Populations at risk for vitamin D deficiency

Infants constitute a population at risk for vitamin D deficiency because of relatively large vitamin D needs brought about by their high rate of skeletal growth. At birth, infants have acquired in utero the vitamin D stores that must carry them through the first months of life. A recent survey of French neonates revealed that 64% had 25-OH-D values below 30nmol/l, the lower limit of the normal range (15). Breast-fed infants are particularly at risk because of the low concentrations of vitamin D in human milk (16). This problem is further compounded in some infants fed human milk by a restriction in exposure to ultraviolet (UV) light for seasonal, latitudinal, cultural, or social reasons. Infants born in the autumn months at extreme latitudes are particularly at risk because they spend the first 6 months of their life indoors and therefore have little opportunity to synthesize vitamin D in their skin during this period. Consequently, although vitamin D deficiency is rare in developed countries, sporadic cases of rickets are still being reported in many northern cities but almost always in infants fed human milk (17–20). Infant formulas are supplemented with vitamin D at levels ranging from 40 international units (IU) or 1mg/418.4kJ to 100IU or 2.5mg/418.4kJ, that provide approximately between 6mg and 15mg of vitamin D, respectively. These amounts of dietary vitamin D are sufficient to prevent rickets. 3.2.2 Adolescents Another period of rapid growth of the skeleton occurs at puberty and increases the need not for the vitamin D itself, but for the active form 1,25- (OH)2D. This need results from the increased conversion of 25-OH-D to 1,25-(OH)2D in adolescents (21). Unlike infants, however, adolescents usually spend more time outdoors and therefore usually are exposed to levels of UV light sufficient for synthesizing vitamin D for their needs. Excess production of vitamin D in the summer and early autumn months is stored mainly in the adipose tissue (22) and is available to sustain high growth rates in the winter months that follow. Insufficient vitamin D stores during this period of increased growth can lead to vitamin D insufficiency (23). 3.2.3 Elderly Over the past 20 years, clinical research studies of the basic biochemical machinery for handling vitamin D have suggested an age-related decline in many key steps of vitamin D action (24), including the rate of skin synthesis, the rate of hydroxylation (leading to the activation to the hormonal form), P045-058 3/12/05 16:57 Page 48 and the response of target tissues (e.g. bone) (25). Not surprisingly, a number of independent studies from around the world have shown that there appears to be vitamin D deficiency in a subset of the elderly population, characterized by low blood levels of 25-OH-D coupled with elevations in plasma PTH and alkaline phosphatase (26). There is evidence that this vitamin D deficiency contributes to declining bone mass and increases the incidence of hip fractures (27). Although some of these studies may exaggerate the extent of the problem by focusing on institutionalized individuals or inpatients with decreased sun exposures, in general they have forced health professionals to re-address the vitamin D intake of this segment of society and look at potential solutions to correct the problem. Table 3.1 presents the findings of several studies that found that modest increases in vitamin D intakes (between 10 and 20mg/day) reduce the rate of bone loss and the incidence of hip fractures. These findings have led several agencies and researchers to suggest an increase in recommended vitamin D intakes for the elderly from 2.5– 5mg/day to a value that is able to maintain normal 25-OH-D levels in the elderly, such as 10–15mg/day. This vitamin D intake results in lower rates of bone loss and is proposed for the middle-aged (50–70 years) and old-aged (>70 years) populations (33). The increased requirements are justified mainly on the grounds of the reduction in skin synthesis of vitamin D, a linear reduction occurring in both men and women that begins with the thinning of the skin at age 20 years (24). 3.2.4 Pregnant and lactating women Elucidation of the changes in calciotropic hormones occurring during pregnancy and lactation has revealed a role for vitamin D in the former but not definitively in the latter. Even in pregnancy, the changes in vitamin D metabolism which occur, namely an increase in the maternal plasma levels of 1,25- (OH)2D (34) due to a putative placental synthesis of the hormone (35), do not seem to impinge greatly on the maternal vitamin D requirements. The concern that modest vitamin D supplementation might be deleterious to the fetus is not justified. Furthermore, because transfer of vitamin D from mother to fetus is important for establishing the neonate’s growth rate, the goal of ensuring adequate vitamin D status with conventional prenatal vitamin D supplements probably should not be discouraged. In lactating women there appears to be no direct role for vitamin D because increased calcium needs are regulated by the PTH-related peptide (36, 37), and recent studies have failed to show any change in vitamin D metabolites during lactation (38, 39). As stated above, the vitamin D content of human 3. VITAMIN D 49 P045-058 3/12/05 16:57 Page 49 VITAMIN AND MINERAL REQUIREMENTS IN HUMAN NUTRITION 50 TABLE 3.1 Randomized, controlled trials with dietary vitamin D supplements Age (years) Duration Reference Study group na Mean SD Regimen (years) Results Dawson-Hughes et al., Healthy, postmenopausal 249 62 0.5 10mg vitamin D 1.0 Reduced late wintertime bone 1991 (28) women living independently + loss from vertebrae 400mg calcium Net spine BMD≠ No change in whole-body BMD Chapuy et al., Healthy, elderly women living 3270 84 6 20mg vitamin D 1.5 Hip fractures 43% Ø 1992 (29) in nursing homes or in + Non-vertebral fractures 32% Ø apartments for the elderly 1200mg calcium In subset (n = 56), BMD of proximal femur 2.7% ≠ in vitamin D group and 4.6% Ø in placebo group Chapuy et al., 3.0 Hip fractures 29% Ø 1994 (30) b Non-vertebral fractures 24% Ø Dawson-Hughes et al., Healthy postmenopausal 261 64 5 2.5mg or 17.5mg 2.0 Loss of BMD from femoral neck 1995 (31) women living independently vitamin D lower in 17.5mg group (-1.06%) + than in 2.5mg group (-2.54%) 500mg calcium No difference in BMD at spine Lips et al., 1996 (32) Healthy, elderly individuals living 2578 80 6 10mg vitamin D No difference in fracture independently, in nursing homes, (1916 women, incidence or in apartments for the elderly 662 men) In subset (n = 248) of women from nursing homes, BMD 2.3% ≠ after 2 years SD, standard deviation; BMD, bone mineral density; ≠, increase; Ø, decrease. a Number of subjects enrolled in the study. b Same study as Chapuy et al. (29) after a further 1.5 years of treatment. Source: adapted, with permission, from reference (25). P045-058 3/12/05 16:57 Page 50 milk is low (16). Consequently, there is no great drain on maternal vitamin D reserves either to regulate calcium homeostasis or to supply the need of human milk. Because human milk is a poor source of vitamin D, rare cases of nutritional rickets are still found, but these are almost always in breast-fed infants deprived of sunlight exposure (17–20). Furthermore, there is little evidence that increasing calcium or vitamin D supplementation to lactating mothers results in an increased transfer of calcium or vitamin D in milk (38). Thus, the current thinking, based on a clearer understanding of the role of vitamin D in lactation, is that there is little purpose in recommending additional vitamin D for lactating women. The goal for mothers who breastfeed their infants seems to be merely to ensure good nutrition and sunshine exposure in order to ensure normal vitamin D status during the perinatal period. 3.3 Evidence used for estimating recommended intakes 3.3.1 Lack of accuracy in estimating dietary intake and skin synthesis The unique problem of estimating total intake of a substance that can be provided in the diet or made in the skin by exposure to sunlight makes it diffi- cult to derive adequate total intakes of vitamin D for the general population. Moreover, accurate food composition data are not available for vitamin D, accentuating the difficulty in estimating dietary intakes. Whereas two recent United States national surveys have avoided even attempting this task, the second National Health and Nutrition Examination Survey (NHANES II) estimated vitamin D intakes to be 2.9mg/day and 2.3mg/day for younger and older women, respectively. A recent study of elderly women by Kinyamu et al. (40) concurred with this assessment, finding an intake of 3.53mg/day. Skin synthesis is equally difficult to estimate, being affected by such imponderables as age, season, latitude, time of day, skin exposure, and sunscreen use. In vitamin D-replete individuals, estimates of skin synthesis are put at around 10mg/day (24, 41), with total intakes estimated at 15mg/day (24). 3.3.2 Use of plasma 25-OH-D as a measure of vitamin D status Numerous recent studies have used plasma 25-OH-D as a measure of vitamin D status, and there is a strong presumptive relationship of this variable with bone status. Thus, it is not surprising that several nutritional committees (e.g. the Food and Nutrition Board of the United States National Academy of Sciences’ Institute of Medicine in conjunction with Health Canada) have chosen to use a biochemical basis for estimating required intakes and have used these estimates to derive recommended intakes (33). The method used involves the 3. VITAMIN D 51 P045-058 3/12/05 16:57 Page 51 VITAMIN AND MINERAL REQUIREMENTS IN HUMAN NUTRITION 52 estimation of the mean group dietary intake of vitamin D required to maintain the plasma 25-OH-D levels above 27nmol/l, which is the level necessary to ensure normal bone health. Previously, many studies had established 27nmol/l as the lower limit of the normal range (e.g. NHANES III [42]). This dietary intake of vitamin D for each population group was rounded to the nearest 50IU (1.25mg) and then doubled to cover the needs of all individuals within that group irrespective of sunlight exposure. This amount was termed adequate intake (AI) and was used in place of the recommended dietary allowance (RDA), which had been used by United States agencies since 1941. The present Expert Consultation decided to use these figures as recommended nutrient intakes (RNIs) because it considered this to be an entirely logical approach to estimating the vitamin D needs for the global population. Because many studies had recommended increases in vitamin D intakes for the elderly, it might have been expected that the proposed increases in suggested intakes from 5mg/day (the RDA in the United States [43] and the RNI in Canada [44]) to between 10 and 15mg/day (AI) would be welcomed. However, a recent editorial in a prominent medical journal attacked the recommendations as being too conservative (45). Furthermore, an article in the same journal (46) reported the level of hypovitaminosis D to be as high as 57% in a population of ageing (mean age, 62 years) medical inpatients in the Boston area. Of course, such inpatients are by definition sick and should not be used to calculate intakes of healthy individuals. Indeed, the new NHANES III study (42) of 18323 healthy individuals from all regions of the United States suggests that approximately 5% had values of 25-OH-D below 27nmol/l (see Table 3.2). Although the data are skewed by sampling biases that favour sample collection in the southern states in winter months and northern states in the summer months, even subsets of data collected in northern states in September give the incidence of low 25-OH-D in the elderly in the 6–18% range (47), compared with 57% in the institutionalized inpatient population (46) mentioned above. Ideally, such measurements in a healthy population should be made at the end of the winter months before UV irradiation has reached a strength sufficient to allow skin synthesis of vitamin D. Thus, the NHANES III study may still underestimate the incidence of hypovitaminosis D in a northern elderly population in winter. Nevertheless, in lieu of additional studies of selected human populations, it would seem that the recommendations of the Food and Nutrition Board are reasonable guidelines for vitamin D intakes, at least for the near future. This considered approach allows for a period of time to monitor the potential shortfalls of P045-058 3/12/05 16:57 Page 52 the new recommendations as well as to assess whether the suggested guidelines can be achieved, a point that was repeatedly raised about the vitamin D RDA. 3.4 Recommended intakes for vitamin D In recommending intakes for vitamin D, it must be recognized that in most locations in the world in a broad band around the equator (between latitudes 42°N and 42°S), the most physiologically relevant and efficient way of acquiring vitamin D is to synthesize it endogenously in the skin from 7-dehydrocholesterol by sun (UV) light exposure. In most situations, approximately 30 minutes of skin exposure (without sunscreen) of the arms and face to sunlight can provide all the daily vitamin D needs of the body (24). However, skin synthesis of vitamin D is negatively influenced by factors which may reduce the ability of the skin to provide the total needs of the individual (24): • latitude and season—both influence the amount of UV light reaching the skin; • the ageing process—thinning of the skin reduces the efficiency of this synthetic process; 3. VITAMIN D 53 TABLE 3.2 Frequency distribution of serum or plasma 25-OH-D: preliminary unweighted results from the third National Health and Nutrition Examination Survey, 1988–1994a 25-OH-Db Percentile (ng/ml)c 1st 7.6 5th 10.9 10th 13.2 50th 24.4 90th 40.1 95th 45.9 99th 59.0 a Total number of samples used in data analysis: 18323; mean: 25.89ng/ml (±11.08). Values are for all ages, ethnicity groups, and both sexes. b High values: four values between 90–98ng/ml, one value of 160.3ng/ml. Values