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Abstract
Abstract
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor
of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for
the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone
and its growth plate are primarily indirect and mediated by its effect on intestinal
calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia
can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency
(serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic
fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate
calcium intake, given to institutionalized or vitamin D–deficient elderly subjects.
VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular,
cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal
effects. These include regulation of cell proliferation, immune and muscle function,
skin differentiation, and reproduction, as well as vascular and metabolic properties.
From observational studies in human subjects, poor vitamin D status is associated
with nearly all diseases predicted by these extraskeletal actions. Results of randomized
controlled trials and Mendelian randomization studies are supportive of vitamin D
supplementation in reducing the incidence of some diseases, but, globally, conclusions
are mixed. These findings point to a need for continued ongoing and future basic and
clinical studies to better define whether vitamin D status can be optimized to improve
many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic
fractures and is associated with many diseases. We review what is established and
what is plausible regarding the health effects of vitamin D.
Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor. To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture. A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008. 500,000 IU of cholecalciferol or placebo. Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels. Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing. Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures. anzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.
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