Vitamin D and Health

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6. Vitamin D and health outcomes 6.1 The purpose of reviewing the evidence for a relationship between vitamin D and various health outcomes was to assess whether they might inform the setting of DRVs for vitamin D. The health outcomes examined were those considered to be of public health concern. 6.2 Serum 25(OH)D concentration represents exposure to vitamin D from UVB containing sunlight and from the diet. Skin synthesis, rather than diet, is the main source of vitamin D for most people. Consideration of the observational evidence was largely confined to studies that compared health outcomes against serum 25(OH)D concentration since this reflects total exposure to vitamin D from both sunlight and diet (from natural sources, fortified foods and supplements). Observational studies which only examined the relationship between vitamin D intake and health outcomes were not considered. 6.3 Studies considered were those that examined whether vitamin D reduced the risk or incidence of specific health outcomes in the general healthy population rather than its effect as a therapeutic agent in pre-existing disease; i.e., disease prevention rather than cure. 6.4 The IOM report on Dietary Reference Intakes for Calcium and Vitamin D (2011) provided a comprehensive reference resource for consideration of the evidence. The IOM report was informed by two systematic reviews of the evidence (Cranney et al., 2007; Chung et al., 2009) which were conducted by the Agency for Healthcare Research and Quality (AHRQ). Prior to its considerations, the SACN vitamin D working group (WG) updated the evidence base to include studies published since the IOM report. It subsequently considered findings from studies identified in an AHRQ update of the evidence (Newberry et al., 2014). The process for reviewing the evidence is described in more detail in chapter 1 (see paragraphs 1.14-1.21). 6.5 For each of the potential health outcomes considered, the first step was to make a judgement on whether the evidence suggested a relationship with vitamin D supplementation or serum 25(OH)D concentration. If data were lacking or inconsistent for a specific health outcome, then it was not considered any further. If the evidence was suggestive of a relationship between a specific health outcome and vitamin D supplementation/serum 25(OH)D concentration then the data were examined further to assess whether a range of serum 25(OH)D concentrations or threshold serum 25(OH)D concentration associated with beneficial effects could be identified. An important limitation to this task was that there is no clear consensus on the threshold serum 25(OH)D concentration used to define vitamin D deficiency or low status and cut-offs varied across studies and were predefined according to different criteria for deficiency. As a consequence, the selected cut-offs were very insecure and made it difficult to assess if there was a dose response relationship. Potential sources of bias and confounding in studies of vitamin D and health outcomes 6.6 A number of factors need to be considered in assessing the evidence on vitamin D and health outcomes. As well as the general confounders in studies of diet and disease (such as smoking, alcohol, physical activity, medical treatment and social class), factors that affect cutaneous synthesis of vitamin D need to be taken into consideration. These include season of year, latitude, skin pigmentation, clothing, time of exposure, sun screen use, urban environment (can reduce/block sunlight), air pollution and cloud cover. 41
6.7 Although serum 25(OH)D concentration is a marker of exposure to vitamin D (from sunlight and the diet), various factors complicate its use in studies of the relationship between vitamin D and health outcomes. Since serum 25(OH)D concentration reflects exposure to vitamin D, its concentration will be affected by factors that influence skin synthesis of vitamin D (see previous paragraph). Another important consideration in observational studies is that people with a higher serum 25(OH)D concentration tend to be healthier than those with lower concentrations. This could be due to greater exposure to sunlight as a result of more outdoor physical activity and/or a healthier diet and/or prophylactic use of supplements. 6.8 In addition to the variability which affects serum 25(OH)D concentration (e.g., time of day/time of year blood sample taken), it can vary considerably (15-20%) depending on the type of assay used. There is also a lack of agreement between different laboratories using the same methods (de la Hunty et al., 2010). Serum 25(OH)D concentration may also decrease in response to acute inflammation which raises further concerns about its reliability as a marker of exposure since a low serum 25(OH)D concentration may simply reflect an underlying inflammatory state. A more detailed consideration of problems relating to measurement of serum 25(OH)D concentration is provided in chapter 4. 6.9 Serum 25(OH)D concentration is also influenced by genetic variation and by physiological state; for example, concentrations are lower during periods of rapid bone growth. It is unclear whether this is because of physiological changes or because vitamin D supply is inadequate to meet requirements. Serum 25(OH)D concentration is also inversely related to BMI. A lower concentration is more prevalent in overweight and obese individuals compared with normal weight individuals (Wortsman, 2000). A further important limitation in many studies assessing the relationship between serum 25(OH)D concentration and health outcomes is the use of only one blood sample, because of individual variability of serum 25(OH)D concentration. A single measurement at baseline also does not allow evaluation of any impact of changes over time. There is also no standardised season for collecting blood samples. 6.10 All these issues have implications for the interpretation of studies, particularly observational studies, that have examined the relationship between serum 25(OH)D concentration and health outcomes. Review of the evidence 6.11 Assessment of the evidence is divided into musculoskeletal (rickets, osteomalacia, bone health indices, fracture prevention, risk of falls and muscle health) and non-musculoskeletal (pregnancy and lactation, cancers, CVD & hypertension, all-cause mortality, immune modulation, infectious diseases, neuropsychological functioning, oral health and age-related macular degeneration) health outcomes. Consideration of each health outcome includes a short summary of the IOM findings for that outcome. Musculoskeletal health outcomes (Tables 1-30, Annex 2) Bone structure and metabolism 6.12 Bone is a composite material with an inorganic mineral component (69%) of calcium phosphate in the form of hydroxyapatite (99%), which provides it with hardness and rigidity, deposited around an organic matrix consisting of collagen (90%) and non-collagen structural proteins. It is a highly specialised, metabolically active tissue which provides both a structural function and a mineral reservoir for calcium and phosphorus. It is composed of an outer layer of dense and solid cortical (compact) bone which surrounds the marrow space and a lighter inner layer of trabecular (cancellous) 42
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Vitamin D and Health i 2016
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Contents Preface ..................
Page 5 and 6: Preface The Scientific Advisory Com
Page 7 and 8: Adviser (Ultraviolet radiation expo
Page 9 and 10: Ms Gemma Paramor Lay representative
Page 11 and 12: Metabolism S.5 Vitamin D is convert
Page 13 and 14: Two studies reported an increase in
Page 15 and 16: Recommendations S.35 Serum 25(OH)D
Page 17 and 18: 1.8 The terms of reference were: to
Page 19 and 20: 1.18 In assessing the evidence on v
Page 21 and 22: there is not absolute correspondenc
Page 23 and 24: Metabolism Absorption of dietary vi
Page 25 and 26: UVB ▼ SKIN: ▼ Previtamin D 3
Page 27 and 28: 2.49 A number of studies have repor
Page 29 and 30: using a bolus dose (I 2 =77%) compa
Page 31 and 32: 2.75 Another RCT 21 (Cashman et al.
Page 33 and 34: 3. Photobiology of vitamin D Ultrav
Page 35 and 36: Erythema and skin cancer 3.10 Two m
Page 37 and 38: CIE spectrum for photoconversion of
Page 39 and 40: Effect of skin pigmentation on skin
Page 41 and 42: increase in mean serum 25(OH)D conc
Page 43 and 44: 4. Measuring vitamin D exposure (fr
Page 45 and 46: the authors cautioned care in the i
Page 47 and 48: 24,25(OH) 2 D 3 which can contribut
Page 49 and 50: 5. Relationship between vitamin D e
Page 51 and 52: latitudes > 49.5 o N or S (which we
Page 53 and 54: increase 25(OH)D concentrations > 5
Page 55: 22.5 nmol/L (IQR, 16.8-34.3) in sum
Page 59 and 60: calcium intake, although this is mo
Page 61 and 62: Evidence considered (Tables 1-5, An
Page 63 and 64: 6.43 Preece et al. (1975) measured
Page 65 and 66: irths (December-February) in the vi
Page 67 and 68: large loss to follow-up 45 and, sin
Page 69 and 70: 6.81 A pilot RCT in India (Khadilka
Page 71 and 72: Evidence considered (Tables 16-18,
Page 73 and 74: Intervention studies 6.107 A 3-year
Page 75 and 76: Compared with men in the top quarti
Page 77 and 78: chair-rising test. Mean baseline se
Page 79 and 80: heterogeneity among trials for dose
Page 81 and 82: the 600 µg (24,000 IU) vitamin D 3
Page 83 and 84: Bone health indices beyond rickets
Page 85 and 86: Intervention studies 6.177 An RCT i
Page 87 and 88: maternal serum 25(OH)D concentratio
Page 89 and 90: Cancers 6.201 Ecological studies ha
Page 91 and 92: (Gallicchio et al., 2010; Mondul et
Page 93 and 94: 6.226 A systematic review and meta-
Page 95 and 96: Summary - CVD and hypertension 6.23
Page 97 and 98: 6.251 VDRs are expressed in cells o
Page 99 and 100: 10 nmol/L increase in cord blood 25
Page 101 and 102: Evidence considered since IOM repor
Page 103 and 104: difference was not significant (RR=
Page 105 and 106: 6.304 Out of 7 RCTs published subse
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(300 µg/12,000 IU per capsule) for
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serum 25(OH)D concentration in neon
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linked specific VDR gene polymorphi
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factors that affect cancer risk. Ob
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As a result, cut-offs for deficienc
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7.8 The IOM noted the paucity of lo
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years) compared to the placebo grou
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children (n=179) received weekly do
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8. Dietary vitamin D intakes and se
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Food FISH TABLE 1- Vitamin D conten
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Serum/plasma 25(OH)D concentrations
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Serum/plasma 25(OH)D concentration
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9. Review of DRVs for vitamin D Bri
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musculoskeletal health at serum 25(
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Modelling the summer sunshine expos
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9.30 Two possible approaches were c
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FIGURE 8: Relation between serum 25
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UK general population aged under 11
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Summary & conclusions 9.59 The RNI
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10. Overall summary and conclusions
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tight homeostatic control. As a mar
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10.30 Evidence from RCTs suggest th
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Serum/plasma 25(OH)D concentration
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10.53 An RNI of 10 µg/d (400 IU/d)
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11. Recommendations 11.1 Serum 25(O
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References Abnet CC, Chen Y, Chow W
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Beadle PC, Burton JL & Leach JF (19
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Brooke OG, Brown IR, Bone CD, Carte
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Clarke B (2008) Normal bone anatomy
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Diffey BL (2010) Modelling the seas
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Ganji V, Milone C, Cody MM, McCarty
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Heaney RP, Armas LA, Shary JR, Bell
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Javaid MK, Crozier SR, Harvey NC, G
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Lappe J, Cullen D, Haynatzki G, Rec
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Mantell DJ, Owens PE, Bundred NJ, M
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Murad MH, Elamin KB, Abu Elnour NO,
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Pirotta S, Kidgell DJ & Daly RM (20
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one mass, and renal function in the
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Sperati F, Vici P, Maugeri-Sacca M,
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Vervel C, Zeghoud F, Boutignon H, T
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Weisse K, Winkler S, Hirche F, Herb
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Annexes ANNEX (1) SACN working proc
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ANNEX (2) Studies considered in rel
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Cardiovascular disease Table 40 Tab
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Study/year/country Population Ricke
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Table 2: Observational studies on r
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Table 3: Before and after studies o
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Table 4: Case control studies on ri
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Table 5: Intervention studies on ri
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Table 7: Case reports of osteomalac
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Table 9: Cohort studies on associat
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Children and adolescents Table 11:
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Table 13: Intervention studies on e
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Table 16: RCTs on effects of vitami
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Table 22: Meta-analyses of trials o
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Table 24: Prospective studies on as
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Table 25: Meta-analyses of RCTs on
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Table 27: Prospective studies on as
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Table 28: Meta-analyses of RCTs on
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Study Methods Results Author conclu
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NON-MUSCULOSKELETAL HEALTH OUTCOMES
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Table 32: Intervention studies on e
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Table 36: Observational studies on
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Table 38: Meta analyses of RCTs and
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Table 39: Prospective studies on 25
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Study/Country Population Mean follo
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Cardiovascular disease Table 40: Me
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Hypertension Table 42: Meta-analyse
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All-cause mortality Table 44: Syste
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Immune modulation Table 46: Systema
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Table 48: Intervention studies on v
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Reference/Country Population Follow
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Infectious disease Table 50: Meta-a
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Table 51: RCTs on vitamin D supplem
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Table 52: Observational studies on
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Neuropsychological functioning Tabl
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Abbreviations used in studies 25(OH
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Table 1: Percentage contribution of
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Table 2 (continued) Food group a Me
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Table 3 (continued) Food group Age
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Table 4 (continued) Food group a Ag
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Table 5 (continued) Food group a Na
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Table 6: Percentage contribution of
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Table 7: Average daily intake of vi
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Table 9: Average daily intake of Vi
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Table 11: Average daily intake of v
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Table 15: Average daily intake of V
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Serum/plasma 25(OH)D concentrations
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Table 20: UK - Adults and children
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Table 22: Northern Ireland - adults
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Table 24: England - adults 65 years
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Table 26: UK - by month blood sampl
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Table 29: English regions by season
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Table 33: England - by ethnicity, a
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Table 36: Scotland - by Body Mass I
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Calcitonin A peptide hormone, produ
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Osteoclast Osteocyte Osteoid Osteom
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