In this prospective case-control pilot study, we have demonstrated that young male subjects with stable CD do not have impaired intestinal calcium absorption at baseline when compared with controls. Further, vitamin D therapy similarly increased calcium absorption in CD and controls. Our findings from this pilot study suggest that patients with clinically stable CD have maintained intestinal calcium absorption at baseline and in response to calcitriol therapy compared with subjects without CD.
All subjects in both groups were vitamin D insufficient at baseline and both groups had similar mean 25(OH)D concentrations. These findings suggest that the intrinsic CD inflammatory state does not impair calcium absorption independently of vitamin D status. In agreement with our study, Kravitt et al
. found that only four out of 31 subjects with CD have a negative calcium balance as evaluated by metabolic and calcium isotope studies [9
Calcium absorption is impaired in other diseases associated with increased inflammation. Sambrook et al
] demonstrated that calcium absorption measured by dual isotope method was impaired in post-menopausal women with RA compared with healthy controls. Similarly, Abrams et al
] found that calcium absorption was impaired in children with juvenile RA compared with healthy controls. A recently developed mouse model of CD characterized by elevated TNF-α concentrations demonstrated decreased intestinal expression of key proteins involved in calcium transport including TRPV6, calbindin-D9k
and PMCA1b [34
]. New therapies to lower TNF levels have been developed for the treatment of CD and RA [35
]. Although their effects on calcium absorption have not been evaluated, there appears to be a favorable effect of anti-TNF therapies on bone mineral density [36
Aging, a condition associated with increased inflammation, has been associated with decreased absorption of calcium. Pattanaungkul et al
] examined younger and older women and found a positive relationship between serum 1,25-dihydroxyvitamin D3
levels only in young but not old women, suggesting that aging resulted in vitamin D resistance in intestinal absorption of calcium. Walters et al
. found decreased intestinal expression with age of the vitamin D-dependant calcium transport protein TRPV6 and vitamin D receptor with aging in women, confirming the increased intestinal vitamin D resistance with age [38
Another aspect of our study was to examine the role of low- and high-dose calcitriol on calcium absorption in a model of inflammation such as CD. We sought to assess whether the intrinsic inflammatory state of CD would prevent a rise in calcium absorption in response to vitamin D when compared with controls. Furthermore, we sought to assess whether higher doses of calcitriol could overcome this so-called vitamin D resistance. Treatment with 1,25(OH)2
D (calcitriol) has been shown to reduce TNF-α levels and markers of bone turnover in patients with CD [21
]. We did not find impaired calcium absorption in response to vitamin D in our subjects with mild CD.
There are limitations to this study. Our sample size was small. We only examined CD patients in remission or with mild disease, half of whom were on 5-ASA agents or azathioprine. We calculate that with this number of subjects enrolled, we had 80% power to exclude a difference of 35% in FCA between the two groups. This information is clinically useful since this approximates the expected rise in FCA in healthy controls comparing baseline to calcitriol-stimulated FCA. We can reject our initial hypothesis that CD patients have no increase in FCA in response to calcitriol. We lacked sufficient power to detect more subtle differences in FCA between these two groups. In order to detect smaller differences, we would require 40 or 150 subjects per
group to detect a difference of 10 or 5%, respectively. Furthermore, our CD group may therefore not have had significant local inflammation of the intestine. None of our CD subjects had detectable systemic TNF-α levels. It could thus be argued that the level of inflammation in our group of CD subjects may not have been enough to interfere with vitamin D-mediated intestinal calcium absorption, and that greater degrees of inflammation may still play a role in impairing vitamin D-mediated calcium absorption. However, studies conducted on CD subjects with similar disease activity have elevated local TNF-α on jejunal biopsy samples [20
]. Our findings are also limited to men since we did not enroll women. There may be differences in response to 1,25(OH)2
D with aging. Walters et al
. demonstrated that men had increases in TRPV6 with serum 1,25(OH)2
D levels in contrast to women where there was no relationship [38
]. Finally, our subjects were primarily African-American and therefore our results may not be generalized to other ethnicities. This study measured the absorption of calcium but did not assess the loss of calcium via
intestinal secretions. It is possible that these are increased in CD, but unlikely that this would be affected by vitamin D therapy.
In conclusion, our study demonstrates that subjects with CD do not have impaired calcium absorption in response to the hormonal form of vitamin D, 1,25(OH)2D (calcitriol), compared with matched controls. The implications of this finding are that stable CD patients may not require increased amounts of calcium and vitamin D supplementation since neither the response to vitamin D nor the intestinal absorption of calcium appears to be impaired. Future studies should evaluate whether impaired calcium absorption occurs in active CD and whether these individuals are resistant to calcium absorption in response to vitamin D.