Lumbar spine T-score Total Corticosteroid present Corticosteroid absent Z-score Total Corticosteroid present Corticosteroid absent
UC (n ¼ 40) Femoral neck
Lumbar spine
Femoral neck
0.63 0.98 1.08 1.13y 0.73 1.23 1.09 1.39 1.28 1.07 1.02 1.57 0.92 1.05 1.17 0.87 0.55 0.95 1.08 1.10y 0.74 1.23 1.09 1.39
0.28 0.95 0.67 1.07y 0.13 0.82 0.52 1.05 0.80 1.48 0.44 1.79 0.34 0.85 0.55 0.44 0.22 0.86 0.70 0.99 0.13 0.82 0.52 1.05
CD, Crohn’s disease; UC, ulcerative colitis * Results are presented as mean SD. y T- and Z-scores were significantly lower at the femoral neck compared with the lumbar spine (P < 0.05). The numbers of patients treated with corticosteroid were 5 in CD and 9 in UC, respectively.
Fig. 1. Serum ucOC and 1,25-(OH)2D levels in patients with UC, patients with CD, and HVs. (A) Serum ucOC concentration in patients with CD was significantly higher than in patients with UC and in HVs. (B) Serum 1,25-(OH)2D concentration in patients with CD and those with UC was significantly lower than in HVs. * P < 0.05 by Kruskal-Wallis test followed by the Mann-Whitney U test with Bonferroni’s correction. 1,25-[OH]2D, 1,25 dihydroxyvitamin D; CD, Crohn’s disease; HV, healthy volunteer; UC, ulcerative colitis; ucOC, undercarboxylated osteocalcin.
Relation between vitamin status and BMD in patients with IBD We then analyzed whether deficiency of vitamins K and D is correlated with BMD in patients with IBD. There was no significant correlation between ucOC and T-score at the lumbar spine or the femoral neck in patients with CD and those with UC (Fig. 2A). In contrast to our speculation that lower vitamin D levels would be associated with decreased BMD, serum 1,25(OH)2D levels were inversely correlated with BMD in the lumbar spine and the femoral neck of patients with UC (P < 0.05; Fig. 2B). There was no significant correlation between 1,25-(OH)2D and T-score in patients with CD (Fig. 2B). We next tested if the level of soluble receptor activator of nuclear factor-kB ligand (sRANKL), which promotes osteoclastogenesis [30,31], is associated with osteopenia in IBD. There were no significant differences in serum sRANKL levels in patients with CD, patients with UC, and HVs (data not shown). The sRANKL expression levels were, however, negatively correlated with T-score at the lumbar spine and the femoral neck in patients with CD (P < 0.05; Fig. 3). There were no correlations between sRANKL and T-score in patients with UC.
Relation between vitamin status and disease activity in patients with IBD Vitamin K has been shown to inhibit the inflammatory process [9]. When we analyzed the association between ucOC and CAI in patients with UC, no correlation was observed between serum ucOC or ucOC/OC, which determines the undercarboxylation ratio in total OC, and CAI in patients with UC (data not shown). Next, we evaluated the correlation between ucOC and CDAI, which is generally accepted as an index to evaluate the clinical disease activity of CD [29]. Serum ucOC was significantly correlated with CDAI in patients with CD (r ¼ 0.32, P < 0.05; Fig. 4A). In addition, the ratio of ucOC to OC was more significantly correlated with CDAI (r ¼ 0.36, P < 0.0001; Fig. 4B). Other inflammatory or nutritional factors (e.g., C-reactive protein, body mass index, and albumin) were not associated with increases in ucOC in patients with UC and those with CD (data not shown). We also investigated the relation between vitamin D level and CAI in UC or CDAI in CD, but there was no significant correlation between serum 1,25-(OH)2D levels and CAI or CDAI in patients with UC or CD (data not shown).
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Fig. 2. Correlation between bone mineral density and serum ucOC or 1,25-(OH)2D in patients with CD and UC. (A) There were no significant correlations between T-scores and ucOC in CD and UC. (B) Negative correlations were found between 1,25-(OH)2D and T-score at the lumbar spine and femoral neck in patients with UC (r ¼ 0.40, P < 0.05, at the lumbar spine; r ¼ 0.47, P < 0.01, at the femoral neck), whereas there were no significant correlations between 1,25-(OH)2D and T-score in patients with CD. 1,25[OH]2D, 1,25 dihydroxyvitamin D; CD, Crohn’s disease; UC, ulcerative colitis; ucOC, undercarboxylated osteocalcin.
Discussion We showed in this study that vitamins K and D are insufficient in patients with CD, as determined by an increase in serum ucOC and a decrease in 1,25-(OH)2D. The levels of 1,25-(OH)2D were decreased in patients with UC, whereas ucOC levels were not significantly different between patients with UC and HVs. Although we did not directly measure serum vitamin K because the measurement requires a special method such as highperformance liquid chromatography, ucOC is widely used as a surrogate marker of vitamin K reserves of bone [18]. The levels of ucOC and 1,25-(OH)2D can be affected by several factors. A previous study (in Kyoto, Japan) reported that vitamin K and D intakes in patients with IBD exceeded the Japanese minimum daily requirement [22]. Thus, an insufficient intake of vitamins K
and D may not be the main reason for the vitamin K and D deficiencies. The second possibility is that absorption of the vitamins by the inflamed intestine is disrupted. The levels of ucOC and 1,25-(OH)2D did not differ, however, among disease locations or between patients with and without a history of bowel resection in patients with CD. The third possible reason can be decreased fat intake, which would affect the absorption of fat-soluble vitamins such as vitamins K and D. Because patients with CD, but not with UC, in Japan are usually treated by a fatdecreased diet with/without elemental nutrition therapy with a severe decrease of fat, the difference in the levels of ucOC between patients with CD and those with UC might be caused by the changes in dietary fat. In addition to the changes in dietary fat, production of vitamin K by intestinal bacteria species may have caused the difference in ucOC levels between patients with
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Fig. 3. The sRANKL was negatively correlated with T-scores at the lumbar spine and the femoral neck in patients with Crohn’s disease. The correlation was significant at the lumbar spine (r ¼ 0.35, P < 0.05) and the femoral neck (r ¼ 0.34, P < 0.05). sRANKL, soluble receptor activator of nuclear factor-kB ligand.
CD and those with UC because the bacterial flora composition of patients with CD is significantly altered from that of healthy controls and patients with UC [32,33]. Further investigation is required to determine the mechanisms for the vitamin K and D deficiencies in IBD. In the present study, vitamin K and D deficiencies were not significantly associated with decreased BMD. Previous reports have shown that vitamin K alters the bone microarchitecture and structural properties and that vitamin K deficiency is a risk for bone fracture independent of an decrease in BMD [34–36]. Therefore, decreased BMD and vitamin K deficiency can be the independent risks of bone fragility in patients with IBD. The active form of vitamin D, 1,25-(OH)2D, has been shown to have a prominent beneficial effect on bone metabolism and disease activity in CD compared with plain vitamin D [24], but we did not find any correlation between 1,25-(OH)2D levels and BMD in patients with CD. Furthermore, we found an inverse correlation between 1,25-(OH)2D levels and BMD in patients with UC. Abreu et al. [25] showed that vitamin D production is increased in the inflamed intestinal tissue of patients with IBD by the local activation of vitamin D–converting enzyme 1a-hydroxylase [25]. According to their findings, we speculate that the active form of vitamin D production is upregulated by the local production of vitamin D–converting enzyme in the inflamed intestine of patients with UC and low BMD. In addition, an increase of serum
sRANKL was significantly correlated with a decrease of BMD in our patients with CD (unpublished observation). Soluble RANKL, which is increased by activated macrophages and T cells, has been shown to be an important trigger of osteoclastogenesis by binding with its receptor RANK in the bone tissue [31,37–39]. The complex relation between immune status and bone homeostasis in IBD requires further investigation. In the present study, we demonstrated a positive correlation between serum ucOC and CDAI in patients with CD. Because ucOC levels are affected by total OC levels that reflect bone turnover [18], we also analyzed the correlation between ucOC/ OC and CDAI. The correlation of ucOC/OC and CDAI was found to be prominent (Fig. 3B). Considering that vitamin K has inhibited inflammation in animal and epidemiologic studies [9,19], vitamin K status may be closely associated with the inflammation of CD. Recent reports have demonstrated that vitamin K serves as a transcriptional regulator by the pregnane X receptor/steroid and the xenobiotic receptor [40]. The role of vitamin K as an inflammatory mediator in intestinal inflammation, such as in IBD, requires further investigation. A vitamin K supplementation study is ongoing in our laboratory. Similarly to vitamin K, 1, 25-(OH)2D has been shown to have immunosuppressive properties [12,41]. In contrast to the correlation between ucOC and CDAI, there was no correlation between 1,25-(OH)2D and CDAI. A decrease of 1,25-(OH)2D may not be observed in patients with
Fig. 4. (A) Serum ucOC (r ¼ 0.32, P < 0.05) and (B) ucOC/OC (r ¼ 0.36, P < 0.0001) correlated significantly with the CDAI in patients with Crohn’s disease. CDAI, Crohn’s disease activity index; ucOC, undercarboxylated osteocalcin.
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a high CDAI, probably because of the local induction of vitamin D–converting enzyme in the inflamed intestine, as discussed earlier. In conclusion, BMD is decreased in patients with IBD. The status of vitamins K and D is different between patients with CD and those with UC. A significant correlation of vitamin K deficiency and clinical disease activity was observed in patients with CD. Further prospective study is needed to clarify the role of vitamin K in patients with IBD.
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