Suomalaisten keskimääräiset kalsidiolitasot ovat talvella 38-46 nmol/l. Kesän ajaksi tasot nousevat noin 20 nmol/l eli tasolle 58-66 nmol/l. Tämä siis normikesänä, jolloin aurinko paistaa edes satunnaisesti. Viime kesän sadekeleillä tasot tuskin nousivat yhtään. Hällä kuitenkin väliä, koska
fysiologinen kalsidiolitaso on noin 150 nmol/l. Eli jäädään todella pahasti paitsioon kesälläkin jos aiotaan luottaa pelkkään UVB:hen. Ja kenellä pirulla on aikaa koko kesän olla vähintään noin puoli tuntia auringossa keskipäivän aikaan JOKA PÄIVÄ.
Huomatkaa ihmiset, että kilpirauhanen alkaa toimimaan oikein vasta, kun tasot ovat yli 80 nmol/l. Vasta tasolla 125 nmol/l D-vitamiinia alkaa varastoitumaan rasvakudokseen eli vasta tällä tasolla kroonista puutetta ei ole! Tasolla 150 nmol/ elimistö
alkaa toimimaan kuten sen pitäisi toimia.
Tämän takia on tärkeää pitää saanti ympäri vuoden kunnossa vitamiinilisillä.
Nykysaantisuosituksilla ja kalsidiolitasoilla ehkäistään riisitauti. Ei sen kummempaa. Tasoja määritellessä ei aiemmin kenellekään saantisuosituspellelle tullut mieleenkään, että D-vitamiinilla olisi jotain muuta vaikutusta kehoon. Ei ollut riittävästi tietoa asiasta. Nyt on:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=vitamin+d&log$=activity
http://www.vitamindcouncil.org/research.shtml
On todella säälittävää, että tulli syynää valmisteita, joita ihmiset ovat tilanneet pysyäkseen hengissä. Välttääkseen syövän, diabeteksen, MS-taudin, astman, osteoporoosin, sydäninfarktin, liikalihavuuden, masennuksen, kilpirauhasen vajaatoiminnan, flunssat, epämääräisen väsymyksen, allergiat, kaljuuntumisen jne. Ja kaikki tämä syynäys vain siksi, että Suomen terveysviranomaiset eivät nosta saantisuosituksia tasoille, joilla kansaa ei enää tapeta. Kusetus jatkuu. Perkele.
Kommentoin Anssin blogissa D-vitamiiniasiaa näin: ja lupaan kyllä heittää viitteitä julkaisuihin, joissa D-vitamiinin suositukset ovat hieman järkevämmällä tasolla. Lääkefirmojen syyttely on Suomessa on kerrassaan huvittavaa - Suomessa lääkefirmat pidetään tiukasti Valtion tossun alla. Hyvä esimerkki on viitehintajärjestelmä - lääkefirmat vikisee, kun Lipitorin ja monen muun uudehkon lääkeaineen patentit "heitetettiin roskakoriin"... No, Orion oli nopea ja toi Intiasta samantien geneerisen vaihtoehdon
D-vitamiinin optimaalisesta annostuksesta on viimeisen parin vuoden aikana käyty kovaa vääntöä arvostetuissakin ravitsemustieteen lehdissä.
Ennen kuin alamme pohtia optimaalista 25-hydroksi-D-vitamiinipitoisuutta plasmassa (huom! usein pitoisuus ilmoitetaan seerumista). Jotta asia olisi vieläkin hankalampi, on D-vitamiinipitoisuuden mittauksessa käytössä 8 eri analyysimenetelmää, jolloin eri labrojen mittaustulokset eivät ole täysin vertailukelpoisia. Samoin yksilölliset erot 25(OH)-D-vitamiinipitoisuuksissa ovat valtavia.
Jostain kumman syystä 250 mikrogrammaa vuorokaudessa on esitetty uudeksi turvallisen saannin rajaksi, sillä perusteella, ettei hyperkalsemiaa tuolla annostuksella aiheudu..HUH HUH mitä logiikkaa...
D-vitamiikeskustelussa huomio keskittynyt liiaksi MAHDOLLISIIN terveysvaikutuksiin suurilla annoksilla ja mahdolliset haittavaikutukset kuten eturauhassyöpään sairastumisen riskin suureneminen on sivuutettu täysin (Tampereen yliopiston Tuohimaan tutkimusryhmän havainto)
Suomen arvostetuin D-vitamiinitutkija (Christel Lamberg-Allardt), joka maailmalla rankataan usein 15 parhaan tutkijan joukkoon pitää noin 20 mikrogramman vuorokausiannosta useimmille optimaalisena TÄMÄN HETKEN tutkimustiedon valossa. Viiden vuoden päästä tiedämme enemmän sekä D-vitamiinin saannin lissämisen hyödyistä että haitoista. Palataan siis asiaan 5 vuoden päästä....
..Nutr Rev lehden 2008-vuosikerrassa on runsaasti laadukkaita katsausartikkeleita D-vitamiinista
Tässä hieman juttua kyseisestä lehdestä...
Vitamin D requirement and setting recommendation levels – current Nordic view
Jan I Pedersen 1
1 The Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, Oslo, Norway
Correspondence to JI Pedersen, Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, P.O. Box 1046 Blindern, 0316 Oslo, Norway. E-mail:
j.i.pedersen@medisin.uio.no, Phone: +47-22851358, Mobile: +47-97534755.
* One IU (international unit) corresponds to 0.025 µg vitamin D.
KEYWORDS
vitamin D deficiency • vitamin D status • osteomalacia • rickets
ABSTRACT
At the latitude of the Nordic countries, where there is almost no dermal formation of vitamin D during winter, dietary intake is required to avoid deficiency. Dietary intake is of the order of 4–5 µg/day but varies widely. The lowest intake is seen among adolescents. Low levels of serum 25(OH)D have been found in population groups in all Nordic countries. The drop in 25(OH)D during the winter months may be considerable, falling below acceptable levels (50 nmol/L) in one half of the population. To ensure an acceptable vitamin D status is maintained in the population and to diminish the seasonal drop in 25(OH)D, the Nordic Nutrition Recommendations 2004 increased the vitamin D recommendation for the age group 2–60 years by 50% from 5 µg/day to 7.5 µg/day. To attain such an intake at the population level, public health actions, including information dissemination and increased fortification of foods, are necessary.
________________________________________
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1753-4887.2008.00101.x About DOI
INTRODUCTION
For several decades, the Nordic countries have collaborated in setting guidelines for dietary composition and recommended intakes of nutrients. Similarities in dietary habits as well as in the prevalence of diet-related diseases warrant a common focus on the gross composition of the diet as well as its contents of micronutrients. The first official Nordic Nutrition Recommendations (NNR) were issued in 1980 and the fourth edition in 2004.1 NNR have served as a basis for national recommendations and have been important for various issues in the areas of food, nutrition, and health policy, for the formulation of food-based dietary guidelines, and for diet and health-related campaigns.
The working group of the 2004 edition reviewed and evaluated scientific work, national and international recommendations, and expert reports. A Nordic perspective was taken into consideration and changes were introduced only when strong scientific evidence had evolved since the previous edition. One important change in NNR 2004 was that the recommendation for vitamin D, which had been unaltered since 1989, was increased by 50% for children and adults up to age 60 years. Some of the arguments for the present recommendations for vitamin D are outlined below.
Vitamin D3 or cholecalciferol* is a steroid-like molecule that is synthesized from 7-dehydrocholesterol in the skin under the influence of ultraviolet B light (wavelength between 290 nm and 315 nm).2 It may also be derived from the diet. Sun exposure of the skin is more important than diet, and dermal production can cover the requirement for the vitamin completely. A rather modest exposure to sunlight is sufficient to produce a satisfactory amount of vitamin D in the skin.2 Exposure of the face, arms, hands, and legs to sunshine for 6–8 min 2–3 times a week is more than adequate to satisfy the requirement.3 Experience demonstrates, however, that under our living conditions and at the latitude of the Nordic countries vitamin D deficiency may occur if the diet is devoid of the vitamin. Infants may develop rickets and elderly people osteomalacia. For this reason, vitamin D has to be considered a micronutrient.
The liver rapidly takes up vitamin D formed in the skin or absorbed from the gut where it is hydroxylated to 25-hydroxyvitamin D [25(OH)D]. This metabolite is transported in plasma bound to the vitamin D binding protein. The circulating concentration of 25(OH)D is a good marker of vitamin D status. The distribution in the healthy population is generally found to be 25–125 nmol/L.
Vitamin D is also a prohormone because 25(OH)D is further converted to a hormone (1,25-dihydroxyvitamin D) in the kidney. The main functions of this hormone are to stimulate calcium absorption in the gut, mobilize calcium from bone and, to a certain extent, stimulate reabsorption of calcium in the kidney. It is now clear that vitamin D has several other functions related to cellular differentiation and metabolism and which are of importance for several health conditions.4,5
There is a strong seasonal variation in serum 25(OH)D.6 A Danish study illustrates the marked downward shift during the winter months, with levels falling below desirable vitamin D status in one half of the population (Figure 1).7
Figure 1 Distribution of plasma 25(OH)D in Danish men and women during winter (n = 189, upper panel) and summer (n = 203, lower panel) months.
Adapted from Mosekilde (2005)7 with permission.
[Normal View ]
Under Nordic climatic conditions, exposure to sunlight is thus insufficient for enough vitamin D to be formed in the skin and for vitamin D status to be maintained during the winter months. A study from northern Finland in 1980 showed that vitamin D status was satisfactory during the summer months but that a large number of subjects had unsatisfactory vitamin D status during winter.8 On the other hand, more satisfactory serum levels of 25(OH)D and greater seasonal variation was found among adults in a similar study from Tromsö in northern Norway.9 The results of these studies indicate that the light intensity at 70 degrees north is sufficient during summer to elicit vitamin D formation in the skin. One explanation for the difference observed in vitamin D status between the two population groups during the winter months is that, at the time of these studies, the consumption of fish and margarine fortified with vitamin D was much higher in Norway than in Finland. Dietary vitamin D is thus essential to ensure satisfactory vitamin D status at northern latitudes, particularly during the winter months. The question is how much is needed and what intake should be recommended?
RECOMMENDED INTAKE VERSUS REQUIREMENT
Recommended intake of a nutrient is not equivalent to the requirement. The requirement is the lowest amount needed to avoid clinical symptoms or to avoid physiological or biochemical changes that might indicate suboptimal health. Recommended intake includes a safety margin that takes into account individual variability and uncertainties in the data. In NNR 2004 the term "recommended intake" (RI) refers to "the amount of a nutrient that according to present knowledge can meet the known requirement and maintain good nutritional status among practically all healthy individuals".10
Recommended intakes, as expressed in the NNR 2004, are primarily valid for groups of healthy individuals and are to be used as a basis for diet planning. As such, they are essential for the health authorities to make decisions on topics such as food fortification.
PROBLEMS IN SETTING RECOMMENDATIONS
A primary problem in setting recommendations is choosing the criteria to be used as a basis for them. Initially, disease states and clinical symptoms were used. Thus, amounts needed to prevent or cure rickets or osteomalacia were used to arrive at recommendations for vitamin D. A daily dose of 2.5 µg of vitamin D was found sufficient to cure or prevent rickets or osteomalacia.11,12 Adding what was considered a reasonable margin of safety, a daily intake of 10 µg was recommended for infants and 5 µg for the other age groups. The effect of dietary vitamin D on the concentration of 25-hydroxyvitamin D in plasma is now the criterion generally used as a basis for recommendations. But this raises a new question, namely, what functional criteria should be used to set reference values for 25(OH)D?
CRITERIA USED FOR EVALUATING VITAMIN D STATUS
Serum 25(OH)D can be used to grade different levels of vitamin D status based on the following clinical and functional criteria.
• 1)
Clinical symptoms: rickets is seen at levels <12 nmol/L,13 osteomalacia is seen in the range of 12–20 nmol/L,14–16 histological signs of osteomalacia may be seen at levels <30 nmol/L.14,17
• 2)
Effect on serum concentration of 1,25(OH)2D that will increase with serum 25(OH)D up to 40–50 nmol/L.18,19
• 3)
Absorption of radiocalcium attains a level with serum 25(OH)D at 50 nmol/L.18
• 4)
Secretion of parathyroid hormone (PTH) increases at low levels of 25(OH)D and the lowest level associated with normal PTH would ideally be a criterion of choice. PTH, however, also depends on other factors like calcium intake and age; therefore, variable values of 25(OH)D, mostly in the range of 38–80 nmol/L, have been reported to not be associated with hyperparathyroidism.7,20
• 5)
Associations with different health outcomes in epidemiological studies have indicated a favorable range of 75–100 nmol/L. Such "soft" endpoints have not, however, been used in connection with recommendations.
• 6)
Results from randomized control studies would be a useful basis for recommendations. Only one such study relevant for vitamin D has been published showing reduced risk of cancer when serum concentration of 25(OH)D was above 80 nmol/L, corresponding to a daily intake of 20 µg vitamin D.21
REFERENCE VALUES OF 25(OH)D FOR EVALUATION OF VITAMIN D STATUS IN THE POPULATION
The values given below have been used to evaluate vitamin D status in the population in two recent official reports from Denmark7,22 and Norway.23 They are in agreement with those proposed by Lips.20
Serum or plasma 25(OH)D > 50 nmol/L is characterized as acceptable, 25–50 nmol/L as suboptimal or reflective of vitamin D insufficiency, 12.5–25 nmol/L as indicative of vitamin D deficiency, and <12.5 nmol/L as serious vitamin D deficiency.
RECOMMENDED DAILY INTAKE OF VITAMIN D
To ensure an acceptable vitamin D status in the population, the daily vitamin D intake according to age, as recommended by NNR 2004,24 is as follows: 6–23 months, 10 µg/day; 2–9 years, 7.5 µg/day; 10–60 years, 7.5 µg/day; >61 years, 10 µg/day.
Compared to the previous edition of NNR, the recommendation for the age groups 2–60 years has been increased by 50% from 5 µg/day to 7.5 µg/day; this is in order to diminish the seasonal drop in plasma 25(OH)D during the winter months. It has been estimated that 12.5 µg/day might be needed to more completely alleviate the drop during winter.25 At the present time, such a high recommendation would be difficult to satisfy at the population level through dietary or fortification measures. For the elderly population >61 years it is, in principle, possible to plan diets containing 10 µg/day, but in practice, most elderly individuals would have to rely on supplementation. Elderly individuals with little or no sun exposure should receive a supplement of 10 µg/day in addition to their dietary intake. This is based on several studies showing the effect of calcium and vitamin D supplementation on the risk of osteoporotic fractures.26
DIETARY INTAKE OF VITAMIN D
The mean intake of vitamin D in Nordic populations is considerably lower than that recommended in all Nordic countries. In a recent report on vitamin D status in the Norwegian population from the National Nutrition Council, vitamin D intake was estimated from several dietary surveys;23 the results are shown in Tables 1 and 2.
Table 1 Dietary intake of vitamin D (supplements excluded) during the last 25 years in Norway, household surveys.
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Measure 1977–79 1986–88 1996–98 1999–01 2001–3
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µg/day (mean) 4.1 4.0 4.5 4.4 4.3
µg/10 MJ 4.0 3.9 4.9 4.7 4.6
________________________________________
Reproduced from the National Nutrition Council (2006).23
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Table 2 Intake of vitamin D (µg/day) in different age groups according to a Norwegian nationwide survey (mean SD).
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Age group No. of subjects Vitamin D without supplement (µg/d) Vitamin D with supplement (µg/d) Below recommended intake (%)
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12 months, not breast fed 1231 9.4 (6.2)
2 years
Girls 852 2.5 (1.2) 10.0 (7.0)
Boys 868 2.8 (1.5) 10.4 (7.0)
4 år years
Girls 185 2.4 (1.5) 7.1 (5.6) 66
Boys 206 2.7 (2.1) 6.8 (5.3) 64
9 years
Girls 411 2.6 (2.1) 5.0 77
Boys 404 3.1 (3.0) 6.4 69
13 years
Girls 517 2.4 (2.5) 3.9 87
Boys 492 2.8 (3.0) 4.5 85
16–29 years
Women 354 3.4 (2.5) 8.8 (9.0) 55
Men 340 5.5 (4.1) 9.8 (10.0) 54
30–59 years
Women 774 4.2 (2.8) 10.3 (9.1) 48
Men 721 5.9 (4.1) 11.0 (10.9) 51
60–79 years
Women 246 4.0 (2.2) 12.5 (10.8) 47
Men 237 5.8 (3.8) 13.9 (11.0) 48
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Data from the National Nutrition Council (2006).23
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More than half of the individuals in the different age groups had intake levels below the recommended amount. Even if supplements are taken into account, the intake is low in many age groups. Most seriously, the intake is very low during adolescence, the period of life when bone formation and the need for absorbed calcium is highest.
The most important sources of vitamin D in Norway are enriched margarine and fish. A large variation in intake is found when considering both dietary and total intake when supplements are included (Figure 2).
Figure 2 Vitamin D intake, including cod liver oil and supplements, in 2651 Norwegian women and men aged 16–79 years (1997). (Data from 21 persons with intakes >50 µg are not shown.)
Reproduced from the National Nutrition Council (2006).23
[Normal View ]
CONCLUSION
Vitamin D intake is at about the same low level in Norway and the other Nordic countries. It is slightly higher in Iceland due to widespread use of cod liver oil and slightly lower in Denmark because, until recently, food fortification has not been used. In all Nordic countries, steps are now taken to increase vitamin D intake at the population level in order to reach the new increased recommendations. In addition to disseminating information, increased fortification of foods is essential to reach this goal.
Acknowledgment
Declaration of interest. The author has no relevant interests to declare.
REFERENCES
Vitamin D requirement and setting recommendation levels: long-term perspectives
Leif Mosekilde 1
1 The Department of Clinical Endocrinology and Metabolism C, Aarhus University Hospital, DK 8000 Aarhus C, Denmark
Correspondence to L Mosekilde, Medicinsk endokrinologisk afdeling C, Aarhus Sygehus, THG, Tage Hansens Gade 2, DK 8000 Aarhus C, Denmark. E-mail:
leif.mosekilde@as.aaa.dk, Phone: +45-89497677.
KEYWORDS
25-hydroxyvitamin D • recommendations • requirements • vitamin D
ABSTRACT
Target intakes of vitamin D to prevent rickets and osteomalacia are difficult to estimate because of the dual sources of vitamin D with dermal production and absorption from the intestine. However, vitamin D deficiency is associated with other diseases, e.g., myopathy, falls, fractures, autoimmune disorders, cardiovascular diseases, and malignancies, which underlines the necessity of redefining recommendations. A plasma level of 25-hydroxyvitamin D (25OHD) <50 nmol/L increases the risk of secondary hyperparathyroidism, whereas levels between 75 and 100 nmol/L appear optimal for maintaining general health. In adults, a minimum dietary intake of 17.5–25 µg/day is necessary to achieve these levels. Perspectives of future research are outlined here.
________________________________________
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1753-4887.2008.00103.x About DOI
INTRODUCTION
Vitamin D is produced in the skin from 7-dehydrocholecalciferol in adequate quantities if sun exposure [ultraviolet B (UVB)] is sufficient and the skin is exposed.1 The production depends on skin pigmentation, both natural and caused by sunburn, with the latter creating a type of negative feedback loop.2 Vitamin D is also absorbed from the intestine depending on dietary fare, fortification, and supplementation.3 On average, around 80–90% of vitamin D is derived from dermal production, with large variations recorded among different populations. As an example, pigmented immigrants from Palestine, Pakistan, India, and Sri Lanka who live in northern Europe often develop severe vitamin D deficiency with proximal myopathy because of the limited availability of sunshine at the higher latitude and low dietary vitamin D intake.4 African Americans also have a higher risk of vitamin D deficiency than Caucasians, which may make racial considerations necessary when vitamin D requirements are established.5,6 By contrast, moderately pigmented Inuit's have adapted to a life with sparse solar exposure through a diet of fatty fish and blubber with a high content of animal vitamin D. At present, this adaptation is threatened by a dietary shift towards more Westernized fare.7
Obviously, it is difficult to estimate the target intakes of vitamin D because of its double source from both skin and intestine, and since its active metabolite, 1,25(OH)2D, is a hormone that is produced according to bodily needs. The vitamin D target intake is often estimated as the intake, which, in the absence of sunlight, protects from overt vitamin D-related skeletal disease like rickets and osteomalacia. However, vitamin D deficiency is associated with many other diseases and conditions, including the following: secondary hyperparathyroidism,8 myopathy, increased sway, psychomotor function and falls,9–13 bone loss, increased bone turnover and osteoporotic fractures,14–19 infectious diseases,20,21 periodontal disease,22 autoimmune diseases like type I diabetes,19,23 rheumatoid arthritis,24 inflammatory bowel disease,25,26 multiple sclerosis,27,28 hypertension,29–32 ischemic heart disease,33 primary hyperparathyroidism,34 and malignancies.19 This highlights the need to continuously redefine the vitamin D requirements in parallel with increasing knowledge of relations among intake, vitamin D status, and preventive consequences. At present, recommendations have been proposed for optimal plasma 25OHD levels to prevent secondary hyperparathyroidism,8 to improve bone mineral density and lower extremity function, and to prevent fractures, periodontal disease, and colon cancer.35 Obviously, these recommendations may change when other diseases are taken into account.
PLASMA 25OHD LEVELS AS AN INDICATOR OF VITAMIN D SUFFICIENCY
Overall vitamin D status can be easily estimated at a specified time point from measurements of plasma levels of total 25OHD,8,19,35,36 which reflect both the amount of vitamin D produced in the skin and the amount absorbed from the intestine. This metabolite is thought to best reflect vitamin D stores because of its unrestricted hepatic production from circulating vitamin D and its rather long half-life in plasma of around 3 weeks. The recent understanding that 25OHD can be converted locally in most tissues to 1,25(OH)2D according to bodily needs further underlines the importance of circulating 25OHD.37
However, the use of plasma 25OHD as a measure of optimal vitamin D status is not without problems that need further clarification. The first problem is related to the accuracy of the methods used to determine plasma 25OHD.38 The most commonly used methods are based either on radioimmunoassays or HPLC. These methods may return different values and need to be cross-calibrated and standardized.38 Furthermore, the influence of concentrations and phenotypes of vitamin D binding protein (DBP) on plasma 25OHD levels and biological effects needs to be explored.39
A second problem is the predictive value of a point measurement of plasma 25OHD for previous and future vitamin D status at the individual level.40 Research on this topic is lacking, but point estimates of plasma 25OHD most likely reflect recent events such as the season, indoor/outdoor activities, and holidays spent in sunny geographical areas rather than the average vitamin D status of the individual person. However, with increasing age, the relative impact of dermal vitamin D production decreases,41 so plasma 25OHD levels in the elderly may reflect more stable lifestyle factors such as average vitamin D intake and vitamin D supplementation. These considerations could indicate that plasma 25OHD measurements are more suitable for estimating vitamin D status in populations or subsets of populations but are less useful for identifying individuals at risk of vitamin D-related disorders. This problem calls for initiatives to improve the general vitamin D status in target populations and not to focus on individuals.
A third problem is alterations in 25OHD levels not related to dietary vitamin D intakes or sun exposure. Several cross-sectional studies have found that plasma 25OHD is inversely related to either total body fat percent, fat mass, or BMI.42–44 Plasma 1,25(OH)2D also decreases with increasing fat mass.44 Hence, obesity may be associated with a reduced bioavailability of vitamin D and complicating secondary hyperparathyroidism.42,44 Furthermore, obese persons have lower levels of vitamin D in plasma after total body UVB irradiation than non-obese individuals, even though the capacity for dermal production is unchanged.42 These observations could indicate increased deposition of vitamin D in body fat or increased degradation. Finally, it is known that 1,25(OH)2D is able to increase expression of the 24-hydroxylase gene in vitamin D target tissues and thereby enhance the degradation of 25OHD as well as of 1,25(OH)2D.45 This could cause reduced plasma levels of 25OHD in individuals with conditions such as primary hyperparathyroidism.34 The consequences of these variations in 25OHD on skeletal or body health are unknown and need to be explored.
OPTIMAL VITAMIN D LEVELS
The optimal serum levels of 25OHD were initially estimated from cross-sectional studies relating plasma 25OHD to calcium and bone metabolism.8,14,15,46 However, subsequent studies have aimed at defining the optimal levels for various other outcomes including muscle function, risk of falls and fractures, periodontal disease, and cancer.22,35
Based on the development of secondary hyperparathyroidism at low levels of 25OHD, it has been proposed that levels <50 nmol/L be classified as reflecting vitamin D insufficiency, values <25 nmol/L as vitamin D deficiency, and values <12.5 nmol/L as severe vitamin D deficiency.8 Using these threshold levels, it has been demonstrated that large proportions of various populations around the world are vitamin D insufficient.5,8,47,48 However, a large proportion of healthy subjects do not develop secondary hyperparathyroidism at low 25OHD levels. The causes and consequences of this functional hypoparathyroidism need to be explored further.
Subsequent epidemiologic studies have disclosed that lower extremity function (8-foot walking, sit-to-stand time), bone mineral density, fracture risk, periodontal disease, and risk of colon cancer depend on plasma levels of 25OHD either inversely or in a bimodal fashion with a threshold value for optimal plasma levels.35 Based on these outcomes, the optimal plasma concentrations for 25OHD are typically between 75 and 100 nmol/L.35 Some of these effects, notably the effects of vitamin D supplementation on muscle function, falls, and fractures have been confirmed in intervention studies and meta-analyses of randomized controlled studies.13,46,49,50 However, in the remaining cross-sectional studies, it is difficult to infer causality. For instance, low plasma levels of 25OHD may impair lower extremity function, and restricted lower extremity function may cause vitamin D insufficiency by preventing outdoor activities. In order to improve our understanding of the optimal threshold levels for plasma 25OHD as to these outcomes, it is essential to implement more randomized controlled studies on the effects of various doses of vitamin D. Such studies should also include the effects of vitamin D on risk of cancer, diabetes, and autoimmune diseases. Furthermore, cohort studies, case-control studies, and nested case-control studies may improve our understanding of causality and dose-relations between vitamin D status and these outcomes by introducing a time interval between exposure and outcome.
TRANSFORMING THRESHOLD VALUES FOR 25OHD TO TARGET INTAKE RECOMMENDATIONS
Having defined optimal plasma levels of 25OHD for skeletal and non-skeletal health, we need to estimate the amount of oral vitamin D that is necessary to obtain these levels. It has been claimed that doses as high as 100 µg/day (4000 IU) are needed,51–53 although this view has been criticized.54 In a 5-month intervention study, 100 µg/day of vitamin D did not increase plasma 25OHD beyond 125 nmol/L and did not induce hypercalcemia.52 However, there was a higher proportion of hypercalciuria in those receiving 100 µg/day compared with those receiving 25 µg/day. In another study, 67 men were treated for 5 months with 0, 25, 125, and 250 µg/day.53 Plasma 25OHD reached a plateau of 150 nmol/L in those receiving 125 µg/day and more than 200 nmol/L in those receiving 250 µg/day with no concurrent changes in plasma calcium. In a study performed in Finland, elderly women receiving a daily supplementation of 20 µg/day increased their plasma 25OHD levels to about 70 nmol/L when their dietary intake was 8–9 µg/day.55 Based on such dose relations, it has been estimated that a daily intake of 20–25 µg/day will be sufficient to maintain a plasma concentration of around 70–100 nmol/L in adult Caucasians.35 However, further studies are needed in subgroups of individuals including children, pregnant and lactating women, elderly, obese, and various ethnic groups.
RECOMMENDED DIETARY VITAMIN D INTAKES
Several countries, regions, and institutional bodies have published recommendations for the dietary intake of vitamin D (Table 1). Most current recommendations specify different needs for subgroups of normal Caucasian whites, including special age groups (e.g., early childhood and elderly) and pregnant and lactating women, and they often supply some advice for high-risk groups. However, the recommendations differ depending on the source, reflecting variations in the approach to providing general dietary guidelines for populations in which dermal vitamin D synthesis is the main source for most people with adequate sun exposure, whereas smaller vulnerable groups rely mainly on diet for their vitamin D supply.61 The dietary recommendations are typically defined in terms of target intakes that are given different names (Table 1). If these target intakes are applied at an individual level, they are supposed to meet the needs of the majority of healthy individuals, including those with the highest requirements.61
Table 1 Dietary vitamin D recommendations for various countries, regions, and institutions.
________________________________________
Recommendation Year Age group Intake (µg/day)
________________________________________
Nordic Nutrition Recommendations. Recommended Intake (RI)56
2004 2 weeks–2 years 10
2–60 years 7.5
≥61 years 10 (+10)*
FAO/WHO. Recommended Nutrient Intake (INR)60
2001 0–50 years 5
51–65 years 10
>65 years 15
France. Apports Nutrionnels Conseillés (ANC)61
2001 <50 years 5
>50 years 5/10–15†
Germany, Switzerland, Austria Referenzwerte57
2000 0–1 year 10
1–64 years 5
≥65 years 10
UK. Dietary Reference Values (DRV). Recommended Nutrient Intake (RNI)58
1998 0–6 moths 8.5
6 months–3 years 7
4–64 years 0 (+10)‡
>65 years 10
USA and Canada. Dietary Reference Intake (DRI). Adequate Intake (AI)59
1997 0–50 years 5
51–70 years 10
>70 years 15
European Community. Population Reference 1993 <50 years 0–10§
Intake (PRI)61
>50 years 0–10/10§,¶
Australia. Recommended Dietary Intake (RDI)61
1991 <50 years 0 (+10)**
>50 years 0 (+10)**
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* Elderly people with little or no sun exposure should receive a supplement of 10 µg/day.
† Higher range in the elderly.
‡ 10 µg/day to risk groups.
§ Higher end of interval for people with minimal endogenous synthesis.
¶ Highest intake for age >65.
** Higher intake for those who are homebound (i.e., nursing homes).
________________________________________
Most countries have no official specific recommendations for minorities, e.g., immigrants to Europe from Asia and Africa, blacks in various countries including the USA, Mexican Americans, Indians, or Inuits, and other minorities in Canada and northern Europe or aboriginals in Australia and New Zealand. Furthermore, there are no recommendations on the optimal serum levels of 25OHD in these subgroups. It is also largely unknown whether vitamin D insufficiency in these populations leads to the same clinical consequences as in Caucasians.5,6,62 It is essential to define optimal dietary intakes of vitamin D for these minority groups, to evaluate proper threshold values for serum 25OHD, and to develop ways to obtain these goals.
Generally, the recommended vitamin D intakes do not match the optimal 25OHD levels described above. Furthermore, in most countries, population-based dietary vitamin D intakes are far lower than the recommended target levels.3 These findings underline the need to adjust recommendations to meet the estimated needs and to improve vitamin D status in the populations.
POSSIBILITIES FOR PREVENTION
There are several ways to improve vitamin D status among the elderly including fortification of food, annual vitamin D injections, and supplementation with tablets containing vitamin D (and calcium). Vigorous exposure to sunshine is controversial because of the risk of skin cancer, and it is less effective among the elderly and during winter at higher latitudes.2 The increased risk of skin cancer with excessive sun exposure makes it essential to negotiate methods of "safe sun exposure" with dermatologists and oncologists.
Fortification of food with vitamin D
Fortification is used in many developed countries.3,55,63 In particular, margarine, vegetable oil, and milk are fortified in Europe, whereas flour, cornflakes, and juice are enriched in the USA. Fortification of bread, other cereals, and margarine is targeted towards the elderly, whereas fortification of bread and oil is targeted towards dark-skinned immigrants from geographical regions such as the Near East, Pakistan, or India. Fortification of several types of food ensures a more even dispersion in the population, independent of individual eating habits. Inadvertent overfortification has been reported once in the USA. In this case, milk was overfortified by a home-delivery dairy from 1985 to 1991, leading to a suspected outbreak of hypervitaminosis D associated with severe illness and death.64 This episode highlights the need to monitor any fortification process65 and to spread fortification over a variety of food items.
An adequate fortification program should secure a supply of at least 20 µg of vitamin D (800 IU) per day to the elderly. To reach this population group, bread and edible fats (butter, oil, and margarine) would be obvious food items to enrich. Simulation in Denmark using information on dietary food intakes in various Danish populations with an average baseline dietary vitamin D intake of 2.5–3 µg/day shows that enrichment of edible fat by 35 µg vitamin D/100 g or of bread and cereals by 10 µg vitamin D/100 g will ensure that half of the elderly population gets 20 µg/day from diet and fortification combined.63 Fortification with a combination of 12 µg vitamin D/100 g fat and 5 µg/100 g cereals will achieve the same result. This strategy indicates that 10% of the elderly will get 28 µg/day of vitamin D and 5% will get at least 32 µg/day. None of the elderly will get more than 50 µg/day – a level considered safe for this group by the European Commission's Scientific Committee on Food.66 However, for children between 4 and 10 years of age, such fortification will supply 14–18 µg/day of vitamin D, but at the same time, 10% will get an oral vitamin D intake close to or above the 25 µg/day that is considered safe.66 Fortification of bread and cereals by 10 µg/100 g will result in a daily intake above 25 µg/day for 5% of children and a combination of edible fat with 12 µg/100 g and breads and cereals with 5 µg/100 g will result in an intake of more than 22 µg/day in 5%. These simulations indicate that fortification with vitamin D to ensure adequate intake by the elderly will result in dietary intakes among children that authorities consider risky. However, these considerations do not exclude a less ambitious fortification program aiming at achieving at least 10 µg/day among younger adults. It should be emphasized that no controlled intervention studies to date have demonstrated the effect of fortification on falls, low-energy fractures, malignant disorders, infectious and autoimmune disorders, or cardiovascular disorders.
Annual injections with vitamin D
At higher latitudes, annual injections in late autumn could prevent drops in plasma 25OHD during winter. From a practical point of view, these injections could be given together with the yearly influenza vaccination to secure reasonable compliance. A Finnish investigation among the elderly demonstrated that a yearly injection of 3.75 mg (150,000 IE) of vitamin D could prevent 20–30% of peripheral fractures.67 However, a recent study performed in the United Kingdom, which included more than 7000 elderly participants, could not demonstrate any effect on fracture risk of 300,000 IU given once a year.68 A previous study demonstrated greater variability in plasma 25OHD following intramuscular injections compared with oral administration.69 Hence, the negative results of the UK study could be explained by lack of bioavailability. Based on these considerations, the intramuscular route seems, at present, to be less attractive for vitamin D administration.
Supplementation with tablets containing vitamin D and calcium
There is good evidence to support general supplementation with 20–25 µg (800–1000 IU) of vitamin D in combination with 1000–1200 mg of calcium to prevent falls and fractures among weak, elderly individuals in nursing homes or other geriatric institutions.70 This will raise plasma 25OHD, suppress plasma PTH, reduce bone turnover, improve muscle force, decrease sway and tendency to fall, improve bone strength and prevent fractures. In the general population in the United Kingdom, supplementation of around 20 µg/day of vitamin D to people over 65 years of age appears to reduce fracture risk either if given daily46 or if given three times a year in doses of 100,000 IU.71 A daily dose of 10 µg/day appears to be ineffective.47 Vitamin D treatment is safe with a tolerable upper intake of 250 µg/day (10,000 IU).72 The average participation in such programs varies by 50–66% depending on the delivery method used. Since baseline vitamin D status may vary according to latitude, climate conditions, lifestyle, clothing habits, dietary vitamin D content, etc., there is presently no evidence that these results can be extrapolated to other regions of the world.
FURTHER RESEARCH
Several initiatives are required to improve the scientific and practical background for assessing vitamin D requirements and setting recommendation levels. The existing assays for 25OHD should be standardized, and the predictive power of a single measurement for future determinations of individual vitamin D status should be evaluated in various populations. Furthermore, the clinical significance of changes in serum 25OHD not related to dietary intakes or sun exposure (e.g., obesity) should be explored. The impact of vitamin D supplementation or the implementation of fortification strategies on plasma 25OHD in various populations should be appraised, and the optimal 25OHD levels for various skeletal and non-skeletal health outcomes should be established. The causality between vitamin D supplementation and fractures, falls, insulin secretion, malignancy, and overall mortality has been proven. However, further studies are required to establish its role in different malignant diseases (breast cancer, prostate cancer, colon cancer), autoimmune diseases (rheumatoid arthritis, multiple sclerosis, type 1 diabetes), cardiovascular diseases (ischemic heart disease, hypertension), and infectious diseases (respiratory diseases, TB).
It is also important to establish evidence-based recommendations for subgroups (age, gender, ethnic subgroups, pregnancy, and lactation) and to adjust recommendations to present documentation of need in relation to new clinical outcomes. Furthermore, the issue of "safe sun exposure" should be determined in cooperation with dermatologists and oncologists.
With respect to fortification, it is essential to simulate the effect of fortification programs based on population-based dietary databases and to evaluate and appraise short- and long-term effects. With respect to supplementation, it is essential to define target groups, to develop optimal pharmaceutical products, to evaluate delivery schedules (e.g., daily, weekly, monthly, yearly) and means, to assess compliance and persistency, and to record long-term effects.
CONCLUSION
Randomized controlled trials have documented that vitamin D prevents fractures, falls, myopathy, overall cancer risk, and overall mortality. These results should serve as incentives to implement public vitamin D fortification programs. Furthermore, basic research and several epidemiological studies suggest that vitamin D and its metabolites are important for preventing a number of frequent and severe infections, diabetes, and autoimmune and cardiovascular diseases, as well as the prevalence and course of several cancers. Besides being considered in the ongoing discussion on vitamin D fortification and supplementation, these observations provide the theoretical basis for large, population-based, long-term, randomized intervention studies that may change future recommendations. Since such studies are unlikely to be financed through the pharmaceutical industry, substantial public funding will be required to ensure sufficient infrastructure and personnel. Furthermore, government-implemented fortification and supplementation programs should, whenever possible, be followed by scientific evaluation of effects and potential disadvantages. Unfortunately, this has not been put into effect until recently. Finally, basic research programs should aim at providing greater understanding of the biological effects of vitamin D and its natural or artificial metabolites on the immune system and cancer biology.
Acknowledgment
Declaration of interest. The author has no relevant interests to declare.
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