Advances in Pediatrics

Shedding Light on Hypovitaminosis D and Rickets

      In 1966, in an article entitled The Disappearance of Rickets, Harrison reported that vitamin D deficiency rickets had become so rare as to be a “medical curiosity” in children [
      • Harrison H.E.
      The disappearance of rickets.
      ]. A number of reports suggest, however, that the recent worldwide prevalence of the disease is increasing [
      • Calikoglu A.S.
      • Davenport M.S.
      Prophylactic vitamin D supplementation.
      ]. In the United States, over 100 cases of rickets have been reported in the last 10 years. These occur primarily in dark-skinned, breast-feeding infants and toddlers with little sun exposure whose intake of dietary vitamin D is low. Not infrequently, they are exclusively breast fed by a mother who receives insufficient dietary vitamin D from milk, meat, eggs, or fish, or who ingests an unsupplemented vegetarian diet [
      • Bhowmick S.K.
      • Johnson K.R.
      • Rettig K.R.
      Rickets caused by vitamin D deficiency in breast-fed infants in the southern United States.
      • Pugliese M.T.
      • Blumberg D.L.
      • Hludzinski J.
      • et al.
      Nutritional rickets in suburbia.
      ]. Hypovitaminosis D is also common in older children, adults, and the elderly. Vitamin D deficiency may also result from malabsorptive conditions, such as celiac disease, biliary obstruction, gastric resection, or pancreatic insufficiency, as well as from accelerated metabolism by anticonvulsants, such as phenytoin, that degrade vitamin D to rapidly excreted water-soluble forms.
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        • Harrison H.E.
        The disappearance of rickets.
        Am J Public Health. 1966; 56: 734-737
        • Calikoglu A.S.
        • Davenport M.S.
        Prophylactic vitamin D supplementation.
        in: Hochberg Z. Vitamin D and rickets, Endocr Dev, vol 6. Karger, Basel (Switzerland)2003: 233-258
        • Bhowmick S.K.
        • Johnson K.R.
        • Rettig K.R.
        Rickets caused by vitamin D deficiency in breast-fed infants in the southern United States.
        Am J Dis Child. 1991; 145: 127-130
        • Pugliese M.T.
        • Blumberg D.L.
        • Hludzinski J.
        • et al.
        Nutritional rickets in suburbia.
        J Am Coll Nutr. 1998; 17: 637-641
        • Mozolowski W.
        Jedrzej Sniadecki (1768–1838) on the cure of rickets.
        Nature. 1939; 143: 121-124
        • Holick M.F.
        Resurrection of vitamin D deficiency and rickets.
        J Clin Invest. 2006; 116: 2062-2072
      1. Hochberg Z. Vitamin D and rickets. Karger, Basel (Switzerland)2003
        • Holick M.F.
        Vitamin D: photobiology, metabolism, mechanism of action and clinical applications.
        in: Favus M. Primer of the metabolic bone diseases and disorders of mineral metabolism. 4th edition. Lippincott Williams and Wilkins, Philadelphia1999: 92-98
      2. Standing Committee on the scientific evaluation of dietary reference intakes: National Academy of Sciences and Food and Nutrition Board.
        National Academy Press, Washington, DC1997
        • Levine N.A.
        Normal mineral homeostasis.
        in: Hochberg Z. Vitamin D and rickets. Karger, Basel (Switzerland)2003: 14-33
        • Holick M.F.
        Vitamin D: photobiology, metabolism and clinical applications.
        in: DeGroot L. Besser H. Burger H.G. Endocrinology. 3rd edition. WB Saunders, Philadelphia1995: 990-1013
        • Bailie G.R.
        • Johnson C.A.
        Comparative review of the pharmacokinetics of vitamin D analogues.
        Semin Dial. 2002; 15: 352-357
        • Armas L.A.G.
        • Hollis B.W.
        • Heaney R.P.
        Vitamin D2 is much less effective than vitamin D3 in humans.
        J Clin Endocrinol Metab. 2004; 29: 5387-5391
        • Holick M.F.
        • Matsuoka L.Y.
        • Wortsman J.
        Age, vitamin D, and solar ultraviolet radiation.
        Lancet. 1989; 4: 1104-1105
        • Holick M.F.
        • Vitamin D.
        New horizons for the 21st century.
        Am J Clin Nutr. 1994; 60: 619-630
        • Root A.W.
        • Diamond Jr., F.B.
        Calcium metabolism.
        in: Sperling Pediatric endocrinology. 2nd edition. Saunders, Philadelphia2002: 65-95
        • Murayama A.
        • Takeyama K.
        • Kitanaka S.
        • et al.
        Positive and negative regulations of the renal 25-hydroxyvitamin D3 l-alpha-hydoxylase gene by parathyroid hormone, calcitonin and l-alpha 25(OH)2D3 in intact animals.
        Endocrinology. 1999; 140: 2224
        • Kumar R.
        Vitamin D metabolism and mechanism of calcium transport.
        J Am Soc Nephrol. 1990; 1: 30
        • Malloy P.J.
        • Pike J.W.
        • Feldman D.
        The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets.
        Endocr Rev. 1999; 20: 156
        • Keen R.W.
        • Egger P.
        • Fall C.
        • et al.
        Polymorphisms of the vitamin D receptor, infant growth, and adult bone mass.
        Calcif Tissue Int. 1997; 60: 233
        • Suda T.
        • Takahashi N.
        • Udagawa N.
        • et al.
        Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families.
        Endocr Rev. 1999; 20: 345
        • Escarot B.
        • Desbarats M.
        1,25-(OH)2D3 down-regulates expression of PHEX, a marker of the mature osteoblast.
        Endocrinology. 1999; 140: 1192
        • Holick M.F.
        Vitamin D: a millennium perspective.
        J Cell Biochem. 2003; 88: 296-307
        • Byers P.H.
        Disorders of collagen biosynthesis and structure.
        in: Scrier C.R. Beaudet A.L. Sly W.S. The metabolic and molecular bases of inheritied disease. 7th edition. McGraw-Hill, New York1995: 4029-4077
        • Schinke T.
        • McKee M.D.
        • Karsenty G.
        Extracellular matrix calcification: where is the action?.
        Nat Genet. 1999; 21: 150
        • Mankin H.J.
        Rickets, osteomalacia, and renal osteodystrophy part l.
        J Bone Joint Surg Am. 1974; 56: 101-128
        • Rauch F.
        The rachitic bone.
        in: Hochberg Z. Vitamin D and rickets. Karger, Basel (Switzerland)2003: 69-79
        • Callaghan A.
        • Booth I.W.
        • RGDk Moy
        • et al.
        Rickets returns.
        Arch Dis Child. 2002; 86: A35
        • Shaw N.J.
        Vitamin D deficiency rickets.
        in: Hochberg Z. Vitamin D and rickets, Endocr Dev, vol 6. Karger, Basel (Switzerland)2003: 93-104
        • Kreiter S.R.
        • Schwartz R.P.
        • Kirkman Jr., H.N.
        • et al.
        Nutritional rickets in African American breast-fed infants.
        J Pediatr. 2000; 137: 153
        • Muhe L.
        • Lulseged S.
        • Mason K.E.
        • et al.
        Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children.
        Lancet. 1997; 349: 1801-1804
        • Narchi H.
        • Jamil M.E.
        • Kulaylat N.
        Symptomatic rickets in adolescence.
        Arch Dis Child. 2001; 84: 501-503
        • Pettifor J.M.
        Rickets and vitamin D deficiency in children and adolescents.
        Endocrinol Metab Clin North Am. 2005; 34: 537-553
        • Baroncelli G.I.
        • Bertelloni S.
        • Ceccarelli C.
        • et al.
        Bone turnover in children with vitamin D deficiency rickets before and during treatment.
        Acta Paediatr. 2000; 89: 513
        • States L.J.
        Imaging of rachitic bone.
        in: Hochberg Z. Vitamin D and Rickets, Endocr Dev, vol 6. Karger, Basel (Switzerland)2003: 80-92
        • Schneider R.
        Radioloic methods of evaluating generalized osteopenia. Symposium on metabolic bone diseases.
        Orthop Clin North Am. 1984; 15: 631-651
        • Bass J.K.
        • Chan G.M.
        Calcium nutrition and metabolism during infancy.
        Nutrition. 2006; 22: 1057-1066
        • Tomlinson C.
        • McDevitt H.
        • Ahmed S.F.
        • et al.
        Longitudinal changes in bone health as assessed by the speed of sound in very low birth weight preterm infants.
        J Pediatr. 2006; 148: 450-455
        • van der Meer I.M.
        • Karamali N.S.
        • Boeke J.P.
        • et al.
        High prevalence of vitamin D deficiency in pregnant non-western women in the Hague, Netherlands.
        Am J Clin Nutr. 2006; 84: 350-353
        • Sachan A.
        • Gupta R.
        • Das V.
        • et al.
        High prevalence of vitamin D deficiency among pregnant women and their newborns in northern India.
        Am J Clin Nutr. 2005; 81: 1060-1064
        • Ainy E.
        • Ghazi A.A.
        • Azizi F.
        Changes in calcium, 25(OH) vitamin D3 and other biochemical factors during pregnancy.
        J Endocrinol Invest. 2006; 29: 303-307
        • Fogelman Y.
        • Rakover Y.
        • Luboshitzky R.
        High prevalence of vitamin D deficiency among Ethiopian women immigrants to Israel: exacerbation during pregnancy and lactation.
        Isr J Med Sci. 1995; 31: 221-224
        • Mohaptra A.
        • Sankaranaryanan K.
        • Kadam S.S.
        • et al.
        Congenital rickets.
        J Trop Pediatr. 2003; 49: 126-127
        • Anatoliotaki M.
        • Tsilimigaki A.
        • Tsekoura T.H.
        • et al.
        Congenital rickets due to maternal vitamin D deficiency in a sunny island of Greece.
        Acta Paediatr. 2003; 92: 389-391
        • Javaid M.K.
        • Crozier S.R.
        • Harvey N.C.
        • et al.
        Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study.
        Lancet. 2006; 367: 36-43
        • Weiler H.
        • Fitzpatrick-Wong S.
        • Veitch R.
        • et al.
        Vitamin D deficiency and a whole-body and femur bone mass relative to weight in healthy newborns.
        CMAJ. 2005; 172: 757-761
        • Diamond Jr., F.B.
        • Root A.W.
        Disorders of calcium metabolism in the newborn and infant.
        in: Sperling M.A. Pediatric endocrinology. 2nd edition. Saunders, Philadelphia2002: 97-100
        • Weisman Y.
        Maternal, fetal and neonatal vitamin D and calcium metabolism during pregnancy and lactation.
        in: Hochberg Z. Vitamin D and rickets, Endocr Dev, vol 6. Karger, Basel (Switzerland)2003: 34-49
        • Hillman L.S.
        • Haddad J.G.
        Human perinatal vitamin D metabolism I: 25-hydroxyvitamin D in maternal and cord blood.
        J Pediatr. 1974; 84: 742-749
        • Kalwarf H.J.
        • Specker B.L.
        • Bianchi D.C.
        • et al.
        The effect of calcium supplementation on bone density during lactation and after weaning.
        N Engl J Med. 1997; 337: 523-528
        • Hollis B.W.
        • Wagner C.L.
        Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for the mother and the nursing infant.
        Am J Clin Nutr. 2004; 80: 1752S-1758S
        • Henderson A.
        Vitamin D and the breastfed infant.
        J Obstet Gynecol Neonatal Nurs. 2005; 34: 367-372
        • Pettifor J.M.
        Nutritional rickets: deficiency of vitamin D, calcium, or both?.
        Am J Clin Nutr. 2004; 80: 1725S-1729S
        • Specker B.L.
        • Valanis B.
        • Hertzberg V.
        • et al.
        Sunshine exposure and serum 25-hydroxyvitamin D concentrations in exclusively breast-fed infants.
        J Pediatr. 1985; 107: 372-376
        • Committee on environmental health
        Ultraviolet light: a hazard to children.
        Pediatrics. 1999; 104: 328-333
        • Gartner L.M.
        • Geer F.R.
        • the Section on Breastfeeding and Committee on Nutrition
        Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake.
        Pediatrics. 2003; 111: 908-910
        • Rauch F.
        • Schoenau E.
        Skeletal development in premature infants: a review of bone physiology beyond nutritional aspects.
        Arch Dis Child Fetal Neonatal Ed. 2002; 86: F82-F85
        • Trindade C.E.
        Minerals in the nutrition of extremely low birth weight infants.
        J Pediatri (Rio J). 2005; 81: S43-S51
        • Sullivan S.S.
        • Rosen C.J.
        • Chen T.C.
        • et al.
        Seasonal changes in 25(OH)D in adolescent girls in Maine.
        J Bone Miner Res. 2003; 18: 407
        • Reeves G.D.
        • Bachrach S.
        • Carpenter T.O.
        • et al.
        Vitmain D deficiency rickets in adopted children from the former Soviet Union: an uncommon problem with unusual clinical and biochemical features.
        Pediatrics. 2000; 106: 1484-1488
        • Guillemenat J.
        • Le H.-T.
        • Maia A.
        • et al.
        Wintertime vitamin D deficiency in male adolescents: effect on parathyroid function and response to vitamin D3 supplements.
        Osteoporos Int. 2001; 12: 8765-8769
        • Meulmeester J.F.
        • van den Berg H.
        • Wedel M.
        • et al.
        Vitamin D status, parathyroid hormone and sunlight in Turkish, Moroccan and Caucasian children in the Netherlands.
        Eur J Clin Nutr. 1990; 44: 461-470
        • Hochberg Z.
        • Bereket A.
        • Davenport M.
        • et al.
        Consensus development for the supplementation of Vitamin D in childhood and adolescence.
        in: Hochberg Z. Vitamin D and rickets, Endocr Dev, vol 6. Karger, Basel (Switzerland)2003: 259-281
        • Kooh S.W.
        • Fraser D.
        • Reilly B.J.
        • et al.
        Rickets due to calcium deficiency.
        N Engl J Med. 1977; 297: 1264-1266
        • Thacher T.D.
        • Glew R.H.
        • Isichei C.O.
        • et al.
        Rickets in Nigerian children: response to calcium supplementation.
        J Trop Pediatr. 1999; 45: 202-207
        • Rigo J.
        • De Curtis M.
        • Pieltain C.
        • et al.
        Bone mineral metabolism in the micropremie.
        Clin Perinatol. 2000; 27: 147
        • Prentice A.
        • Barclay D.V.
        Breast-milk calcium and phosphorus concentrations of mothers in rural Zaire.
        Eur J Clin Nutr. 1991; 45: 611-617
        • Legius E.
        • Proesmans W.
        • Eggermont E.
        • et al.
        Rickets due to dietary calcium deficiency.
        Eur J Pediatr. 1989; 148: 784-785
        • Bachrach L.K.
        • Hastie T.
        • Wang M.-C.
        • et al.
        Bone mineral acquisition in healthy Asian Hispanic, black and Caucasian youth: a longitudinal study.
        J Clin Endocrinol Metab. 1999; 84: 4702
        • Bailey D.A.
        • McKAy H.A.
        • Mirwald R.L.
        • et al.
        A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: The University of Saskatchewan bone mineral accrual study.
        J Bone Miner Res. 1999; 14: 1672
        • Chesney R.W.
        Vitamin D deficiency and rickets.
        Rev Endocr Metab Disord. 2001; 2: 145-151
        • Pettifor J.M.
        • Ross P.
        • Wang J.
        • et al.
        Rickets in children of rural origin in South Africa: is low dietary calcium a factor?.
        J Pediatr. 1978; 92: 320-324
        • Oginni L.M.
        • Worsfold M.
        • Oyelami O.A.
        • et al.
        Etiology of rickets in Nigerian children.
        J Pediatr. 1996; 128: 692-694
        • Thacher T.D.
        • Fischer P.R.
        • Pettifor J.M.
        • et al.
        A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children.
        N Engl J Med. 1999; 341: 563-568
        • Oginni L.M.
        • Sharp Ca
        • Worsfold M.
        • et al.
        Healing of rickets after calcium supplementation.
        Lancet. 1999; 353: 296-297
        • Clements M.R.
        • Johnson L.
        • Fraser D.R.
        A new mechanism for induced vitamin D deficiency in calcium deprivation.
        Nature. 1987; 325: 62-65
        • Halloran B.P.
        • Bikie D.D.
        • Levens M.J.
        • et al.
        Chronic 1,25-Dihydroxyvitamin D3 administration in the rat reduces the serum concentration of 25-hydroxyvitamin D by increasing metabolic clearance rate.
        J Clin Invest. 1986; 78: 622-628
        • Steinbock R.T.
        Rickets and osteomalacia in the Cambridge world history of human disease.
        Cambridge Press, 1993 (p. 978–80)
        • Garabedian M.
        • Ben Mekhbi H.
        Rickets and vitamin D deficiency.
        in: Holick M.F. Vitamin D physiology, molecular biology and clinical applications. Humana Press, Totowa (NJ)1999: 273-286
        • Looker A.C.
        • Dawson-Huges B.
        • Calvo M.S.
        • et al.
        Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III.
        Bone. 2002; 30: 708-714
        • Chesney R.W.
        Requirements and upper limits of vitamin D intake in the term neonate, infant and older child.
        J Pediatr. 1990; 116: 159
        • Root A.W.
        • Diamond Jr., F.B.
        Disorders of calcium metabolism in the child and adolescent.
        in: Sperling Pediatric endocrinology. 2nd edition. Saunders, Philadelphia2002: 629-669
        • Holick M.F.
        Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis.
        Am J Clin Nutr. 2004; 79: 362-371
        • Holick M.F.
        Vitamin D: its role in cancer prevention and treatment.
        Biophys and Mol Biol. 2006; 92: 49-59
        • Dalhoff K.
        • Dancy J.
        • Astrup L.
        • et al.
        A phase II study of the vitamin D analogue seocalcitol in patients with inoperable hepatocellular carcinoma.
        Br J Cancer. 2003; 89: 252-257
        • Hypponen E.
        • Laara E.
        • Reunanen A.
        • et al.
        Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study.
        Lancet. 2001; 358: 1500-1503