Rev Osteoporos Metab Miner. 2010; 2 (2): 7-9
At present, vitamin D deficiency constitutes a pandemic which affects more than half the population of the whole world2, and is a significant factor in age-related loss of bone and muscle mass , falls and fractures2,3.
In addition, in developed societies, vitamin D deficiency is associated with a higher risk of degenerative and chronic diseases, such as autoimmune diseases: diabetes mellitus, multiple schlerosis; cancer: colon and breast; infectious diseases, such as tuberculosis and seasonal flu; cardiovascular diseases, cardiac insufficiency, hypertension, and acute myocardial infarction, and even a higher risk of cardiovascular death, or death by any other cause2,3. Although, the great majority of the studies are associative and not interventional, the biological plausability generated by knowledge of non-hormonal actions, intracrines and paracrines of the endocrine system of vitamin D, give consistency to the potential problem which, for the public health system, a deficiency or insufficiency of vitamin D may constitute3.
“Vitamin D” in circulation is made up of vitamin D3 and D2, the first mainly acquired by subcutaneous formation by ultraviolet B radiation, and in smaller qualities by ingesting the few natural dietary sources which contain it, as well as fortified foods or supplements, the second solely from these last two sources4. Once acquired, the vitamin D, and later its metabolites, are transported by means of a vitamin D transporter protein, also known as “gc-globulin (group-specific component)”, which also participates in transport within cells2,3<7sup>.
In the liver, by the action of, above all, the microsomal enzyme CYP2R1, the “vitamin D” is converted in to 25 hydroxyvitamin D (calcifediol), the most stable and abundant metabolite, biomarker for the status of the organism of vitamin D2,3.
Calcitriol is a key hormone in the homeostasis of bone and calcium which controls the regulation of the transcription of the genes involved by binding them to a high affinity receptor (HAR) in the classic target organs: intestine, kidneys, bone (osteoblasts-osteocytes)2,3.
Calcitriol is also synthesised in other organs and tissues, such as muscle, heart, brain, breast, colon, pancreas, prostate, skin, immune system. Those which possess the enzyme CYP27B1-hydroxylase activator for the synthesis of calcitriol and the inactivator enzyme (24-hydroxylase, CYP24A1), which favours its catabolism, and the HAR receptor.
Calcitriol regulates approximately 3% of the human genome, with three generic effects: regulation of hormonal secretion, inhibiting rennin, stimulating the secretion of insulin and its action; it regulates the growth and proliferation of cells and modulates acquired and innate immunity2.
At present, there is a significant controversy regarding three aspects related to calcifediol. Its quantification; the establishment of minimum adequate, and optimum, levels; and the apparent paradox of vitamin D deficiency in sunny regions, in young people from these regions, and in osteoporotic patients, treated, or not, with vitamin D.
Despite its importance, the measurement of 25(OH)D has always been problematic and even now generates concerns5. In fact, until relatively recently it was restricted to research centres, which used methods based on protein competition or high resolution liquid chromatography (HRLC). At the end of the last century other methods were validated for use in care, such as RIA, ELISA or chemiluminescence. The spread of availability of the CLAR technologies, coupled in tandem with mass spectrometry (LC-MS/MS) has improved the performance of the measurement of 25(OH)D and is allowing the standardisation of the result obtained with conventional techniques6.
Even nowadays, there is no unanimous consensus on the recommended minimum blood levels of 25(OH)D to ensure bone health, and other health objectives mediated through vitamin D. Last October, in Bruges, Belgium, during the 14th “Workshop” on vitamin D a round table was convened to reach a consensus on this matter7.
The debate became focussed around two options, the European one, led by Roger Bouillon and Paul Lips, who proposed minimum blood levels of calcifediol of 20 ng/ml, and the American, defended in presentations by Robert Heaney and Reinold Vieth, both proposing levels of 25(OH)D higher than 40 ng/ml7, without an agreement being reached. In any case, these levels should always be higher than 20ng/ml, which would suppose average blood levels in the population to be higher than 30 ng/ml. Surprisingly, a target for minimum levels was proposed, but not one for maximum blood levels.
The upper limit for vitamin D in the blood is also not clearly established. But in populations highly exposed to the sun, blood levels of 25(OH)D are not usually found above 60 ng/mL, and no complications of hypercalcaemia or hypercalciuria are found8. Therefore, reaching blood levels of calcidiol of between 20 and 30 (higher than 20 in any case) and 60 ng/mL, seems recommendable from a physiological point of view. Surprisingly, even in a country as sunny as Spain, and independently of the region we consider, the insufficiency and even the clear deficiency in vitamin D, is that described in scientific publications9,10,11, and that which we find in normal clinical practice. On the other hand, in patients treated with calcium and vitamin D in postmenopausal osteoporosis there is evidence of insufficiencies in calcium and vitamin D in more than 60% of the population, both in Spain11 as well as in other countries12,13.
In this edition of the Review of Osteoporosis and Mineral Metabolism14 a higher prevalence of insufficiency or deficiency in vitamin D is described in a group of medical students from Las Palmas de Gran Canaria, which confirm the data found in young junior doctors (Residentes) who began their specialisation at the 12th October Hospital in Madrid15. These data coincide with the descriptions of young people in countries or geographical regions which are sunny and have a good climate, such as Hawaii16, or of colder and less sunny regions17.
These descriptions and observations of low levels of vitamin D even in situations favourable to finding adequate levels, produce great perplexity among researchers and medical practitioners, because, at least theoretically, exposure to sunlight or a sufficient intake of vitamin D should be enough to maintain the status of adequate vitamin D.
We know that personal habits and socio-cultural factors, which can modify the diet and exposure to sun, are the main determinants of the availability of vitamin D in the blood. The concentration of 25(OH)D is higher in summer and autumn, and lower in spring and winter18. However, only a quarter of the variability in blood levels of 25(OH)D can be attributed to the season, latitude and intake of vitamin D19,20. Association studies of families and twins suggested that genetic factors contributed the most to the individual variability observed, with more than 50% of this variability being inherited21. In fact some rare Mendelian alterations, such as the Smith-Lemli-Optiz syndrome are associated with vitamin D deficiency22.
Almost at the same time that this edition of the Review of Osteoporosis and Mineral Metabolism 14 published the apparent contradiction of being young, knowing the importance of taking sun and living in a sunny region of Spain, and having low levels of vitamin D, Wang et al. in The Lancet, give a possible explanation23. By means of a large consortium of experts (“SUNLIGHT consortium”), a study of some 30,00 persons in five selected epidemiological cohorts, which were then increase to 15, stated that at least 3 or 4 genes contribute to the variability in concentration of 25(OH)D in the blood23.
The genes involved code for three key enzymes in the metabolism of vitamin D: 7-dehydrocholesterol (7-DHC), reductase (responsible for the availability of 7-DHC in the skin); hepatic 25-hydroxylase CYP2R1 (involved in the conversion of vitamin D to 25-hydroxyvitamin D) and CYP24A1 (key enzyme in the catabolism of vitamin D). In addition, the GC gene which codes for the vitamin D transporter protein. The polymorphisms in GC had the greatest effect on the blood concentration of vitamin D24.
The authors propose that those patient found in the higher quartile of a “score” constructed with those genotypes studied multiply by two their risk of having vitamin D insufficiency.
This finding could constitute the Rosetta Stone to start deciphering the hieroglyphics of the variability in blood concentrations of 25(OH)D in patients who, according to environmental factors, should have high levels and “surprisingly” have low levels. If confirmed, it would help us to understand the “inexplicable” variations in the corporal status of vitamin D cited earlier, and would demonstrate that some polymorphisms could protect or accelerate the step to deficiency or insufficiency in vitamin D. Posing the following question: do these genes modify the response to supplementation with vitamin D?, the answer has important pharmacological or nutrigenomic implications.
In any case, the battle against vitamin D deficiency continues, and while we know, in depth, the mechanisms involved, we should propose as an unrenounceable public health objective, the correction of vitamin D deficiency, from infancy and throughout life, to prevent its impact on bone and to achieve other health objectives, and in osteoporotic women treated with anticatabolic drugs, to optimise their therapeutic response25.
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21. Lauridsen AL, Vestergaard P, Hermann AP, Brot C, Heickendorff L, Mosekilde L, et al. Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women. Calcif Tissue Int 2005; 77:15-22.
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