Objectives: Many patients with Crohn's disease (CD) have low bone mineral density (BMD) that may not be solely attributable to glucocorticoid use. We hypothesised that low BMD in patients with CD is associated with elevated circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH) 2 D). We further hypothesised that this was secondary to increased synthesis of 1,25(OH) 2 D by inflammatory cells in the intestine. The aim of this study was to examine the relationship between 1,25(OH) 2 D levels and BMD in patients with CD. Methods: An IRB approved retrospective review of medical records from patients with CD (n = 138) or ulcerative colitis (UC, n = 29). Measurements of vitamin D metabolites and immunoreactive parathyroid hormone (iPTH) were carried out. BMD results were available for 88 CD and 20 UC patients. Immunohistochemistry or real time reverse transcription-polymerase chain reaction (RT-PCR) for the enzyme 1a-hydroxylase was performed on colonic biopsies from patients with CD (14) or UC (12) and normal colons (4). Results: Inappropriately high levels of serum 1,25(OH) 2 D (.60 pg/ml) were observed in 42% of patients with CD compared with only 7% in UC, despite no differences in mean iPTH. Serum 1,25(OH) 2 D levels were higher in CD (57 pg/ml) versus UC (41 pg/ml) (p = 0.0001). In patients with CD, there was a negative correlation between 1,25(OH) 2 D levels and lumbar BMD (r = 20.301, p = 0.005) independent of therapeutic glucocorticoid use. 1,25(OH) 2 D levels also correlated with CD activity. Lastly, immunohistochemistry and RT-PCR demonstrated increased expression of intestinal 1a-hydroxylase in patients with CD.Conclusions: These data demonstrate that elevated 1,25(OH) 2 D is more common in CD than previously appreciated and is independently associated with low bone mineral density. The source of the active vitamin D may be the inflamed intestine. Treatment of the underlying inflammation may improve metabolic bone disease in this subgroup of patients.A serious and silent complication of inflammatory bowel disease (IBD) is the development of osteoporosis. [1][2][3][4] Estimates of osteopenia in IBD range from 31% to 59% 5 6 and osteoporosis from 5% to 41%. 1 7-10 Some studies have found that osteoporosis is more prevalent in patients with Crohn's disease (CD) than in those with ulcerative colitis (UC).1 4 11-13 Other studies however, have found similar degrees of bone loss in CD and UC.14 15 Lower bone mineral density (BMD) may be present at diagnosis, 13 16 suggesting factors other than medication may contribute to bone loss. The consequences of low BMD in patients with IBD include an increased risk of vertebral or hip fractures and their associated morbidity. [17][18][19][20] Indeed, recent data suggest that the risk of fractures in patients with CD may be underestimated. In a prospective study of CD patients, asymptomatic fractures were found in 14% of steroid free patients (including steroid naïve patients) and 15% of steroid dependent patients. 21Similar results were repor...