Worldwide Vitamin D Status

C H A P T E R

59 Worldwide Vitamin D Status Natasja van Schoor, Paul Lips VU University Medical Center, Amsterdam, The Netherlands

O U T L I N E Introduction15

Multicenter and Global Studies Using a Central Laboratory Facility

26

Vitamin D Status in North America (Including Canada and Mexico)

16

Ethnicity/Migration34

Vitamin D Status in South America

21

Nutrition34

Vitamin D Status in Europe

21

Risk Groups

Vitamin D Status in Middle East

21

Implications34

Vitamin D Status in Asia

21

Conclusions35

Vitamin D Status in Africa

21

References35

Vitamin D Status in Oceania

26

INTRODUCTION

result in bias of 25% between 25(OH)D measurements resulting in large differences in the segment of the population that should be treated for inadequate vitamin D status [7]. Last decade, efforts have been made to standardize assays. Liquid chromatography followed by tandem mass spectrometry has become the method of choice due to its better precision compared with immune-based methods. The Vitamin D External Quality Assessment Scheme (DEQAS) distributes sera to more than 1000 laboratories and provides the results as the difference from the overall mean value [8]. The Vitamin D Standardization Program uses standards provided by the National Institute of Standardization Technology to improve the accuracy of the assays [9,10]. This facilitates comparison between current surveys (Fig. 59.1). However, epidemiological studies done in the past can also be standardized when frozen samples are available. This enables unbiased comparison between different countries and different studies as has been done in the ODIN study [11]. The vitamin D status depends on the available amount of ultraviolet light in the sunlight which varies with latitude

The vitamin D status has been determined in numerous studies covering all continents and many countries. The measurement of 25-hydroxyvitamin D (25(OH)D) is used to assess vitamin D status, to diagnose vitamin D deficiency, and to determine the effect of vitamin D supplementation. There is not a complete agreement on the required serum 25(OH)D concentration for optimal health. However, most clinicians agree that clinical vitamin D deficiency only occurs when serum 25(OH)D is lower than 25 nmol/L (10 ng/mL) [1,2]. According to the Institute of Medicine, vitamin D deficiency occurs when the serum 25(OH)D concentration is below 30 nmol/L [3]. Opinions differ on whether the optimal serum 25(OH)D for optimal bone mineral density, bone turnover, muscle strength, and nonclassical effects should be 50 nmol/L, 75 nmol/L, or higher [4,5] (differing opinions are discussed in Chapters 60 and 61). Another related problem, when comparing vitamin D status between countries, results from assay differences among various studies [6]. These differences may

Vitamin D, Volume 2: Health, Disease and Therapeutics, Fourth Edition http://dx.doi.org/10.1016/B978-0-12-809963-6.00059-6

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© 2018 Elsevier Inc. All rights reserved.

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59.  WORLDWIDE VITAMIN D STATUS

FIGURE 59.1  Standardization according to Vitamin D Standardization Program protocol. The relationship between serum 25(OH)D in a subsample of the Health 2011 (A), Oslo Health (B), Health 2006 (C), and Vitamin D (D) samples measured by original 25(OH)D assay and standardized LC-MS/MS. 25(OH)D, 25-hydroxyvitamin D; LC-MS/MS, liquid chromatography followed by tandem mass spectrometry. (D) At University College Cork, Cashman KD, Dowling KG, Skrabakova Z, Kiely M, Lamberg-Allardt C, Durazo-Arvizu RA, Sempos CT, Koskinen S, Lundqvist A, Sundvall J, Linneberg A, Thuesen B, Husemoen LL, Meyer HE, Holvik K, Grønborg IM, Tetens I, Andersen R. Standardizing serum 25-hydroxyvitamin D data from four Nordic population samples using the vitamin D standardization program protocols: shedding new light on vitamin D status in Nordic individuals. Scand J Clin Lab Invest November 2015;75(7):549–61.

and season, on actual sunlight exposure and on skin pigmentation, and the use of sunscreen and clothing. The latter also varies depending on cultural and religious background. The lower the actual sun exposure, the more nutrition becomes important, especially the consumption of fatty fish, vitamin D-fortified foods, and vitamin D supplements. In the following paragraphs, vitamin D status and the occurrence of vitamin D deficiency will be discussed in different continents, North America, South America, Europe, Middle East, Asia, Africa, and Oceania. The number of surveys on vitamin D status is ever growing, and excellent reviews have been published last years (e.g., Refs. [12,13]). In the current review, we have only included a selection of recent studies published in the last decade, that is, from 2006 onward. Subsequently, studies on vitamin D status in one or more continents performed in a central laboratory will be presented. In these studies, interlaboratory variation in serum 25(OH)D assays does not play a role. In the next sections, ethnic issues and nutrition will be discussed as far as these have consequences for vitamin D status

in different countries and continents. In addition, risk groups will be discussed. In the final section, the consequences, that is, the part of the population being vitamin D deficient or vitamin D insufficient will be discussed and finally conclusions will be drawn.

VITAMIN D STATUS IN NORTH AMERICA (INCLUDING CANADA AND MEXICO) Several large studies examined the vitamin D status in North America. Data of a selection of studies are shown in Table 59.1. The table includes data on country, latitude, study population, age, mean levels of serum 25(OH)D in nmol/L, and percentage of the population with serum 25(OH)D below 25 nmol/L and below 50 nmol/L if available. In North America (including Canada and Mexico), the latitudes ranged from N 70° to N 19°. The largest study is the National Health and Nutrition Examination Survey. This US

VII.  POPULATION STUDIES: VITAMIN D DEFICIENCY, NUTRITION, SUNLIGHT, GENES & TRIALS

TABLE 59.1  Vitamin D Status and Prevalence of Vitamin D Deficiency in North America (Including Canada and Mexico)

References

Country Latitude °N/S

25(OH)D Study Population

N

Age (Years)

Men and women

5306

6–79

Greene-Finestone Population-based sample 2011 [57] from seven cities (CaMos), Canada

Men and women

1912

35 to 70+

Langlois [58]

Representative sample of Canada (Atlantic provinces, Quebec, Ontario, the Prairies, British Columbia)

Community-dwelling

5306

El Hayek [19]

Inuit preschoolers living in 16 Arctic communities 51–70 N

Inuit preschoolers: Selected in summer Reassessed in winter

282 52

Sloka [18]

Newfoundland & Labrador, Canada 47–58°N

Pregnant women: End of winter End of summer

304 289

Genuis [59]

Edmonton, Alberta, Canada 53°N

Clinical practices

1433

Chao [60]

Majority from Northern Alberta, Canada 53 ± 3°N

Workers

Aucoin [20]

Calgary, Canada 51°N

Baraké 2010 [61]

Québec, Canada 45–48°N

Mean ± SD, nmol/L

<25 nmol/L %

<50 nmol/L %

5.4 (<30)

25.7

70.4 (SE: 0.55)

2.3 (<27.5)

20.4

6–79 6–11 12–19 20–39 40–59 60–79

67.7 (65.3–70.1)a 75.0 (70.3–79.7)a 68.1 (63.8–72.4)a 65.0 (61.0–69.0)a 66.5 (63.8–69.2)a 72.0 (69.4–74.5)a

4.1 (<27.5) 10.6 (<37.5)

4.4 ± 0.9

48.3 (32.7–71.4)a 37.8 (21.5–52.9)a

13.9 34.1

52.1 72.7

52.1 68.6

6.6 (deficient) 1.7 (deficient)

89 (insuff) 64 (insuff)

<19 to >60

68.3 ± 29.0

3.4

16.8 (<40)

6101

42 ± 14

84 ± 42

3 (<27.5) 8 (<37.5)

40 (37.5–75)

Refugee: Women Children

461 756

20–45 years 0–19 years

46.2 (44.1–48.3) a 55.5 (53.8–57.2)

21 10

61 42

Healthy, independently living elderly: men, women

405

68–82

Comments

CANADA Whiting [56]

Representative sample (CHMS), Canada

<37.5 Winter: 12.6 Summer: 5.7 Winter: 8.7, summer: 1.9 Continued

     

      TABLE 59.1  Vitamin D Status and Prevalence of Vitamin D Deficiency in North America (Including Canada and Mexico)—cont’d

References

Country Latitude °N/S

25(OH)D Study Population

N

Age (Years)

Mean ± SD, nmol/L

<25 nmol/L %

<50 nmol/L %

Comments

1.5–12.6 (≤27.5) 1.5–10.1 (≤27.5)

7.8–37.8 (≤37.5) 13.0–34.5 (≤37.5)

January–May

Mark [62]

Québec, Canada 45–48°N

French Canadian Youth

1753

9, 13, 16

Boys: 42.7–51.5 Girls: 41.3–48.6

Lacroix [63]

Sherbrooke, Canada 45°N

Pregnant women (6–13 weeks)

655

28.4 ± 4.5

63.0 ± 18.8

26.7

Hayek 2013 [64]

Greater Montreal (CHMS), Canada 45°N

Preschoolers

508

2–5

74.4 [60.3–93.5]b

4.5 (<40)

Omand 2014 [65]

Toronto, Canada 43°N

Healthy children from practice-based network: non-Western, Western

1540

Median 36 months

85 89

5

Gernand [66]

12 medical centers across the United States

Pregnant women (≤26 weeks)

2048

<20 to 30+

51.2 ± 27.2

Ganji [14]

Nationally representative sample (NHANES), USA

NHANES 2001–2006 NHANES 1988–1994

23,424 18,641

Shea 2011 [67]

Random sample of wellfunctioning older adults (70–81 years) (Health ABC study), USA

Older adults: Black White

Ginde [15]

Nationally representative sample (NHANES)

Mansbach [16]

Ginde [17]

The difference between groups was explained by known vitamin D determinants

USA 22.3 (<30)

55.4

<2 to 70+ 55.2 (eight different 60.7 age groups)

5 2

32 29

977 1607

70–81

52.5 ± 26.0 73.0 ± 27.3

9 2

54 18

Pregnant Nonpregnant

928 5173

13–44

65 [61–68]a 59 [57–61]a

7 10

33 42

Nationally representative sample (NHANES)

Children

1799

1–11

Age 1–11: 68 1 [66–70]a Age 1–5: 70 [68–73]a Age 6–11: 66 [64–68]a

18

Nationally representative sample (NHANES)

NHANES III 1988–94 NHANES 2001–04

18,883 13,369

12 to ≥60

75 (72.5–75)a 60 (57.5–62.5)a

22 36

2 6

Assayadjusted

     

Orwoll [68]

Alabama, Minnesota, California, Pennsylvania, Oregon

Older men from general community

1606

73.8 ± 5.9

62.8 ± 19.8

2.9

Egan [69]

South-eastern USA

African-American: Men Women White: Men Women

99 99 99 98

50.3 (8.3) 51.6 (9.7) 53.8 (9.2) 54.7 (10.0)

42.5 (31.5–60.3)b 35.5 (22.3–50.5)b 69.5 (51.3–90.8)b 64.8 (43.3–79.8)b

5 (<20) 15 (<20) 2 (<20) 1 (<20)

Fohner [70]

Rural Southwest Alaska, USA 63°N

Yup’ik Alaska native people

743

14–93

77 ± 31.5

Campagna [21]

Minnesota, USA 44°N

Immigrant and refugee US-born

1378 151

Young [71]

Rochester, 43°N Baltimore, 39°N, USA

Pregnant adolescents (≈26 weeks) Cord blood

168

17.1 ± 1.1

Penrose [72]

Massachusetts, USA 41–42°N

Refugees

2610

23 median age at arrival

Merewood [73]

Boston, Massachusetts 42°N

Newborns Mothers

376 433

<20–43

43 (40–47)a 62 (58–64.5)a

Araujo [74]

Boston, Massachusetts 42°N

Hispanic men: Puerto Rican Dominican Central American South American

121 82 82 73

50.4 ± 11.6 52.6 ± 12.3 46.3 ± 10.8 46.6 ± 11.4

82.5 ± 40.8 91.8 ± 59 87.5 ± 34.3 91 ± 47.8

Lappe [75]

Eastern Nebraska 41°N

Rural postmenopausal white women

1179

66.7 ± 7.3

71.8 ± 20.3 April–October: 71.1 ± 20.0

15.1 7.9 55.3 ± 25.5 52.0 ± 25.5

25.7

60.0 35.1 50

38.0 (<37.5) 23.1 (<37.5)

43

25(OH)D <50 nmol/L most prevalent in refugees from Middle East

58 35.8

Primarily lowincome black and Hispanic

26.1 21.1 10.8 8.5 4 (<37.5)

14.4

Continued

TABLE 59.1  Vitamin D Status and Prevalence of Vitamin D Deficiency in North America (Including Canada and Mexico)—cont’d

References

Country Latitude °N/S

25(OH)D Study Population

N

Age (Years)

Mean ± SD, nmol/L

<25 nmol/L %

Bodnar [76]

Pittsburgh, Pennsylvania 40°N

Pregnant: White Black Cord blood: White Black

200 200

<20 to ≥30

4–21w: 73.1 (69.4–76.9)a 37–42w: 80.4 (76.0–85.1)a 4–21w: 40.2 (37.9–42.7)a 37–42w: 49.4 (46.1–52.9)a 67.4 (63.8–71.3)a 39.0 (36.3–41.8)a

2.0 (<37.5) 5.0 (<37.5) 44.9 (<37.5) 29.2 (<37.5) 9.7 (<37.5) 45.6 (<37.5)

Dong [77]

Georgia, USA 33°N

Adolescents

559

16.2 ± 1.2

73.7 ± 38.0

5.2

Cole [78]

Atlanta, Georgia 33°N

Low-income minority children: Hispanic Non-Hispanic black

141 149

2.7 ± 1.2 2.3 ± 1.1

64.7 ± 14.8 66.3 ± 22.3

Flores [79]

Nationally representative sample, Mexico

Children

366 659

2–5 6–12

78.3 105.8

0.5 (<20) 0.2 (<20)

Moodley [80]

Tijuana, Mexico 32°N

Mother Newborns

49 49

18+

65.5 47.3

10 (<37.5) 23 (<37.5)

ElizondoMontemayor [81]

Monterrey, Mexico 25°N

Children: Obese Nonobese

99 99

9.0 ± 2.0 8.9 ± 2.0

57.8 ± 13.5 66 ± 15.3

Clark [82]

Toluca, Mexico 19°N

Healthy subjects

585

41.1 ± 15

52.3

<50 nmol/L %

Comments

28.8

Black had significantly lower levels

18.1 26.3

MEXICO

a95%

24.6 10.2 Baseline data RCT (preterm, low birth weight excluded) 27.3 13.1

2.0

43.6

Confidence interval. range. 25(OH)D, 25-hydroxyvitamin D; NHANES, National Health and Nutrition Examination Survey; RCT, randomized controlled trial; SD, standard deviation; SE, standard error. bInterquartile

     

Summer (June)

Vitamin D Status in Africa

study comprised a nationally representative sample of pregnant and nonpregnant women, children, adolescents, adults, and older people [14–17]. Furthermore, different time periods were studied. From 1988–1994 to 2001–2006, the prevalence of serum 25(OH)D <30 nmol/L increased from 5% to 10% in all participants, from 3% to 8% in men, from 22% to 38% in blacks, from 3% to 8% in 12- to 15-year-old adolescents, from 5% to 12% in 20- to 30-year-old adults, from 6% to 14% in nonsupplement users, and from 8% to 17% in persons with BMI >80th percentile (P < .001) [14]. A very high prevalence of low serum 25(OH)D was observed in pregnant women from Newfoundland and Labrador in Canada (89% “insufficient” at the end of winter; 64% “insufficient” at the end of summer) [18], Inuit preschoolers living in Arctic communities (52.1% < 50 nmol/L in summer; 72.7% < 50 nmol/L in winter) [19], immigrants, and refugees (60%–61% < 50 nmol/L) [20,21].

21

persons and patients with hip fracture and the institutionalized. Similarly, very low serum 25(OH)D levels were observed in noninstitutionalized elderly in Switzerland. Also in Italy and Greece, very low serum 25(OH)D levels were observed while sunshine is abundant in these countries. This may be caused by a more pigmented skin and by sun-avoidance behavior especially in summer because of the high temperatures. Vitamin D status usually is very poor in immigrants from non-Western countries [33,34], compared with native people (Fig. 59.3). This is even worse in pregnant non-Western immigrants [35], in which serum 25(OH)D often is lower than 25 nmol/L or undetectable.

VITAMIN D STATUS IN MIDDLE EAST

Last decade, many studies have been published on vitamin D status in South American countries (Table 59.2). Latitudes range from N 14° to S 55°. In several studies, a very high prevalence of persons having serum 25(OH)D below 50 nmol/L was observed, especially in Koya Indian children living in Argentina (92.7% and 96.6%) [22,23], healthy children living in Chile (96.3%) [24], and institutionalized women living in Argentina (86%) [25].

Serum 25(OH)D is lower in these countries than should be expected based on the abundance of sunshine (Table 59.4). In Turkey, Jordan and Saudi Arabia serum 25(OH)D was lower in women than in men. In women, vitamin D status depended on clothing style being lower in traditionally clothed women than in women with Western style clothing. A very low serum 25(OH)D was observed in Saudi Arabia even with the very sunny climate. This may be explained by the often completely covered skin in this country. Similar trends were visible in Egypt and Iran. Another issue to explain the low levels of 25(OH)D in this part of the world is the extreme heat leading people to avoid being outdoors during the sunny parts of the day.

VITAMIN D STATUS IN EUROPE

VITAMIN D STATUS IN ASIA

Vitamin D status has been studied extensively in many European countries in different age groups (Table 59.3). Eastern Europe is less well represented but has been summarized in a recent review [26]. Data from Iceland, Norway, Ireland, the UK, the Netherlands, Germany, and Greece have recently been standardized by the European ODIN study [11], making all these data comparable. A general trend in these data is that vitamin D status is usually better in Nordic countries than around the Mediterranean despite higher latitude. This difference may be caused by the traditional high intake of cod, cod liver, and cod liver oil in Norway and Sweden [27]. In studies using a central laboratory facility [28,29], a similar trend is visible, showing a positive correlation between serum 25(OH)D and latitude. The expected south–north gradient with a decreasing serum 25(OH)D from south to north was visible in the French SUVIMAX study, where mean serum 25(OH)D decreased from 94 nmol/L in the south–west to about 43 nmol/L in the most northern regions of France [30]. Representative data have been obtained in the United Kingdom in the National Dietary and Nutrition Survey [31] (Fig. 59.2). As expected, serum 25(OH)D was lower in older persons than in adults. Unexpectedly, serum 25(OH)D was low in adolescents [31,32]. Vitamin D status was poor in older

Recently, many studies on vitamin D status in Asian countries have been published (Table 59.5). Vitamin D status was poor in patients with hip fracture in Yekaterinburg, Russia [36] and in older control subjects. A low vitamin D status was also observed in Mongolian women. Rickets is very common in Mongolia [31]. Similarly, adolescent boys and girls in China had a very low serum 25(OH)D [37]. Contrary to expectation, vitamin D status was poor to moderate in India situated at a latitude between 13° and 27°. This may be due to pigmented skin, skin covering, and a sun-avoidance behavior. Vitamin D status was better in south-eastern Asian countries such as Malaysia and Japan.

VITAMIN D STATUS IN SOUTH AMERICA

VITAMIN D STATUS IN AFRICA The number of studies on vitamin D status in Africa is relatively small. The literature was recently reviewed [38]. Studies from Africa are summarized in Table 59.6. The vitamin D status in East and West Africa was good in these studies. Even in patients with tuberculosis, the vitamin D status was very good. However, even in South Africa, low serum 25(OH)D concentrations are observed [39].

VII.  POPULATION STUDIES: VITAMIN D DEFICIENCY, NUTRITION, SUNLIGHT, GENES & TRIALS

TABLE 59.2  Vitamin D Status and Prevalence of Vitamin D Deficiency in South America

References

City, State Latitude °N/S

25(OH)D Study Population

N

Age (Years)

Mean ± SD, nmol/L

<25 nmol/L %

<50 nmol/L %

Sud [83]

Quetzaltenango, Guatemala 14°N

Healthy older Mayans

108

69.0 ± 7.2

53.3 ± 15.0

46.3

Gilbert– Diamond [84]

Bogota, Colombia 4°N

School-age children

479

8.9 ± 1.6

73.2 ± 19.8

10.2

Orces [85]

Andes mountains and coastal regions, Ecuador

Older adults participating in national health survey

2374

71.0 ± 8.3

60–69 years, 69.0 ± 28.8 70–79 years, 63.8 ± 24.3 ≥80 years, 64.8 ± 33.0

21.6

Del Brutto [86]

Atahualpa, Ecuador 1°S

Community-dwelling older 220 adults

70.9 ± 7.8

Issa [87]

Joao Pessoa, Brazil 7°S

Random sample of elderly

142

≥60

64.1 ± 8.2

40.8 (<75)

Cabral [88]

Recife, Brazil 8°S

Random sample of elderly men from basic care unit

284

69.4 ± 6.5

69.7 ± 33.8

31.5

Tomaino [89]

Lima 12 STumbes 3°S, Peru

Population-based sample of adolescents

1074

14.9 ± 0.8

Lima: 52.0 ± 14.3 Tumbes: 75.3 ± 23.0

Cobayashi [90]

Acrelandia, Brazil 9°S

Amazonian children

974

5.4 ± 2.8

66 (86–105)b

Lopes [91]

Sao Paulo, Brazil 23°S

Community-dwelling elderly

908

72.8 ± 4.8

48.5 ± 23.3

Martini [92]

Sao Paulo, Brazil 23°S

Population-based sample

636

Peters [93]

Sao Paulo, Brazil 23°S

Healthy adolescent students: Boys Girls

64 72

25

11.0 14.4

58.0

Boys, 28.1 ± 10.6 Adult men, 48.4 ± 22.9 Elderly men, 50.9 ± 21.9 Girls, 33.2 ± 14.7 Adult women, 51.0 ± 26.1 Elderly women, 53.9 ± 18.9 18.0 ± 0.1 18.3 ± 1.0

Comments

71.8 ± 21.3 74.0 ± 22.8

     

Differences in season of sampling between life stages

0 0

63.9 (<75) 60.6 (<75)

Fall (April and May) Rural

     

Eloi [94]

Sao Paulo greater area, Brazil 23°S

Database of laboratory results

39,004 2–95

63.9 ± 28.6

Unger [95]

Sao Paulo, Brazil 23°S

Healthy volunteers from a university hospital

603

47.8 ± 13.4

Median 53.5

Winter 13.8 Summer 3.8 <37.5

Winter 76.5 Summer 37.3 <75

Hirschler [22]

San Antonio de los Cobres, Argentina 24°S

Koya Indian children from three schools

355

9.6 ± 2.3

36.4 ± 10.1

14.1

92.7

Hirschler [23]

San Antonio de los Cobres, Argentina 24°S

Koya Indian children from four schools

290

10.6 ± 2.9

25.1 (19.9–52.1)b

49.7

96.6

Santos [96]

Curitiba, Brazil 25°S

Apparently healthy girls

234

13.0 ± 1.9

53.3 ± 17

36.3

Premaor [97]

Porto Alegre, Brazil 30°S

Resident physicians

73

26.4 ± 1.9

44.8 ± 20

57.4

Gonzalez [98]

Santiago, Chile 33°S

Healthy women: Premenopausal Postmenopausal

30 60

32.6 ± 7.4 63.7 ± 9.7

61.3 ± 19.5 48.8 ± 24.8

0 (<22.5) 12 (<22.5)

27 60

Hirschler [99]a

Buenos Aires, Argentina 34°S

Boys (mixed population)

116

11.3 ± 2.51

49.0 ± 9.7

0.9

46.6

Portela [25]

Buenos Aires, Argentina 34°S

Institutionalized women

48

81.3 ± 7.9

34.0 ± 15.3

32

86

Brinkmann [24]

Punta Arenas, Chile 53°S

Healthy children

108

9.6 ± 0.5

Median 27.3

62 (<30)

96.3

Tau [100]

Ushuaia, Argentina 55°S

Children

18

7.3 ± 4.4

Before treatment: 73.3 ± 14.8

aBecause

of overlap with Hirschler [99], only the results of Buenos Aires boys were reported. (interquartile range). 25(OH)D, 25-hydroxyvitamin D. bMedian

Half: winter (June–September) Half: summer (December–March)

End of summer

TABLE 59.3  Vitamin D Status and Prevalence of Vitamin D Deficiency in Different European Countries 25(OH)D

Country Latitude °N/S

Study Population

N

Age (Years)

Mean ± SD nmol/L

<25 nmol/L %

<50 nmol/L %

Comments

Cashman [11]

Iceland 64°N

Adult men and women Regionally representative

5519

66–96

57.0 ± 17.8

4.2

33.6

ODIN

Cashman [11]

Norway (Tromso) 69°N

Regionally representative

12,817

30–87

65.0 ± 17.6

0.3

18.6

ODIN

Cashman [10]

Norway (Oslo) 60°N

866

30–76

71.0 ± 19.5 (white)

0.1 (white)

14.9 (white)

Melhus [101]

Sweden 58°N

Older men

1194

71

68.7 ± 19.1

0.8

17

Buchebner [102]

Sweden 56°N

OPRA women

995

80 (80–81)

78 ± 30

0

16

Cashman [10]

Finland 60–70°N

Nationally representative

4102

29–77

67.7 ± 13.2

0.2

6.6

Kauppi [103]

Finland 60–68°N

2736 men 3299 women

51 (30–97) 53 (30–94)

45.1 (5–132) 45.2 (7–134)

Cashman [10]

Denmark (Copenhagen) 56°

Regionally representative

3409

19–72

65.0 ± 19.2

0

23.6

Cashman [11]

UK 50–59°N

Children, teens, and adults Nationally representative

1488

1.5–91

47.4 ± 19.8

15.4

56.4

Carson [32]

Northern Ireland 54–55°N

Girls and boys Regionally representative

1015

11 and 15 years

41.9 ± 16.0

16.7

66.2

Cashman [104]

Ireland 51–54°N

Nationally representative

1118

18–84

56.4 ± 22.2

6.0

45.0

Cashman [11]

Netherlands 52°N

LASA 2009 Nationally representative

915

61–99

64.7 ± 22.6

2.4

28.5

ODIN

Cashman [11]

Netherlands 52°N

Regionally representative

2625

40–66

59.5 ± 21.7

4.9

33.6

ODIN

Hoge et al. [105]

Belgium 51°N

Adults

697

42.7 (32–53)

49.3 (35–65)

7.3

51.1

Cashman [11]

Germany 47–55°N

Nationally representative

6995

18–79

50.1 ± 18.1

4.2

54.5

References

     

MrOs

ODIN

ODIN

     

Cashman [11]

Germany 48–52°N

Nationally representative Children and adolescents

10,015

1–17

54.0 ± 19.2

6.0

44.5

Souberbielle [106]

France 43–49°N

Varieté Study

892

18–89

60 ± 20

6.3

34.6

Cashman [11]

Greece 35–40°N

Regionally representative

806

9–14

47.3 ± 12.5

2.2

62.4

ODIN

Cashman [11]

Greece 37°N

Regionally representative

222

3–6

54.3 ± 15.7

1.4

40.5

ODIN

Snellman [107]

Norway 60°N

Twins

204

84.8 ± 27.4

0

8

Viljakainen [108]

Finland 60–68°N

Mothers Newborns

98 98

30.5 ± 4

45 ± 12 29.2

Pekkarinen [109]

Finland 60–68°N

Older women

1604

62–79

45 (spring) 53 (fall)

8.6

60.3

Roddam [110]

UK 51–58°N

Pat with fractures Controls

730 1445

52 52

82 ± 40 81 ± 38

Prentice [31]

UK 51–58°N

Nat Diet Nutr. Survey

16–80+

See Fig. 59.2

5–20

20–60

Van Schoor [49]

Netherlands 52°N

LASA

1311

75.5 ± 6.6

53.5 ± 24.2

11.3

48.4

Van Dam [111]

Netherlands 52°N

Hoorn cohort: Men Women

271 267

69.4 ± 6.3 69.8 ± 6.7

Summer: 1.7 Winter: 6.6

33.7 50.9

Van der Meer [34]

Netherlands 52°N

Adult women and men

613: Dutch Turkish Moroccan Suriname Asian Suriname Creole African

18–65

Kocjan [112]

Slovenia 46°N

448

17–89

Laktasic [113]

Croatia 45°N

120

61.1 ± 8.8

Postmenop. women

25(OH)D, 25-hydroxyvitamin D; SD, standard deviation.

67 27 30 24 27 33

46.9 ± 16.8

21.7 20.9

6 41 37 51 45 19

30.5

66.4

14.2 (<30)

63.3

ODIN

26

59.  WORLDWIDE VITAMIN D STATUS

FIGURE 59.2  Percentage of the population in the United Kingdom with serum 25-hydroxyvitamin D lower than 25 nmol/L (vitamin D deficiency) or lower than 50 nmol/L (vitamin D deficiency and insufficiency). Data from the National Dietary and Nutrition Survey [31]. The prevalence of low serum 25(OH) D levels is remarkably high in adolescents and young adults.

Serum 25-hydroxy vitamin D < 25 nmol/l 60

51,4

50

41,3

40

45,3

36,5 29,1

% 30 20 10

19,3 5,9

0

er th O

su S b-

=5 5) (N

) 07

7) =5

5) =7

an

ric Af

(N =1

) 02

(N

=1

n ia

(N

As

e

h ut

6) =9

ol re

n

C

So

(N

a ar

(N

ah

e am

e

an

) 21

h tc Du

=1 (N

s ou

am

rin

rin

Su

Su

c oc

sh

n ge

ki

or

M

r Tu

di in

FIGURE 59.3  Prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D <25 nmol/L) in different ethnicities in the Netherlands. Data from van der Meer I, Boeke AJ, Lips P, Grootjans-Geerts I, Wuister JD, Deville WL, Bouter LM, Middelkoop BJ. Fatty fish and supplements are the greatest modifiable contributors to the serum 25-hydroxyvitamin D concentration in a multiethnic population. Clin Endocrinol (Oxf) March 2008;68(3):466–72 .

VITAMIN D STATUS IN OCEANIA A selection of studies in Oceania, that is, Australia, Pacific Islands, and New Zealand, is reported in Table 59.7. Latitudes in these studies range from 18° to 46°S. Although Oceania has a very sunny climate, vitamin D deficiency is very prevalent with the highest prevalence in East African immigrant children living in Melbourne, Australia (87% having serum 25(OH)D <50 nmol/L) [40], refugee children in Sidney, Australia (61% < 50 nmol/L) [41], and Northeast-Asian immigrants aged 30–39 years living in Canberra, Australia (68.8% < 50 nmol/L) [42]. In a study performed in three different regions in Australia, higher mean 25(OH)D values were

observed at lower latitudes with a high prevalence of serum 25(OH)D <50 nmol/L in Tasmania (67.3%) [43].

MULTICENTER AND GLOBAL STUDIES USING A CENTRAL LABORATORY FACILITY Some studies have involved many countries or even several continents using one central laboratory facility. The advantage of these studies is that different assays for serum 25(OH)D and different laboratories are excluded as a source of variation. This is a great advantage as noted earlier, interlaboratory variation

VII.  POPULATION STUDIES: VITAMIN D DEFICIENCY, NUTRITION, SUNLIGHT, GENES & TRIALS

TABLE 59.4  Vitamin D Status and Prevalence of Vitamin D Deficiency in Middle East Countries According to Different Studies

References

Country Latitude °N/S

Hekimsoy [114]

25(OH)D Study Population

N

Age (Years)

Mean ± SD, nmol/L

Turkey

Men Women

119 272

45.1 ± 17.5 45.1 ± 17.2

Buyukuslu [115]

Turkey

Female students

100

Omrani [116]

Iran

Adult women

Hosseinpanah [117]

Iran

Saliba [118]

<50 nmol/L %

Comments

51.8 ± 38.7 38.1 ± 28.7

66.4 78.7

Manisa; low levels related to clothing style

20.9 ± 2.1

65.7 ± 25

34.0

Istanbul; low levels related to clothing style

676

42.3 ± 13.4

28.9 ± 23.0

52.2 (<23)

Healthy adults

251

56.7 ± 11.7

45.2 (27.5–77.5)

19.1

53.8 (<37.5)

Israel

Men Women

198,834

0 to >80

54.8 ± 24.2 50.7 ± 24.6

10.0 16.2

45.0 51.8

Nichols [119]

Jordan 31°N

Women

2032

15–50

27.5 (22.7–33.7)

60.3 (<30)

95.7

Hussain [120]

Saudi Arabia

Men Women

3363 7346

0 to >60

50.5 41.9

23.7 35.6

Alfawaz [121]

Saudi Arabia

Men Women

756 2719

46.9 ± 16.3

35.5 ± 30.6

36.1 48.8

72.4 78.1

Al-Ghamdi [47]

Saudi Arabia

Boys Girls

30 19 42 11

13–14 15–18 13–14 15–18

49.0 ± 12.9 39.3 ± 14.0 29.0 ± 9.1 22.0 ± 9.4

0 0 31.0 63.6

60 52.3 97.6 100

Low levels related to clothing style

Narchi 2015 [48]

United Arab Emirates

Female adolescents

293

15.3 ± 2.0

21.5 ± 10.0

78.8

98.6

Low levels related to clothing style

Olama [122]

Egypt

Healthy women

50

33.1 ± 9.7

47.0 ± 13.5

6 (<20)

30

Controls of a fibromyalgia study

25(OH)D, 25-hydroxyvitamin D; SD, standard deviation.

     

<25 nmol/L %

Shiraz Controls of a cardiovascular outcomes study

Low levels related to clothing style Riyadh; serum 25(OH) D <25 nmol/L in 49% of adolescents

      TABLE 59.5  Vitamin D Status and Prevalence of Vitamin D Deficiency in Asian Countries According to Different Studies 25(OH)D

Country Latitude °N/S

Study Population

N

Age (Years)

Mean ± SD nmol/L

<25 nmol/L %

Bakhtiyarova [36]

Asian Russia 57°N

Hip fracture Controls

64 97

69 ± 10 70 ± 8

22 ± 11 28 ± 10

65 47

Fraser [123]

Mongolia 42–50°N

Rachitic children Healthy children Pregnant women

40 22 57

Ganmaa [124]

Mongolia 48°N

Women

420

34.9 ± 4.8

19.0 ± 10.0

88.6 (<30)

Fraser [123]

China 40°N

Girls

1277

12–14

12–13 winter 25–30 summer

45 (<12.5) 6 (<12.5)

Zhou [125]

China 42°N

Women and men

100

65.7 years

31.0 ± 12.3

40

Zhao [126]

China 40°N

Postmenopausal women

1724

64.1 ± 9.2

33.0 ± 13.5

Wu [37]

China 39°N

Adolescent boys Adolescent girls

111 111

12–15 12–15

30.9 ± 8.8 28.2 ± 8.3

Yu 2015 [127]

China 43.5°N China 39.5 China 39.0 China 30.3 China 23.1 China 43.5 China 39.5 China 39.0 China 30.3 China 23.1

Men

178 191 265 220 223 224 224 215 217 216

40.6 ± 13.6

Lu [128]

China 31

Men Women

649 1939

Song [129]

China 39.5

Pregnant women

Xiao [130]

China 31.5

Pregnant women

Ke [131]

China 22

Zhen 2015 [132]

China 36°N

Li 2015 [133]

References

<50 nmol/L %

7 ± 1 41 ± 3 26 ± 2

Comments

Rickets very common 98.8

Ulaanbaatar

Shenyang 89.7

Beijing

61 (<30)

97

Beijing

51 ± 15.5 44 ± 15.7 58.5 ± 16.0 51.5 ± 14.5 55.7 ± 12.5 41.5 ± 16.5 37.5 ± 14.8 49.5 ± 15.5 43.2 ± 13.0 51.2 ± 11.5

2.2 11.0 0.8 3.6 0.4 11.1 20.1 4.2 6.0 0

53.9 66.5 32.1 49.1 32.2 77.2 79.5 54.4 72.4 47.2

Urumqi Beijing Dalian Hangzhou Guangzhou Urumqi Beijing Dalian Hangzhou Guangzhou

45.5 ± 14.8 42.2 ± 15.9

57.0 median 50.2 median

2 3.6

30 46

Shanghai

125

28.4 ± 2.9

28.4 ± 9.5

44.8

96.8

Beijing

5823

26.4 ± 3.1

34.0 median

40.7 (<30)

78.7

Wuxi

566

19–84

50.6 ± 17

55

Macau

Women 7136 Men 2902

7136 2902

40–75

39.2 ± 17.8 45.3 ± 15.7

75.2

Lanzhou

China 28°N

Postmenopausal women

578

62.2 ± 6.1

43.5 ± 14.3

72.1

Changsha

Chan [134]

China 22°N

Men

939

72.8 ± 5.1

77.9 ± 20.5

5.9

Hong Kong

Xu [135]

China 22°N

Children Adults Adults adults

1165 933 544 51

6–17 18–44 45–64 65+

39–53* 42–57 47–69 41–56

Women

Hong Kong

Japan

Japan 38°N

Korea

Korea

Malaysia 3°

Malaysia 3

Vietnam

Thailand

Cambodia

Singapore

Singapore

Indonesia Malaysia Thailand Vietnam

Bangladesh 24°N

India 28.4°N

India 13.4°N

India

India

India

Pakistan

Pakistan

Nakamura [137]

Nakamura [138]

Choi [139]

Kim [140]

Chee [141]

Moy [142]

Laillou [143]

Pratumvinit [144]

Smith [145]

Loy [146]

Bi [147]

Poh [148]

Islam [149]

Goswami [150]

Harinarayan [151]

Kumar [152]

Marwaha [153]

Shivane [154]

Mehboobali [155]

Junaid [156]

Women

Women Men

Young men Young women

Pregnant women

Men, urban Men, rural Women, urban Women, rural

Men Women

Women

Boys and girls

Men Women

Pregnant women

Women

Pregnant women

Women Children

Adults men Women

Postmenopausal women

Adolescents boys Adolescent girls

Women Men

Men Women

women

Women Men

215

507 351

558 579

541

134 109 807 96

32 25

121

276 861 495 384

59 55

940

725

147

541 485

158 222

178

1095 967

3878 3047

9084

151

179 203

28.4 ± 7.2

18–60

25–35

46 43 46 43

42.8 ± 16.6 43.4 ± 12.6

18–60

0–12

30.9 ± 11.9 32.2 ± 13.0

30.5 ± 5.1

15–49

28.9 ± 6.4

32.9 3.7

48.5 ± 5.2

59.7 ± 5.0

10–18 10–18

45.0 ± 19.3 42.4 ± 19.6

60.1 ± 9.3 59.3 ± 9.2

66 ± 7

69.6 ± 9.0

40.4 ± 34.4

42.3 ± 17.2 60.1 ± 19.3

47.2 ± 22.2 39.5 ± 22.7

23.2 ± 12.2

46.3 59.5 38.8 47.5

44.2 ± 24.4 26.9 ± 15.9

52.7 55.2 59.6 56.3

58.2 ± 16.5 49.5 ± 16.7

81.0 ± 27.2

69.7 ± 31.2

61.6 ± 19.3

44.5 43.4

56.2 ± 18.9 36.2 ± 13.4

60.4 ± 15.6

45.9 ± 15.7 42.4 ± 14.7

45.5 ± 17.7 53.0 ± 18.7

55.9 ± 18.8 45.2 ± 16.6

60 ± 7

70.8 ± 27.0

25(OH)D, 25-hydroxyvitamin D; NHANES, National Health and Nutrition Examination Survey; SD, standard deviation.

China 22°N

Wat [136]

     

43

12.0 26.4

35

0 4.1 2.0 11.1

1.5 5.5

4.1

0.7

17 (<30) 21 (<30)

11.7 15.4

10.4 4.7

5

0.8

73

76 33

62.0 76.1

96.3

62 44 75 70

68.5

44 43.7 33.7 48.2

30.5 54.5

29

34

57 58

67.9

50.6

64.2 72.6

64.5 47.3

53.6

22.5

Lahore

Karachi Low income

Rural

SEANUTS

41% < 75 nmol/L

Bangkok

Kuala Lumpur

Kuala Lumpur

4th Korea NHANES

4th Korea NHANES

Niigata Prefecture

Winter, positive relation with fish

Hong Kong

     

TABLE 59.6  Vitamin D Status and Prevalence of Vitamin D Deficiency in Africa According to Different Studies 25(OH)D

References

Country Latitude °N/S

Study Population

N

Age (Years)

Mean ± SD, nmol/L

<25 nmol/L %

<50 nmol/L %

Comments

El Maghraoui [157]

Morocco

Women >50 years

178

58.8 ± 8.2

39.5 ± 29.0

51.6

65.7

Osteoporosis 25%

Wakayo [158]

Ethiopia

Urban students Rural students

89 85

11–18

48.2 ± 14.0 61.0 ± 15.1

61.8 21.2

25(OH)D <50 nmol/L Christians 35% Muslims 68.6%

Gebreegziabher [159]

Ethiopia

Women

202

30.8 ± 7.8

14.8 (<30)

Olayiwola 2014 [160]

Nigeria

Adults

240

>60

51.4

Mehta [161]

Tanzania 2–10°S

HIV-infected women: Low D Adequate D

347 537

24.6 ± 5 24.6 ± 5

60.5 ± 15 107.8 ± 22.5

Friis [162]

Tanzania

Healthy adults Tuberculosis pt

355 1223

<25 to >55

84.4 ± 25.6 110.9 ± 35.7

Luxwolda [163]

Tanzania 2–4°S

Nonpregnant adults Pregnant women

88 139

33 ± 10

106.8 ± 28.4 138.5 ± 35.0

Glew [164]

Nigeria 6°S

Fulani men Fulani women

22 29

47.6 ± 8.3 55.5 ± 13.5

Wejse [165]

Guinea-Bissau 10°S

Tuberculosis pt

365

37 ± 14

78.3 ± 22.8

Haarburger [39]

South Africa 22–34°S

Unselected

216

All ages

48.3 (5.5–106)

George [166]

South Africa

African Asian Indian

373 344

41.6 ± 13.1 43.5 ± 12.9

70.9 (51–95) 41.8 (29–57)

Kruger [167]

South Africa

Adults

179 298 129 52

<50 50–60 60–70 >70

77.3 71.2 66.2 64.7

25(OH)D, 25-hydroxyvitamin D; SD, standard deviation.

0

84.2 Older Yoruba in Ibadan

4.3 2.5

Case–control study in Mwanza

1

Traditional outside lifestyle

45 (<75) 83 (<75)

37 (<45) 3 (<30) 15 (<30)

Johannesburg

     

TABLE 59.7  Vitamin D Status and Prevalence of Vitamin D Deficiency in Australia and New Zealand According to Different Studies

References

City, State Latitude °N/S

Robinson [168]

25(OH)D Study Population

N

Age (Years)

Mean ± SD, nmol/L

<25 nmol/L %

<50 nmol/L %

Comments

Australia

Female patients from GPs with no known osteoporosis or fragility fracture

907

≥70

48.5 ± 22.7

12.2

55.2

Not taking vitamin D supplements

Heere [169]

Pacific Islands 18°S

Fijian women: Indigenous Fijian Indian Fijian

511 306 205

15–44

76 (73–78)a 80 (76–84)a 70 (66–74)a

11

Mean 25(OH)D higher in rural than in urban women

Jones [170]

Perth, Australia 31°S

Pregnant women (36– 40 weeks of gestation)

209

21.8 ± 4.4

77.7 ± 24.6

13.9

Pregnant women undergoing screening for allergy prevention trial, 84% white Caucasian

Willix [171]

Kalgoorlie, Australia 31°S

Pregnant Aboriginal Pregnant nonaboriginal

100 100

24.8 ± 6.2 29.5 ± 5.1

46.7 ± 21.7 65.4 ± 18.4

Black [172]

Perth, Australia 31°S

Adolescents

1045

14 17

86 ± 27 75 ± 24

Hirani [173]

Sidney, Australia 33°S

Community-dwelling men

1659

Sheikh [41]

Sidney, Australia 33°S

Refugee children attending an outpatient general health clinic

215

Gill [174]

Adelaide, Australia 34°S

Adults

Bowyer [175]

Sydney, Australia 34°S

Perampalam [176]

Daly [177]

18 2

56 20 4.4 12.2

55.9 ± 22.2

9.6 (<30)

43

0–17

46 ± 24

21

61

2413

50.6 ± 16.6

69.2 ± 26.4

0.9

22.7

Pregnant women Neonates

971 901

29.8 (23.2–37.1)b

52 (range: 17–174) 60 (range: 17–245)

15 11

48 40

Canberra 35°S and Campbelltown 34°S, Australia

Pregnant women (midpregnancy)

100 101

30.8 ± 5.6 27.9 ± 6.6

61.3 ± 23.4 57.6 ± 26.9

4 12

35 46

Australia 30–35°S

Adults

11,218

≥25

62.8 ± 25.4

4

31

Same participants at age 14 and 17 years. Deseasonalized 25(OH)D

Majority (76%) from Africa

Continued

     

TABLE 59.7  Vitamin D Status and Prevalence of Vitamin D Deficiency in Australia and New Zealand According to Different Studies—cont’d

References

City, State Latitude °N/S

25(OH)D Study Population

N

Age (Years)

Mean ± SD, nmol/L

<25 nmol/L %

<50 nmol/L %

Comments

4 (<30)

16 (30–50)

Higher prevalence in winter (8% and 22%)

38.5 68.8 30.0 10.5

Total sample: mean 25(OH)D = 60.2 ± 23.5; 36% < 50 nmol L; 3% < 25 nmol L

42%

Of those enrolled in winter/spring, 43% of European, 67% of Māori, 80% of Pacific, and 59% of women of other ethnic groups had 25(OH) D < 50 nmol/L.

55%

Women with 25(OH) D < 75 nmol/L were recommended to take 1000 IU/day and had an additional measurement at 28 weeks

25.8

Rural

Zhou [178]

Adelaide, Australia 35°S

Representative population sample of preschool children

221

1–5

73 ± 26

Guo [42]

Canberra, Australia 35°S

Northeast-Asian immigrants

43 17 21 19

18–29 30–39 40–49 50–80

58.6 (23.6) 46.3 (21.2) 58.7 (18.9) 76.8 (21.0)

Ekeroma [179]

South Auckland, New Zealand 36°S

Ethnically diverse sample of pregnant women (27 weeks of gestation)

Davies-Tuck [180]

Victoria, Australia 36°S

Early pregnancy

1550

Teale [181]

Shepparton, North Victoria, Australia 36°S

Women attending antenatal clinic: Winter Summer

330

Grant [182]

Auckland, New Zealand 36°S

Urban children

353

6–11 mo 12–17 mo 18–23 mo

Bolland [183]

Auckland, New Zealand 36°S

Adults

21,987

>18

Wishart [184]

Auckland, New Zealand

Refugees

869

17 (9–27)b

30.0 ± 5.4

47.0 (12–178)

57.3 ± 21.4 (winter) 76.8 ± 28.6 (summer)

5.2

62 (42–78)b 58 (44–76)b 49 (39–61)b

10 (<27.5)

48

17

54

     

McGillivray [40]

Melbourne, Australia 37°S

East African immigrant children

232

8.9 ± 4.4

Bolland [185]

Auckland, New Zealand 37°S

Community-dwelling men

378

57 ± 11

Camargo [186]

Wellington 41 Sand Christchurch 43°S, New Zealand

Cord blood of newborns: Wellington Christchurch

474 455

van der Mei [43]

Three regions, Australia (Southeast Queensland, SQ 27°S; Geelong region, G 38°S; Tasmania, T 43°S)

Population based: SQ: men women G: women T: men women

211 167

44

87

85 ± 31

Summer 0 Winter 0–2

Summer 0–17 Winter 0–20

45(31–79)b 42 (27–77)b

18 21

55 59

Winter/spring SQ: 7.1

Winter/spring Three different SQ: 40.5 studies

G: 7.9

G: 37.4

T: 13.0

T: 67.3

72.2 67.0 75+

561

75.5

298 432

55.2 51.1

Nessvi [187]

Auckland 36 Sand Dunedin 45°S, New Zealand

Multiethnic sample of adult 133 volunteers 121 130 119

18–34 35–49 50–64 65–85

45.2 (SE 1.8) 44.6 (SE 2.0) 52.0 (SE 1.9) 51.3 (SE 2.0)

Polak [188]

Otago, New Zealand 45°S

Healthy university student volunteers

19.5 ± 1.5

64.1 ± 26.6

Rockell [189]

Invercargill and Volunteers Dunedin, New Zealand 45–46°S

a95%

615 342

Confidence interval. (interquartile range). 25(OH)D, 25-hydroxyvitamin D; GPs, general practitioners; SD, standard deviation; SE, standard error. bMedian

Late summer: 79 Early spring: 51

34

59.  WORLDWIDE VITAMIN D STATUS

may be as high as 25% [6]. The Euronut Seneca study was done in older persons in European countries from the Mediterranean to Northern Europe [29]. In this study, there was a positive correlation between serum 25(OH)D and latitude, that is, higher values in northern countries, the inverse of what was expected by sunlight exposure. This was confirmed by the baseline data of the MORE study, a study on the effect of raloxifene versus placebo in postmenopausal women with osteoporosis [28], and baseline data of the bazedoxifene study [44]. In the latter (bazedoxifene) study, the correlation between serum 25(OH)D and latitude in other continents was negative as should be expected. The baseline data of the bazedoxifene study also showed a relationship between serum 25(OH)D and affluence with lower 25(OH)D levels in Eastern Europe than in Western and Northern Europe. The MORE study, the bazedoxifene study, and another global study [28,44,45] were all done in postmenopausal women with osteoporosis. Vitamin D status in these studies usually was better than in other studies because women participating in clinical trials usually are more concerned about their health. These three studies show a very poor vitamin D status in middle-eastern countries confirming the data of national studies. Recently, values from different European countries were standardized by the ODIN study [11]. The studies included in the European ODIN study usually are nationally representative and therefore a better estimate of the actual situation at least in Europe.

ETHNICITY/MIGRATION Vitamin D status in immigrants from non-Western countries was poor in North America, Norway, the Netherlands, and Australia [20,21,33–35,40]. A review on this subject concluded that serum 25(OH)D in non-Western immigrants in the Netherlands was much lower than in those born in the Netherlands and was also lower than in people in their country of origin [46].

NUTRITION In Europe, a north–south gradient was observed for serum 25(OH)D with higher levels in Scandinavia and lower levels in Southern and Eastern European countries [28,29]. This indicates that other determinants than sunshine are of importance, for example, nutrition, food fortification, and supplement use. Fortification of dairy products is practiced in the United States where vitamin D 400 IU is added per quart of milk. Fortification of milk is now also practiced in Sweden, Finland, and Ireland.

RISK GROUPS Vitamin D deficiency is very common in certain risk groups, such as children with low birth weight (premature and small for gestational age), pregnant women, older people, and non-Western immigrants. Vitamin D status can be poor in adolescents as is seen

in studies in Europe, the Middle East, and Asia [11,31,32,37,47,48]. Pregnant women, especially non-Western pregnant women and their children, are at high risk of vitamin D deficiency [35]. The dermal synthesis of vitamin D decreases with age, and especially older nursing home residents who do not come outside frequently are at high risk. Non-Western immigrants migrating to countries at higher latitudes with limited Ultraviolet B irradiation are at high risk because of more pigmented skin, the habit to stay out of the sun, the wearing of well-covering clothes, and a diet low in dairy products [33–35,40,46].

IMPLICATIONS Vitamin D deficiency has been classically associated with mineralization defects, bone loss, osteoporosis, and fractures [44,49]. The causal relationship between vitamin D deficiency and fractures has been confirmed by randomized clinical trials [50]. Vitamin D deficiency has also been linked to muscular weakness, decreased physical performance, and falls [51–53]. The latter relationship has also been confirmed by clinical trials [54]. In recent years, vitamin D deficiency has been associated with nonclassical outcomes, such as cardiovascular disease, diabetes mellitus, multiple sclerosis, tuberculosis, respiratory infections, and several types of cancer [55]. However, for all these nonclassical outcomes, many clinical trials have been negative and causality has not been established. The magnitude of the negative health effects attributed to vitamin D deficiency also depends on the percentage of the population having a low vitamin D status. Roughly about 50% of the Western-European population has a serum 25(OH) D level below 50 nmol/L at least in winter. This percentage is lower in North America and appears higher in South America. The prevalence of vitamin D deficiency was more than 50% in South Africa, and around 50% in Oceania. From the Middle East and Asia, only prevalence rates were reported for serum 25(H)D <25 nmol/L, revealing severe vitamin D deficiency in the Middle East, China, Mongolia, and India. It is important to do more research in these countries, especially in Asia, where a relatively large part of the world population lives. In summary, to be able to estimate the burden of vitamin D deficiency, more prevalence studies are needed in Eastern Europe, the Middle East, Asia, and Africa. Quality control of the serum 25(OH) D assays should be done at least by participation in a quality assurance scheme such as DEQAS [8], and the % deviation from the overall mean should be reported. Preferably, results should be standardized by participating in a program such as Vitamin D Standardization Program [11]. Prevention requires moderate sunlight exposure, consumption of fish, fortification of foods, and the use of vitamin D supplements. A supplement of vitamin D3 400 IU/ day can be recommended for children and for adults who do not come outside or have a dark skin. Pregnant and lactating women may require 400–800 IU/day. Older persons also require a supplement of 400–800 IU/day, the higher dose with insufficient sun exposure or dark skin. Patients with osteoporosis and older persons in rest or nursing homes require

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References

800 IU/day. It will require an enormous effort to bring up serum 25(OH)D levels to more than 50 nmol/L in all continents all year long.

CONCLUSIONS Vitamin D deficiency (serum 25(OH)D <25 nmol/L) and insufficiency (serum 25(OH)D 25–50 nmol/L) are very common in most countries around the world. Severe vitamin D deficiency is common in the Middle East, China, Mongolia, and India. Risk groups are children, especially those with low birth weight, adolescents, pregnant women, older persons, and non-Western immigrants. Probably less than 50% of the world population has an adequate vitamin D status (serum 25(OH)D >50 nmol/L) at least in winter. Prevention requires moderate sunlight exposure, consumption of fish, fortification of foods, and the use of vitamin D supplements.

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VII.  POPULATION STUDIES: VITAMIN D DEFICIENCY, NUTRITION, SUNLIGHT, GENES & TRIALS