J Clin Invest 116(8): 2062-2072

Resurrection of vitamin D deficiency and rickets

Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, and Vitamin D, Skin and Bone Research Laboratory, Boston University Medical Center, Boston, Massachusetts, USA.

Address correspondence to: Michael F. Holick, Boston University School of Medicine, 715 Albany Street, M-1013, Boston, Massachusetts 02118, USA. Phone: (617) 638-4545; Fax: (617) 638-8882; E-mail: ude.ub@kcilohfm .

Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, and Vitamin D, Skin and Bone Research Laboratory, Boston University Medical Center, Boston, Massachusetts, USA.

Abstract

The epidemic scourge of rickets in the 19th century was caused by vitamin D deficiency due to inadequate sun exposure and resulted in growth retardation, muscle weakness, skeletal deformities, hypocalcemia, tetany, and seizures. The encouragement of sensible sun exposure and the fortification of milk with vitamin D resulted in almost complete eradication of the disease. Vitamin D (where D represents D₂ or D₃) is biologically inert and metabolized in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D that is used to determine vitamin D status. 25(OH)D is activated in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)₂D], which regulates calcium, phosphorus, and bone metabolism. Vitamin D deficiency has again become an epidemic in children, and rickets has become a global health issue. In addition to vitamin D deficiency, calcium deficiency and acquired and inherited disorders of vitamin D, calcium, and phosphorus metabolism cause rickets. This review summarizes the role of vitamin D in the prevention of rickets and its importance in the overall health and welfare of infants and children.

Abstract

Acknowledgments

This work was supported in part by NIH grants M01RR00533 and AR36963 and the UV Foundation.

Acknowledgments

Footnotes

Nonstandard abbreviations used: 1-OHase, 25-hydroxyvitamin D-1α-hydroxylase; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; DBP, vitamin D–binding protein; FGF23, fibroblast growth factor 23; PHEX, phosphate-regulating endopeptidase homolog, X-linked; PTH, parathyroid hormone; RANKL, receptor activator of NF-κB ligand; RXR, retinoic acid X receptor; SPF, sun protection factor; UVB, ultraviolet B; VDR, vitamin D receptor; VDRE, vitamin D–responsive element.

Conflict of interest: The author has declared that no conflict of interest exists.

Citation for this article:J. Clin. Invest.116:2062–2072 (2006). doi:10.1172/JCI29449.

Footnotes

References

1. Holick, M.F. 2005. Vitamin D. InModern nutrition in health and disease. 10th edition. M. Shils et al., editors. Lippincott Williams & Wilkins. Baltimore, Maryland, USA. 329–345. [PubMed]
2. Rajakumar KVitamin D, cod-liver oil, sunlight, and rickets: a historical perspective. Pediatrics. . 2003;112:132–135.[PubMed][Google Scholar]
3. Mozolowski WJedrzej Sniadecki (1768–1838) on the cure of rickets. Nature. . 1939;143:121–124.[PubMed][Google Scholar]
4. Palm T.AThe geographical distribution and etiology of rickets. Practitioner. . 1890;45:270–342.[PubMed][Google Scholar]
5. Huldschinsky KHeilung von Rachitis durch künstliche Höhensonne. Dtsch. Med. Wochenschr. . 1919;45:712–713.[PubMed][Google Scholar]
6. Huldschinsky, K1928.The ultra-violet light treatment of rickets. Alpine Press. New Jersey, USA. 3–19. [PubMed]
7. Hess A.F., Unger L.JThe cure of infantile rickets by sunlight. JAMA. 1921;77:39–41.[PubMed][Google Scholar]
8. Mellanby TThe part played by an “accessory factor” in the production of experimental rickets. . J. Physiol. 1918;52:11–14.[PubMed][Google Scholar]
9. McCollum E.F., Simmonds N., Becker J.E., Shipley P.GStudies on experimental rickets; and experimental demonstration of the existence of a vitamin which promotes calcium deposition. . J. Biol. Chem. 1922;53:293–312.[PubMed][Google Scholar]
10. Hess A.F., Weinstock MAntirachitic properties imparted to inert fluids and to green vegetables by ultraviolet irradiation. J. Biol. Chem. . 1924;62:301–313.[PubMed][Google Scholar]
11. Steenbock H., Black AThe reduction of growth-promoting and calcifying properties in a ration by exposure to ultraviolet light. J. Biol. Chem. 1924;61:408–422.[PubMed][Google Scholar]
12. Hess, A.F1929.Rickets including osteomalacia and tetany. Lea & Febiger. Philadelphia, Pennsylvania, USA. 401–429. [PubMed]
13. Hess, A.F1936.Collected writings. Volume 1. Charles C. Thomas. Springfield, Illinois, USA. 669–719. [PubMed]
14. Eliot, M.M., and Park, E.A. 1938. Rickets. InBrennemann’s practice of pediatrics. Volume 1. W.F. Prior Company Inc. Hagerstown, Maryland, USA. 1–110. [PubMed]
15. MacLaughlin J.A., Anderson R.R., Holick M.F Spectral character of sunlight modulates photosynthesis of previtamin D₃ and its photoisomers in human skin. . Science. 1982;216:1001–1003.[PubMed][Google Scholar]
16. Clemens T.L., Henderson S.L., Adams J.S., Holick M.F Increased skin pigment reduces the capacity of skin to synthesise vitamin D₃ . . Lancet. 1982;1:74–7.[PubMed][Google Scholar]
17. Matsuoka L.Y., Ide L., Wortsman J., MacLaughlin J., Holick M.F Sunscreens suppress cutaneous vitamin D₃synthesis. . J. Clin. Endocrinol. Metab. 1987;64:1165–1168.[PubMed][Google Scholar]
18. Holick M.F., MacLaughlin J.A., Doppelt S.H Regulation of cutaneous previtamin D₃ photosynthesis in man: skin pigment is not an essential regulator. . Science. 1981;211:590–593.[PubMed][Google Scholar]
19. Webb A.R., Kline L., Holick M.F Influence of season and latitude on the cutaneous synthesis of vitamin D₃ : exposure to winter sunlight in Boston and Edmonton will not promote vitamin D₃ synthesis in human skin. . J. Clin. Endocrinol. Metab. 1988;67:373–378.[PubMed][Google Scholar]
20. Holick M.FVitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am. J. Clin. Nutr. 2004;79:362–371.[PubMed][Google Scholar]
21. DeLuca H.FOverview of general physiologic features and functions of vitamin D. Am. J. Clin. Nutr. . 2004;80(Suppl.):1689S–1696S.[PubMed][Google Scholar]
22. Bouillon, R. 2001. Vitamin D: from photosynthesis, metabolism, and action to clinical applications. InEndocrinology. L.J. DeGroot and J.L. Jameson, editors. W.B. Saunders. Philadelphia, Pennsylvania, USA. 1009–1028. [PubMed]
23. Markestad T., Halvorsen S., Halvorsen K.S., Aksnes L., Aarskog DPlasma concentrations of vitamin D metabolites before and during treatment of vitamin D deficiency rickets in children. Acta Paediatr. Scand. 1984;73:225–231.[PubMed][Google Scholar]
24. Holick M.FHigh prevalence of vitamin D inadequacy and implications for health. Mayo Clin. Proc. . 2006;81:353–373.[PubMed][Google Scholar]
25. Christakos S., Dhawan P., Liu Y., Peng X., Porta ANew insights into the mechanisms of vitamin D action. J. Cell. Biochem. 2003;88:695–705.[PubMed][Google Scholar]
26. Khosla SThe OPG/RANKL/RANK system. Endocrinology. . 2001;142:5050–5055.[PubMed][Google Scholar]
27. Brown E.M., et al Cloning and characterization of an extracellular Ca^{-sensing receptor from bovine parathyroid. .}Nature. . 1993;366:575–580.[PubMed][Google Scholar]
28. Aiken C.G.A., Sherwood R.A., Lenney WRole of plasma phosphate measurements in detecting rickets of prematurity and in monitoring treatment. Ann. Clin. Biochem. . 1993;30:469–475.[PubMed][Google Scholar]
29. Gultekin A., Ozalp I., Hasanoglu A., Unal ASerum-25-hydroxycholecalciferol levels in children and adolescents. Turk. J. Pediatr. . 1987;29:155–162.[PubMed][Google Scholar]
30. Garabedian, M., and Ben–Mekhbi, H. 1999. Rickets and vitamin D deficiency. InVitamin D physiology, molecular biology, and clinical applications. M.F. Holick, editor. Humana Press. New Jersey, USA. 273–286. [PubMed]
31. David, L. 1991. Common vitamin D₃ deficiency rickets. InRickets. Nestle nutrition workshop series. F.H. Glorieux, editor. Raven Press. New York, New York, USA. 107–122. [PubMed]
32. Pettifor, J.M. 2005. Vitamin D deficiency and nutritional rickets in children. InVitamin D. 2nd edition. D. Feldman, J.W. Pike, and F.H. Glorieux, editors. Elsevier Academic Press. Boston, Massachusetts, USA. 1065–1084. [PubMed]
33. Henderson J.B., et al The importance of limited exposure to ultraviolet radiation and dietary factors in the etiology of Asian rickets: a risk-factor model. Q. J. Med. 1987;63:413–425.[PubMed][Google Scholar]
34. Thacher T.D., et al A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N. Engl. J. Med. . 1999;41:563–568.[PubMed][Google Scholar]
35. DeLucia M.C., Mitnick M.E., Carpenter T.ONutritional rickets with normal circulating 25-hydroxyvitamin D: a call for reexamining the role of dietary calcium intake in North American infants. J. Clin. Endocrinol. Metab. . 2003;88:3539–3545.[PubMed][Google Scholar]
36. Mawer E.B., Stanbury S.W., Robinson M.J., James J., Close CVitamin D nutrition and vitamin D metabolism in the premature human neonate. Clin. Endocrinol. 1986;25:641–649.[PubMed][Google Scholar]
37. Lee J.M., et al Vitamin D deficiency in a healthy group of mothers and newborn infants. Clin Pediatr. 2006 In press. [[PubMed][Google Scholar]
38. Sullivan S.S., Rosen C.J., Halteman W.A., Chen T.C., Holick M.FAdolescent girls in Maine are at risk for vitamin D insufficiency. J. Am. Diet. Assoc. . 2005;105:971–974.[PubMed][Google Scholar]
39. Gordon C.M., DePeter K.C., Feldman H.A., Grace E., Emans S.JPrevalence of vitamin D deficiency among healthy adolescents. Arch. Pediatr. Adolesc. Med. . 2004;158:531–537.[PubMed][Google Scholar]
40. Looker A.C., Dawson-Hughes B., Calvo M.S., Gunter E.W., Sahyoun N.RSerum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone. 2002;30:771–777.[PubMed][Google Scholar]
41. Iqbal S.J., Kaddam I., Wassif W., Nichol F., Walls JContinuing clinically severe vitamin D deficiency in Asians in the UK (Leicester). Postgrad. Med. J. . 1994;70:708–714.[Google Scholar]
42. Binet A., Kooh S.WPersistence of vitamin D-deficiency rickets in Toronto in the 1990s. Can. J Public Health. . 1996;87:227–230.[PubMed][Google Scholar]
43. Lamberg-Allardt C., Ojaniemi R., Ahola M., Räsänen LThe vitamin D intake of children and adolescents in Finland. Hum. Nutr. Appl. Nutr. . 1984;38A:377–382.[PubMed][Google Scholar]
44. Hoogenboezem H.J., et al Vitamin D metabolism in breast-fed infants and their mothers. Pediatr. Res. . 1989;31:623–628.[PubMed][Google Scholar]
45. Calvo M.S., Whiting S.J., Barton C.NVitamin D fortification in the United States and Canada: current status and data needs. Am. J. Clin. Nutr. 2004;80(Suppl.):1710S–1716S.[PubMed][Google Scholar]
46. Bhattacharyya, A.K. 1992. Nutritional rickets in the tropics. InNutritional triggers for health and in disease. A.P. Simopoulos, editor. Kruger. Basel, Switzerland. 141–197. [PubMed]
47. Taha S.A., Dost S.M., Sedrani H25-Hydroxyvitamin D and total calcium: extraordinarily low plasma concentrations in Saudi mothers and their neonates. Pediatr. Res. . 1984;18:739–741.[PubMed][Google Scholar]
48. Marwaha R.K., et al Vitamin D and bone mineral density status of healthy schoolchildren in northern India. Am. J. Clin. Nutr. . 2005;82:477–482.[PubMed][Google Scholar]
49. Arthur ARickets in the welfare state. NZ Med. J. . 2000;113:374–377.[PubMed][Google Scholar]
50. Nehama H., et al Seasonal variation in paired maternal newborn serum 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations in Israel. Isr. J. Med. Sci. . 1987;23:274–277.[PubMed][Google Scholar]
51. Lawson D.E.M., et al Aetiology of rickets in Egyptian children. Hum. Nutr. Clin. Nutr. . 1987;41C:199–208.[PubMed][Google Scholar]
52. Leung S.S.F., Lui S., Swaminathan RVitamin D status of Hong Kong Chinese infants. Acta Paediatr. Scand. . 1989;413:303–306.[PubMed][Google Scholar]
53. Feliciano E.S., et al Seasonal and geographical variations in the growth rate of infants in China receiving increasing dosages of vitamin D supplements. J. Trop. Pediatr. . 1994;40:162–165.[PubMed][Google Scholar]
54. Elzouki A.Y., Markestad T., Elgarrah M., Elhoni N., Aksnes LSerum concentrations of vitamin D metabolites in rachitic Libyan children. J. Pediatr. Gastroenterol. Nutr. . 1989;9:507–512.[PubMed][Google Scholar]
55. El-Hajj Fuleihan G., et al Hypovitaminosis D in healthy school children. Pediatrics. . 2001;107:E53.[PubMed][Google Scholar]
56. Docio S., et al Seasonal deficiency of vitamin D in children: a potential target for osteoporosis-preventing strategies? J. Bone Miner. Res. . 1998;13:544–548.[PubMed][Google Scholar]
57. McGrath J.J., Kimlin M.G., Saha S., Eyles D.W., Parisi A.VVitamin D insufficiency in south-east Queensland. Med. J. Aust. 2001;174:150–151.[PubMed][Google Scholar]
58. Hayward I., Stein M.T., Gibson M.INutritional rickets in San Diego. Am. J. Dis. Child. . 1987;141:1060–1062.[PubMed][Google Scholar]
59. Stein E.M., et al Serum 25-hydroxyvitamin D concentrations in girls aged 4-8 y living in the southeastern United States. Am. J. Clin. Nutr. 2006;83:75–81.[PubMed][Google Scholar]
60. Tylavsky F.A., Ryder K.A., Lyytikainen A., Cheng SVitamin D, parathyroid hormone, and bone mass in adolescents. J. Nutr. . 2005;135:2735S–2738S.[PubMed][Google Scholar]
61. Cooper C., Javaid K., Westlake S., Harvey N., Dennison EDevelopmental origins of osteoporotic fracture: the role of maternal vitamin D insufficiency. J. Nutr. 2005;135:2728S–2734S.[PubMed][Google Scholar]
62. Casella S.J., Reiner B.J., Chen T.C., Holick M.FA possible defect in 25-hydroxylation as a cause of rickets. J. Pediatr. . 1994;124:929–932.[PubMed][Google Scholar]
63. Gascon–Barre, M. 2005. The vitamin D 25-hydroxylase. InVitamin D. 2nd edition. D. Feldman, J.W. Pike, and F.H. Glorieux, editors. Elsevier Academic Press. Boston, Massachusetts, USA. 47–68. [PubMed]
64. Fraser D., et al. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N. Engl. J. Med. . 1973;289:817–822.[PubMed]
65. Kitanaka S., et al Inactivating mutations in the human 25-hydroxyvitamin D₃ 1alpha- hydroxylase gene in patients with pseudovitamin D-deficient rickets. . N. Engl. J. Med. . 1998;338:653–661.[PubMed][Google Scholar]
66. Malloy, P.J., Pike, J.W., and Feldman, D. 2005. Hereditary 1,25-dihydroxyvitamin D resistant rickets. InVitamin D. 2nd edition. D. Feldman, J.W. Pike, and F.H. Glorieux, editors. Elsevier Academic Press. Boston, Massachusetts, USA. 1207–1237. [PubMed]
67. Brooks M.H., et al Vitamin-D-dependent rickets type II: resistance of target organs to 1,25-dihydroxyvitamin D. N. Engl. J. Med. 1978;298:996–999.[PubMed][Google Scholar]
68. Chen H., Hewison M., Hu B., Adams J.SHeterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance. Proc. Natl. Acad. Sci. U. S. A. 2003;100:6109–6114.[Google Scholar]
69. Balsan S., et al Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in heredity resistance to 1,25-dihydroxyvitamin D. J. Clin. Invest. 1986;77:1661–1667.[Google Scholar]
70. Drezner, M.K. 2005. Clinical disorders of phosphate homeostasis. InVitamin D. 2nd edition. D. Feldman, J.W. Pike, and F.H. Glorieux, editors. Elsevier Academic Press. Boston, Massachusetts, USA. 1159–1187. [PubMed]
71. Econs, M.J. 2005. Disorders of phosphate metabolism: autosomal dominant hypophosphatemic rickets, tumor induced osteomalacia, fibrous dysplasia, and the pathophsiological relevance of FGF23. InVitamin D. 2nd edition. D. Feldman, J.W. Pike, F. H. Glorieux, editors. Elsevier Academic Press. Boston, Massachusetts, USA. 1189–1195. [PubMed]
72. Portale A.A., Halloran B.P., Murphy M.M., Morris R.COral intake phosphorus can determine the serum concentration of 1,25-dihyroxyvitamin D by determining its production rate in humans. J. Clin. Invest. 1986;77:7–12.[Google Scholar]
73. Kolek O.I., et al 1,25-Dihydroxyvitmin D₃ upregulates FGF23 gene expression in bone; the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. . Am. J. Physiol. Gastrointest. Liver Physiol. . 2005;289:1036–1104.[PubMed][Google Scholar]
74. Perwad F., et al Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology. . 2005;146:5358–5364.[PubMed][Google Scholar]
75. Shimada T., et al Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc. Natl. Acad. Sci. U. S. A. . 2001;98:6500–6505.[Google Scholar]
76. Yeung S.J., McCutcheon I.E., Schultz P., Gagel R.FUse of long-term intravenous phosphate infusion in the palliative treatment of tumor-induced osteomalacia. J. Clin. Endocrinol. Metab. 2000;85:549–555.[PubMed][Google Scholar]
77. Whyte M.P., Podgornik M.N., Wollberg V.A., Eddy M.C., McAlister W.HPseudo-(tumor-induced) rickets. J. Bone Miner. Res. . 2001;16:1564–1571.[PubMed][Google Scholar]
78. Ward L.M., et al Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producting tumour of the distal ulna. Bone. . 2004;34:905–911.[PubMed][Google Scholar]
79. Roth D.E., et al Are national vitamin D guidelines sufficient to maintain adequate blood levels in children? Can. J. Public Health. . 2005;96:443–449.[PubMed][Google Scholar]
80. Koo W., et al Effect of three levels of vitamin D intake in preterm infants receiving high mineral-containing milk. J. Pediatr. Gastroenterol. Nutr. 1995;21:182–189.[PubMed][Google Scholar]
81. Salle B.L., et al Early oral administration of vitamin D and its metabolites in premature neonates, effect on mineral homeostasis. Pediatr Res. . 1982;16:75–78.[PubMed][Google Scholar]
82. Holick M.FThe vitamin D epidemic and its health consequences. J. Nutr. . 2005;135:2739S–2748S.[PubMed][Google Scholar]
83. Dawson-Hughes B., et al Estimates of optimal vitamin D status [editorial]. Osteoporos. Int. 2005;16:713–716.[PubMed][Google Scholar]
84. Vieth R Why the optimal requirement for vitamin D₃ is probably much higher than what is officially recommended for adults. . J. Steroid Biochem. Mol. Biol. 2004;88–89:575–579.[PubMed][Google Scholar]
85. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. 1997. Vitamin D. InDietary reference intakes. Chapter 7. National Academy Press. Washington, DC, USA. 250–287. [PubMed]
86. Shah B.R., Finberg LSingle-dose therapy for nutritional vitamin D deficiency rickets: a preferred method. J. Pediatr. 1994;125:487–490.[PubMed][Google Scholar]
87. Hollis B.W., Wagner C.LAssessment of dietary vitamin D requirements during pregnancy and lactation. Am. J. Clin. Nutr. 2004;79:717–726.[PubMed][Google Scholar]
88. Aris R.M., et al Guide to bone health and disease in cystic fibrosis. J. Clin. Endocrinol. Metab. . 2005;90:1888–1896.[PubMed][Google Scholar]
89. Brot C., et al Vitamin D status and its adequacy in healthy Danish perimenopausal women: relationships to dietary intake, sun exposure and serum parathyroid hormone. Br. J. Nutr. . 2001;86:1–11.[PubMed][Google Scholar]
90. Hollis B.W., Wagner C.LVitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant. Am. J. Clin. Nutr. 2004;80(Suppl. 6):1752S–1758S.[PubMed][Google Scholar]
91. Simpson R.U., Thomas G.A., Arnold A.JIdentification of 1,25-dihydroxyvitamin D, receptors and activities in muscle. J. Biol. Chem. . 1985;260:8882–8891.[PubMed][Google Scholar]
92. Bischoff-Ferrari H.A., et al Effect of vitamin D on falls: a meta-analysis. JAMA. . 2004;291:1999–2006.[PubMed][Google Scholar]
93. Black P.N., Scragg RRelationship between serum 25-hydroxyvitamin D and pulmonary function in the Third National Health and Nutrition Examination Survey. Chest. . 2005;128:3792–3798.[PubMed][Google Scholar]
94. Camargo C.A. , et al2006Prospective study of maternal intake of vitamin D during pregnancy and risk of wheezing illness in children at age 2 years [abstract]. J. Allergy Clin. Immunol. 117721–722. [PubMed][Google Scholar]
95. Spina C., et al Colon cancer and solar ultraviolet B radiation and prevention and treatment of colon cancer in mice with vitamin D and its Gemini analogs. J. Steroid Biochem. Mol. Biol. 2005;97:111–120.[PubMed][Google Scholar]
96. Feldman D., Zhao X.Y., Krishnan A.VEditorial/mini-review: vitamin D and prostate cancer. Endocrinology. . 2000;141:5–9.[PubMed][Google Scholar]
97. Grant W.B. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. . 2002;94:1867–1875.[PubMed]
98. Grant W.B., Holick M.FBenefits and requirements of vitamin D for optimal health: a review. Altern. Med. Rev. . 2005;10:94–111.[PubMed][Google Scholar]
99. Gorham E.D., et al Vitamin D and prevention of colorectal cancer. J. Steroid Biochem. Mol. Biol. 2005;97:179–194.[PubMed][Google Scholar]
100. Chang E.T., et al Family history of hematopoietic malignancy and risk of lymphoma. J. Natl. Cancer Inst. . 2005;97:1466–1474.[PubMed][Google Scholar]
101. Berwick M., et al 2005Sun exposure and mortality from melanoma . J. Natl. Cancer Inst. 97195–199. [[PubMed][Google Scholar]
102. McGrath JDoes ‘imprinting’ with low prenatal vitamin D contribute to the risk of various adult disorders? Med. Hypotheses. . 2001;56:367–371.[PubMed][Google Scholar]
103. Hernán M.A., Olek M.J., Ascherio AGeographic variation of MS incidence in two prospective studies of US women. Neurology. . 1999;51:1711–1718.[PubMed][Google Scholar]
104. Ponsonby A.L., McMichael A., van der Mei IUltraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology. . 2002;181–182:71–78.[PubMed][Google Scholar]
105. Hypponen E., Laara E., Jarvelin M.-R., Virtanen S.MIntake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. . 2001;358:1500–1503.[PubMed][Google Scholar]
106. Cantorna M.T., Zhu Y., Froicu M., Wittke A Vitamin D status, 1,25-dihydroxyvitamin D₃ , and the immune system. . Am. J. Clin. Nutr. . 2004;80(Suppl.):1717S–1720S.[PubMed][Google Scholar]
107. Stene L.C., Joner G., and Norwegian Childhood Diabetes Study Group 2003Use of cod liver oil during th e first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am. J. Clin. Nutr. 781128–1134. [[PubMed][Google Scholar]
108. Mathieu C., Adorini L The coming of age of 1,25-dihydroxyvitamin D₃ analogs as immunomodulatory agents. . Trends Mol. Med. . 2002;8:174–179.[PubMed][Google Scholar]
109. Chiu K.C., Chu A., Go V.L.W., Saad M.FHypovitaminosis D is associated with insulin resistance and β cell dysfunction. Am. J. Clin. Nutr. . 2004;79:820–825.[PubMed][Google Scholar]
110. Rostand S.GUltraviolet light may contribute to geographic and racial blood pressure differences. Hypertension. 1979;30:150–156.[PubMed][Google Scholar]
111. Zittermann A., et al Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J. Am. Coll. Cardiol. . 2003;41:105–112.[PubMed][Google Scholar]
112. Li Y., et al 1,25-dihydroxyvitamin D₃ is a negative endocrine regulator of the renin-angiotensin system. . J. Clin. Invest. . 2002;110:229–238. doi: 10.1172/JCI200215219.] [[Google Scholar]
113. Krause R., Buhring M., Hopfenmuller W., Holick M.F., Sharma A.MUltraviolet B and blood pressure. Lancet. 1998;352:709–710.[PubMed][Google Scholar]
114. Holick M.F. , 2005Vitamin D for health and in chronic kidney disease. Semin. Dial. 18266–275. [[PubMed]
115. Bikle, D.D. 2005. Vitamin D: role in skin and hair. InVitamin D. 2nd edition. D. Feldman, J.W. Pike, and F.H. Glorieux, editors. Elsevier Academic Press. Boston, Massachusetts, USA. 609–630. [PubMed]
116. Schwartz G.G., Whitlatch L.W., Chen T.C., Lokeshwar B.L., Holick M.F Human prostate cells synthesize 1,25-dihydroxyvitamin D₃ from 25-hydroxyvitamin D_3.. Cancer Epidemiol. Biomarkers Prev. 1998;7:391–395.[PubMed][Google Scholar]
117. Rachez C., Freedman L.P Mechanisms of gene regulation by vitamin D₃ receptor: a network of coactivator interactions. . Gene. 2000;246:9–21.[PubMed][Google Scholar]
118. Liu P.T., et al Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;3:1770–1773.[PubMed][Google Scholar]
119. Krause, R., et al. 1999. Suberythemal UV–irradiation increases immunological capacity in children with frequent cold. InBiological effects of light 1998: proceedings of a symposium, Basel, Switzerland, November 1–3, 1998. Basel, Switzerland. M.F. Holick and E.G. Jung, editors. Kluwer Academic Publishers. Boston, Massachusetts, USA. 49–51. [PubMed]
120. Kreiter S.R., et al Nutritional rickets in African American breast-fed infants. J. Pediatr. 2000;137:153–157.[PubMed][Google Scholar]
121. Morley R., Carlin J.B., Pasco J.A., Wark J.DMaternal 25-hydroxyvitamin D and parathyroid hormone concentrations and offspring birth size. J. Clin. Endocrinol. Metab. . 2006;91:906–912.[PubMed][Google Scholar]
122. Jones G., Dwyer TBone mass in prepubertal children: gender differences and the role of physical activity and sunlight exposure. J. Clin. Endocrinol. Metab. . 1998;83:4274–4279.[PubMed][Google Scholar]
123. . British Pediatric Association 1956Hypercalcemia in infants and vitamin D. Br. Med. J.2149–151. [PubMed][Google Scholar]
124. Gartner L.M., Greer F.R., Section on Breastfeeding, and Committee on Nutrition, American Academy of Pediatrics Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics. 2003;111:908–910.[PubMed][Google Scholar]
125. Kennedy C., Basidik C.D., Willemze R., de Gruiil F.R., Bavinck J.NThe influence of painful sunburns and lifetime of sun exposure on the risk of actinic keratoses, seborrheic warts, melanocytic nevi, atypical nevi, and skin cancer. J. Invest. Dermatol. . 2003;120:1087–1093.[PubMed][Google Scholar]
126. Gamgee, K.M.L. 1927. The artificial light treatment of children in rickets, anaemia & malnutrition. P.B. Hoeber Inc. New York, New York, USA. 172 pp. [PubMed]