Osteoporosis is a well recognised complication of CD and UC.4,14,15
What is less clear however are the factors that result in its development and the best approach to its treatment and prevention.17–19,61–63
Based on our findings, we suggest that elevated 1,25(OH)2
D is an additional risk factor predisposing to development of osteoporosis in a subset of CD patients.
Our finding of normal 25(OH)D and elevated 1,25(OH)2
D is in contrast with previous studies demonstrating low 25(OH)D and secondary hyperparathyroidism in patients with CD.39,40
Some have suggested vitamin D supplementation in patients with CD to prevent bone loss47
whereas others have found normal 25(OH)D and serum calcium levels in CD.64
The reasons for the divergent results may be geographic location (Southern California versus northern climates) and limited intestinal resections in recently ascertained patient cohorts. Patients with extensive surgical resections for CD were commonplace at the time most of the previous vitamin D studies were performed33,37
and may have had reduced absorption of cholecalciferol and 25(OH)D.65
The change in treatment of CD away from surgery and, to some extent, away from systemic glucocorticoids, requires a revisiting of established tenets with respect to vitamin D.
Our study demonstrated an inverse correlation between 1,25(OH)2D levels and BMD. Although we demonstrated this correlation, it is not possible to demonstrate causality between the two. We believe that the increase in systemic 1,25(OH)2D is the result of the underlying inflammation in CD. Consistent with this notion, disease activity correlated with 1,25(OH)2D levels, and biopsies from patients with active CD and elevated 1,25(OH)2D demonstrated increased expression of 1α-hydroxylase required for conversion of 25(OH)D to its active 1,25(OH)2D form. Elevated 1,25(OH)2D may therefore be a direct cause of bone loss or a surrogate marker for the type of intestinal inflammation resulting in osteoporosis. Because of the retrospective nature of our study, it is not possible to determine whether the increase in 1,25(OH)2D predates the onset of osteoporosis or is related to the severity of the underlying CD. Multivariate analyses demonstrated that 1,25(OH)2D is an independent risk factor for low BMD but the use of corticosteroids was high in this patient population. Nevertheless, our findings help to identify a subgroup of patients with an additional risk factor for osteoporosis and one that can be used to make decisions on further evaluation and therapy.
We have shown previously that intestinal epithelial cells normally express 1α-hydroxylase.56
The present study shows for the first time that lamina propria mononuclear cells also express 1α-hydroxylase and therefore have the ability to generate 1,25(OH)2
D locally. Furthermore, in the presence of intestinal inflammation, the increased number of lamina propria mononuclear cells combined with the availability of 25(OH)D as the substrate for 1α-hydroxylase results in the generation of higher levels of 1,25(OH)2
D. We propose a model in which excess 1,25(OH)2
D from the inflamed gut spills over into the circulation and may have the unintended effect of contributing to metabolic bone disease in patients with CD (fig 6). This situation is similar to that seen in other granulomatous diseases such as sarcoidosis51
in which mature macrophages express 1α-hydroxylase resulting in hypercalcaemia and hypercalciuria.50,59,60
In both sarcoidosis and CD, the most likely function of extrarenal 1,25(OH)2
D production is as an endogenous feedback response to inflammation. A variety of studies have documented the immunosuppressive properties of 1,25(OH)2
D, stimulating interest in the potential use of synthetic analogues of vitamin D as therapy for autoimmune disease and transplantation rejection.66–68
However, recent data from our group suggest that vitamin D may also fulfil a protective role, with macrophages, dendritic cells, and epithelial cells being potential sources of immunomodulatory 1,25(OH)2
. CD is characterised by Th1 mediated intestinal inflammation with a subset of patients demonstrating microgranuloma.71,72
Thus the goal of local 1,25(OH)2
D production may be suppression of Th1 cytokine secretion and T cell proliferation, as we and others have described in other systems.44,73,74
Indeed, in animal models of colitis limiting the substrate for 1,25(OH)2
D or using mice with disruption of the VDR gene results in worse colitis.75,76
Clearly, in many instances of CD, local synthesis of 1,25(OH)2
D may not be sufficient to suppress tissue inflammation, and in these cases unregulated 1α-hydroxylase may lead to raised circulating levels of the hormone. As with sarcoidosis, the extent to which this occurs is likely to be dependent on the severity of the disease but also on serum levels of 25(OH)D or, in other words, vitamin D status.
Figure 6 Model of elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) in patients with Crohn’s disease. The inflamed intestine in Crohn’s disease is characterised by an infiltrate of mononuclear cells, including (more ...)
The clinical implications of our work are several. Firstly, elevated 1,25(OH)2
D may serve as a marker of CD. The positive and negative predictive values for supranormal (>60 pg/ml) 1,25(OH)2
D in patients with CD are 97% and 75%, respectively. These numbers are comparable with serological tests currently available for distinguishing CD from UC.77–79
Secondly, clinicians frequently recommend that patients take calcium and vitamin D supplementation to prevent or treat osteopenia and osteoporosis in patients with IBD. Based on our work, measuring vitamin D metabolites is important in identifying those patients with an additional risk factor for developing low BMD. Moreover, we have also found that patients with elevated 1,25(OH)2
D frequently have hypercalciuria and may be prone to renal nephrolithiasis (data not shown). The correct intervention in these patients is not established. Strategies to reduce bone loss in these patients may include non-glucocorticoid treatment of the underlying IBD and potentially hydroxychloroquine which inhibits the conversion of 25(OH)D to 1,25(OH)2
In sarcoidosis patients with hypercalcaemia secondary to elevated 1,25(OH)2
treatment with hydroxychloroquine is effective in reducing serum calcium.81
Preliminarily, we have treated several CD patients with low dose (200 mg daily) oral hydroxychloroquine and lowered serum 1,25(OH)2
D levels and urinary calcium excretion (unpublished studies). Finally, if elevated 1,25(OH)2
D is an indirect marker of Th1 mediated inflammation, we may be able to use this test to better predict who will respond to medical therapy directed at Th1 cytokines in CD. More research will need to be done to better characterise this interesting subgroup of patients.