THE ROLE OF CALCIUM AND VITAMIN D
Calcium is the most abundant mineral in the body. Approximately 1.2 kg (equivalent to about 300 mmol) is contained within the human body, with 99% of this calcium being located within the bones and teeth. Calcium is also located in body fluids and soft tissues. It has two key roles: (1) supporting structural integrity; (2) regulating metabolic function. Cellular structure, intercellular and intracellular metabolism, signaling, heart muscle contractions, nerve function, enzyme activity, and normal blood clotting are all dependent on calcium. There is no functional marker of calcium status, since its role in normal blood clotting takes priority and hence plasma calcium is maintained within very narrow limits .
The jejunum, ileum, and colon are the primary sites for calcium absorption. Uptake occurs by active transport and simple passive diffusion. Active transport is more prevalent when calcium intake is low, but when intake rises, more calcium is absorbed through non-specific routes. The metabolite of vitamin D (1,25-dihydroxycholecalciferol) stimulates calcium transport across the intestinal cells by inducing the production of a calcium-binding protein. This process occurs within the villus cells through the normal process of receptor binding, DNA interaction and messenger RNA production. Hence, vitamin D is critical for effective calcium absorption .
Vitamin D refers to vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol). Ergocalciferol is produced from irradiated fungi or yeast. Cholecalciferol is produced in skin or found naturally in fatty fish such as salmon or mackerel. Although food can be fortified with both types of vitamin D, only cholecalciferol can be produced endogenously in skin. 7-dehydrocholesterol, a substance found in the skin, is converted into previtamin D3, which isomerizes to form vitamin D3, when exposed to ultraviolet B (UVB) radiation between the wavelengths of 290 and 315 nm. The amount of vitamin D3 made in the skin can be affected by an individual’s skin color, age, and use of sunscreen products, as well as the time of day, season, and latitude .
Once vitamin D is made in the skin (D3) or obtained in the diet (D2 or D3), it enters the circulation bound to vitamin D–binding protein. The main form of vitamin D that circulates in the body is 25-hydroxyvitamin D (25(OH)D), which is created in the liver by the hydroxylation of vitamins D2 and D3 complex. The best marker for determining vitamin D level is 25(OH)D, which reflects both endogenous and exogenous sources. To generate the physiologically active form of vitamin D, 25(OH)D undergoes hydroxylation by the 1α-hydroxylase enzyme in the kidneys to produce 1,25-dihydroxyvitamin D (1,25(OH)2D; calcitriol). 1,25(OH)2D circulates bound to vitamin D–binding protein, enters the target cell, and binds to the vitamin D receptor (VDR) in the cytoplasm, which then enters the nucleus and heterodimerizes with the retinoic acid X receptor to increase transcription of vitamin D–dependent genes important for bone metabolism, calcium absorption, and other nonclassical functions (e.g., inhibition of genes important in cancer growth) [2, 3].
The Advantage of Calcium and Vitamin D
Osteoporosis is defined as a metabolic bone disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. According to estimates, three million people worldwide, roughly one in three women and one in twelve men aged > 50 years, will have osteoporosis at some point in their lives .
Bone is a living tissue. Active bone formation (through the activity of osteocytes and osteoblasts) and bone resorption (involving osteoclasts) occur continuously. Osteoclasts are attracted to a quiescent bone surface and then excavate an erosion cavity. Mononuclear cells smooth off the erosion cavity, which is a subsequent site for the attraction of osteoblasts that synthesize an osteoid matrix. Continuous new bone matrix synthesis is followed by calcification of the newly-formed bone. When complete, lining cells once more overlie the trabecular surface .
It is well known that vitamin D promotes calcium absorption in the gut and kidney and helps to maintain adequate serum calcium concentrations to enable normal mineralization of the bone. Osteoblasts and osteoclasts need vitamin D to develop bones and repair them . Bone matrix formation and bone maturation are stimulated by vitamin D. Additionally, it enhances osteoclastic activity and some evidence points to the possibility that it may influence differentiation of bone cell precursors . Although vitamin D is utilized to enhance bone health, there is currently limited and conflicting evidence that vitamin D supplements alone have an impact on fracture outcomes. Thus, calcium and vitamin D work together synergistically on the bone .
Several randomized, placebo-controlled trials in both institutionalized and ambulatory elderly subjects have been shown that vitamin D with or without calcium reduced the incidence of hip and/or nonvertebral fractures by 20% to 30%. According to meta-analysis, taking vitamin D supplements along with calcium considerably lowers the risk of hip fractures (by 18%) and other nonvertebral fractures (by 12%). The majority of studies used at least 800 IU of vitamin D and the minimum 25(OH)D level of 29.7 ng/mL (74 nmol/L) was found to be effective in preventing fractures, suggesting a threshold for optimal vitamin D status .
The Role in Cancer
There is a strong biological rationale for the association between a vitamin D deficiency and an elevated risk of cancer, as well as for the use of vitamin D or its bioactive analogues in the prevention and treatment of cancer. VDR is expressed in most cancerous tissues; in vitro cell culture studies and in vivo animal studies demonstrate that 1,25(OH)2D inhibits cell proliferation, angiogenesis, invasion and promotes differentiation and apoptosis. In cancer cells, 1,25(OH)2D/VDR stimulates TGF-β activity, activates cyclin-dependent kinase inhibitors (e.g., p21, p27), and inhibits mitogenic growth factors including IGF-1 and EGF, thus inhibiting cell proliferation and cancer growth. 1,25(OH)2D/VDR signaling has the capacity to downregulate cyclooxygenase-2, prostaglandin, and NF-kB pathways, which prevents inflammation associated with tumors. It can also suppress antiapoptotic proteins (e.g., Bcl2) and to activate proapoptotic proteins (e.g., Bax, RAK). Acting together, all these can suppress cancer growth .
It indicates that 1,25(OH)2D/VDR plays a role in maintaining the homeostasis of oral epithelium and of oral immunity. Oral keratinocytes contain VDR, which has a ligand-independent role in limiting keratinocyte proliferation. 1,25(OH)2D/VDR signaling has an even stronger inhibitory effect on keratinocytes proliferation. Studies conducted in vitro and in vivo demonstrate that vitamin D deficiency causes oral keratinocyte proliferation to increase but without any morphological or histological alterations .
The anti-inflammatory, antimicrobial, and immunomodulating effects of the 1,25(OH)2D/VDR pathway most probably play roles in maintaining the homeostasis of oral tissues in general, thus providing some protection against the development of bacterial plaque-induced periodontal diseases. There is evidence that vitamin D deficiency or VDR polymorphism are associated with increased risk of chronic periodontitis. Therefore, administering biologically active vitamin D may be a useful addition to the standard treatment for chronic periodontitis .
In post-menopausal women, estrogen loss affects calcium homeostasis in a variety of ways, including increasing bone resorption, reducing calcium absorption and increasing in urinary calcium loss. Ovariectomy does not reduce serum 1,25(OH)2D levels in rats, despite the fact that low estrogen levels seen in post-menopausal women are associated with reduced serum levels of 1,25(OH)2D. On the other hand, oophorectomy decreased 1,25(OH)2D-induced intestinal calcium absorption in young women and this was restored by estrogen repletion. Although the loss of tissue VDR levels following estrogen loss is not observed in all studies, other findings imply that the effect of estrogen loss on the intestine responsiveness to 1,25(OH)2D is caused by reduced VDR levels .
High intakes of calcium and vitamin D have been found to be modestly associated with lower risk of early menopause. Contrarily, supplemental calcium intake was positively related with early menopause but supplemental vitamin D intake was not .
Calcium supplement users are aware of their propensity to cause gastrointestinal upset, particularly constipation. The latter can be a serious concern for frail elderly, who are already prone to this issue. There is evidence that calcium supplements increase the risk of myocardial infarction and, possibly, stroke. Studies on nephrology patients who were given calcium to bind phosphate also show an increase in mortality. As previously mentioned, calcium supplementation acutely elevates serum calcium concentration and higher serum calcium levels have been associated in cohort studies with increased risk of myocardial infarction, stroke, and mortality .
Most studies of vitamin D supplements have used doses of 400–1000 IU/day. These doses have not been associated with evidence of adverse effects, and it is generally held that doses up to 2000 IU/day are safe. However, trials have shown that vitamin D 4000 IU/day, 60,000 IU/month, or 300,000–500,000 IU/year increase the risk of falls and/or fractures, and a recent 3-year study found that 4000 IU/day and 10,000 IU/day both accelerate bone loss. Use of these large doses is not justified because the threshold for vitamin D’s advantages on bones is fulfilled with doses of 400–1000 IU/day. Supplemental doses above 2000 IU/day should only be used under strict control and in unusual cases .
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