Review Article: Vitamin D and Inflammatory Bowel Disease

Established Concepts and Future Directions

M. Garg; J. S. Lubel; M. P. Sparrow; S. G. Holt; P. R. Gibson


Aliment Pharmacol Ther. 2012;36(4):324-344. 

In This Article

Classical Role of Vitamin D: Calcium Homeostasis and Musculoskeletal Health

The predominant actions of vitamin D are to increase serum calcium and phosphate, and to promote bone mineralisation. Parathyroid hormone is the main stimulus to synthesis of the active metabolite 1,25(OH)2D. Hypophosphatemia also promotes 1α-hydroxylase production and thereby increases 1,25(OH)2D.[16,48]

1,25(OH)2D stimulates proximal intestinal calcium and phosphate absorption, and, together with PTH, increases distal renal tubular calcium reabsorption. Both calcium and phosphate absorption occur via saturable and nonsaturable pathways across the intestinal epithelium. 1,25(OH)2D mediates transcriptional and possibly rapid nontranscriptional regulation of calcium absorption via mechanisms that remain to be clarified.[49] 1,25(OH)2D also regulates the sodium dependent type II phosphate cotransporter NaPi-IIb in the intestine.[50] Details of these mechanisms are beyond the scope of this review.[49,50]

25(OH)D causes a net increase in bone density by promoting osteoblast differentiation and mineralisation following intracellular conversion to 1,25(OH)2D.[51] 1,25(OH)2D and PTH stimulate osteoblast secretion of receptor activator of nuclear factor-kB ligand (RANKL), which in turn induces osteoclastogenesis and osteoclastic bone resorption and calcium mobilisation.[16,52] This effect is attenuated by increasing levels of 25(OH)D.[51] 1,25(OH)2D promotes the secretion of FGF23 from osteocytes, and this inhibits 1α-hydroxylase and upregulates 24-hydroxylase. PTH secretion is inhibited by both elevation of calcium and directly by 1,25(OH)2D, completing the negative feedback endocrine loop.[16,53]

There is a wealth of human clinical data regarding the integral role of vitamin D in the maintenance of skeletal health. Osteomalacia, and rickets in children, are conditions characterised by a defect or delay in bone mineralisation, respectively. Typically, 25(OH)D levels in patients with osteomalacia are less than 20 nmol/L (8 ng/mL), and consequent calcium and phosphorus deficiency result in failure of organic osteoid mineralisation with bone pain or deformities.[51] Originally recognised in 1650 by Francis Glisson, its incidence increased dramatically during the industrial revolution in the 19th century.[5] Cod liver oil, one teaspoonful of which contains about 375 IU of vitamin D, was recognised as a folk remedy for rickets in infants.[11] Following the fortification of foods with vitamin D in the early 20th century, the incidence of rickets fell markedly.[5]

Osteoporosis is a condition of bone microarchitectural disruption with increased fragility but without an increase in unmineralised osteoid, and it is defined by a reduction in BMD at any major skeletal site of more than 2.5 standard deviations below the mean for young normal adults (a T score ≤ −2.5).[54] Though believed to be multifactorial in origin, vitamin D deficiency with secondary hyperparathyroidism, which increases bone resorption and results in cortical bone thinning, contributes to these pathological changes. Vitamin D supplementation at doses of 700–800 IU/day has been shown to reduce loss of BMD,[55] and in multiple randomised controlled trials (RCTs) to reduce the risk of vertebral and nonvertebral fractures;[55–60] however, most of these trials also entailed calcium supplementation in the same arm. A recent analysis of 12 RCTs of patients receiving vitamin D supplementation for nonvertebral fracture prevention found an optimal benefit at a serum 25(OH)D level of 75–110 nmol/L.[61] Trials of vitamin D alone have provided conflicting results,[60,62–65] but the doses of vitamin D in the negative studies may have been too low to provide true benefit for fracture prevention. Observational studies corroborate a positive correlation between 25(OH)D levels and BMD, with maximal suppression of PTH,[66,67] bone turnover markers[67] and pathological osteoid accumulation[68] with 25(OH)D levels above 75 nmol/L.

Vitamin D deficiency has also been associated with reduced muscle strength and appendicular muscle mass, muscle pain, increased body sway and risk of falls in observational studies.[52,69,70] In myocytes, vitamin D exerts VDR-mediated genomic regulation of expression of calcium pumps, calcium binding and cytoskeletal proteins, and phosphate metabolism.[71] Furthermore, rapid and direct nongenomic effects on calcium uptake via G-protein-mediated activation of phospholipase C, and mitogen-activated protein kinase (MAPK) pathways, have been recognised.[44,71] Vitamin D deficiency results in atrophy of fast twitch type II muscle fibre atrophy,[71] which are the first group of muscle fibres recruited during postural correction. Interventional trials assessing for changes in muscle strength and function using vitamin D have found conflicting results due to heterogeneity in dosage of vitamin D administered and levels attained,[72] but overall an improvement in hip muscle strength and reduction in falls has been demonstrated.[69,72]


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