Su1135 High Vitamin D Diet Leads to a Paradoxical Decrease of Bone Mineral Density in Adoptive T-Cell Transfer Colitis

Abstract

Background: Inflammatory Bowel Disease is not only characterized by an aberrant immune response against commensal intestinal bacterial flora and mucosal damage but can also affect bone metabolism and bone mineral density (BMD) with osteopenia and osteoporosis as the two major extra-intestinal symptoms of IBD. Low BMD along with 25(OH) vitamin D3 deficiency have been reported in both Ulcerative colitis and Crohn's Disease and is associated with an increased risk of fracture. In IBD patients, inflammation-associated pro-inflammatory mediators, poor nutritional status and malabsortion affecting vitamin D3 and Ca2+ homeostasis, have been postulated to be the cause of altered bone morphology and metabolism. Moreover, immunomodulatory role of vitamin D3 has been reported in both innate and adaptive immune system. Therefore, vitamin D3 supplementation has been considered as a viable adjunctive therapeutic strategy in IBD. Vitamin D3 plays a pleiotropic role in bone modeling and regulates the balance of bone formation and bone resorption depending of the physiological environment. Moreover, a significant fraction of adult and pediatric IBD patients with low BMD have elevated levels of circulating 1,25(OH)2 D3. We hypothesized that vitamin D3 supplementation in active IBD may lead to a paradoxical loss in BMD. Methods: We evaluated the effect of vitamin D3 supplementation in adoptive IL-10-/-CD4+ T cell transfer model of chronic colitis. In this model, we evaluated the effect of vitamin D3 supplementation (switch from human equivalent dose of 730 IU to 3,648 IU daily) on established colitis and on BMD (μCT), bone metabolism and turnover. Results: 12-day highdose vitamin D3 supplementation during established disease had negligible effects onmucosal inflammation. Plasma level of vitamin D3 metabolites correlated with diet, but not with the disease status. Colitis reduced BMD. High vitamin D3 supplementation did not affect cortical bone structure but led to a further deterioration of trabecular bone morphology. High D3 diet negatively affected bone formation markers; osteocalcin and bone alkaline phosphatase, and increased bone resorption markers; RANKL/OPG transcript ratio, plasma OPG level and osteoclast activation marker ACp5. Consistently, expression of bone vitamin D receptor (VDR) was increased in mice with chronic colitis, especially in mice fed high vitamin D3 diet. Conclusion: Our data collectively suggests that vitamin D3 in a dose which does not improve inflammation, adversely affects BMD and bone turnover. The data provided by this study should be taken into consideration in the planning of further clinical studies with high vitamin D3 supplementation in IBD patients with active disease.