(IBD). Vitamin D 3 has been considered a viable adjunctive therapy in IBD. However, vitamin D 3 plays a pleiotropic role in bone modeling and regulates the bone formation-resorption balance, depending on the physiological environment, and supplementation during active IBD may have unintended consequences. We evaluated the effects of vitamin D 3 supplementation during the active phase of disease on colonic inflammation, BMD, and bone metabolism in an adoptive IL-10 Ϫ/Ϫ CD4 ϩ T cell transfer model of chronic colitis. High-dose vitamin D 3 supplementation for 12 days during established disease had negligible effects on mucosal inflammation. Plasma vitamin D 3 metabolites correlated with diet, but not disease, status. Colitis significantly reduced BMD. High-dose vitamin D 3 supplementation did not affect cortical bone but led to a further deterioration of trabecular bone morphology. In mice fed a high vitamin D3 diet, colitis more severely impacted bone formation markers (osteocalcin and bone alkaline phosphatase) and increased bone resorption markers, ratio of receptor activator of NF-B ligand to osteoprotegrin transcript, plasma osteoprotegrin level, and the osteoclast activation marker tartrate-resistant acid phosphatase (ACp5). Bone vitamin D receptor expression was increased in mice with chronic colitis, especially in the high vitamin D3 group. Our data suggest that vitamin D3, at a dose that does not improve inflammation, has no beneficial effects on bone metabolism and density during active colitis or may adversely affect BMD and bone turnover. These observations should be taken into consideration in the planning of further clinical studies with high-dose vitamin D3 supplementation in patients with active IBD. inflammatory bowel disease; bone mineral density; 1,25-dihydroxyvitamin D3; bone turnover INFLAMMATORY BOWEL DISEASE (IBD) is characterized by an inappropriate and persistent immune response against commensal intestinal microbiota and by intestinal inflammation and mucosal damage. However, this chronic inflammatory disease can also affect bone metabolism and bone mineral density (BMD), with osteopenia and osteoporosis as the two major extraintestinal symptoms. Low BMD has been reported in Crohn's disease (CD) and ulcerative colitis (UC). The relative risk of fracture is 40% higher in the IBD patient than in the general population (3), and although this has not been systematically studied, it is expected that children with IBD do not reach the optimal peak bone mass in early adulthood. The prevalence of osteopenia and osteoporosis in IBD varies depending on the population studied, geographic location, and study design, with a range of 22-77% for osteopenia and 17-41% for osteoporosis (3). Vitamin D 3 increases intestinal and renal Ca 2ϩ and P i absorption and is typically considered an anabolic hormone that positively affects osteoblast differentiation and bone matrix synthesis. Moreover, its immunomodulatory effects, including promotion of macrophage antimicrobial responses to pathogens, regulation of ...