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Questions Remain About Vitamin D

      To the Editors:
      I read with great interest the recent article in the Journal: “Recommended Vitamin D Intake and Management of Low Vitamin D Status in Adolescents: A Position Statement of the Society for Adolescent Health and Medicine” [
      • Harel Z.
      • Cromer B.
      • DiVasta A.D.
      • Gordon C.M.
      Recommended vitamin D intake and management of low vitamin D status in adolescents: A position statement of the Society for Adolescent Health and Medicine.
      ].
      Although I agree with the essence of the position statement and use vitamin D supplementation in appropriate clinical situations, clinicians should be aware that there are several caveats that need to be addressed.
      Vitamin D has become a hot topic in the past 3–5 years, but a true understanding of the interpretation of vitamin D levels is still in its infancy.
      The following list exemplifies the problematic issues:
      • 1.
        Vitamin D levels are not to be interpreted in the same manner as electrolyte levels. Vitamin D must be viewed as more similar to other steroid hormones because it is also influenced by a binding protein—vitamin D binding protein (VDBP). Variations in VDBP have been well documented [
        • Fang Y.
        • van Meurs J.B.
        • Arp P.
        • et al.
        Vitamin D binding protein genotype and osteoporosis.
        ,
        • Fu L.
        • Yun F.
        • Oczak M.
        • et al.
        Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation.
        ,
        • Sinotte M.
        • Diorio C.
        • Bérubé S.
        • et al.
        Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women.
        ]. These differences influence the response to exogenous vitamin D.
      • 2.
        What qualifies as a normal vitamin D level is still open to debate, especially in children and adolescents [
        • Greer F.R.
        Defining vitamin D deficiency in children: Beyond 25-OH vitamin D serum concentrations.
        ].
      • 3.
        Large, randomized control studies in children and adolescents are lacking, especially longitudinally [
        • Greer F.R.
        Defining vitamin D deficiency in children: Beyond 25-OH vitamin D serum concentrations.
        ].
      • 4.
        In studies of adults, the major end point for interpretation of results is fracture rate or osteoporosis rate. Similar end points are rarely described in studies of youth [
        • Misra M.
        • Pacaud D.
        • Petryk A.
        • et al.
        Vitamin D deficiency in children and its management: Review of current knowledge and recommendations.
        ].
      • 5.
        Rickets, an accepted marker of vitamin D deficiency, has been documented to occur at vitamin D levels that are considered normal [
        • DeLucia M.C.
        • Mitnick M.E.
        • Carpenter T.O.
        Nutritional rickets with normal circulating 25-hydroxyvitamin D: A call for reexamining the role of dietary calcium intake in North American infants.
        ].
      • 6.
        In a study of 93 young adult Hawaiian sun worshipers not using sunscreen, 51% had vitamin D levels below 30 ng/mL (75 nmol/L), the minimal level considered to be adequate [
        • Binkley N.
        • Novotny R.
        • Krueger D.
        • et al.
        Low vitamin D status despite abundant sun exposure.
        ].
      • 7.
        In a study of 58 obese adolescents (body mass index, >95% for age), 29% had vitamin D levels below 20 ng/mL (deficient) but none had elevated parathyroid hormone levels (a marker of inadequacy of vitamin D) and none had bone mineral densities that were deficient [
        • Lenders C.M.
        • Feldman H.A.
        • Von Scheven E.
        • et al.
        Relation of body fat indexes to vitamin D status and deficiency among obese adolescents.
        ].
      • 8.
        Genetic issues: Just as there are variations in VDBP, there are variations in the vitamin D receptor and genetic polymorphisms that relate to bone mineral density and osteoporosis. Studies indicate that variations in VDBP and vitamin D receptor have a role in susceptibility to rickets and bone disease [
        • Fischer P.R.
        • Thacher T.D.
        • Pettifor J.M.
        • et al.
        Vitamin D receptor polymorphisms and nutritional rickets in Nigerian children.
        ,
        • Ames S.K.
        • Ellis K.J.
        • Gunn S.K.
        • et al.
        Vitamin D receptor gene Fok1 polymorphism predicts calcium absorption and bone mineral density in children.
        ].
      • 9.
        Accuracy of measurement of 25(OH) vitamin D: There is no reference standard as yet, but chromatographic techniques such as high-performance liquid chromatography and liquid chromatography-tandem mass spectroscopy are superior to immunochemical and competitive protein-binding assays. Thus, any single number cutoff for “normal” is questionable [
        • Binkley N.
        • Krueger D.
        • Lensmeyer G.
        25-hydroxyvitamin D measurement, 2009: A review for clinicians.
        ].
      • 10.
        Finally, recommendations regarding calcium intake were not mentioned. Adequate calcium intake is needed along with vitamin D to accomplish good bone health [
        • Misra M.
        • Pacaud D.
        • Petryk A.
        • et al.
        Vitamin D deficiency in children and its management: Review of current knowledge and recommendations.
        ].
      I urge the Society for Adolescent Health and Medicine to help develop a collaborative multicenter, randomized control study of vitamin D and calcium metabolism in normal adolescents on a longitudinal basis addressing the above issues. Only in this way can a better understanding of what is truly normal and when and how to intervene in growing adolescents be derived.

      References

        • Harel Z.
        • Cromer B.
        • DiVasta A.D.
        • Gordon C.M.
        Recommended vitamin D intake and management of low vitamin D status in adolescents: A position statement of the Society for Adolescent Health and Medicine.
        J Adolesc Health. 2013; 52: 801-803
        • Fang Y.
        • van Meurs J.B.
        • Arp P.
        • et al.
        Vitamin D binding protein genotype and osteoporosis.
        Calcif Tissue Int. 2009; 85: 85-93
        • Fu L.
        • Yun F.
        • Oczak M.
        • et al.
        Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation.
        Clin Biochem. 2009; 42: 1174-1177
        • Sinotte M.
        • Diorio C.
        • Bérubé S.
        • et al.
        Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women.
        Am J Clin Nutr. 2009; 89: 634-640
        • Greer F.R.
        Defining vitamin D deficiency in children: Beyond 25-OH vitamin D serum concentrations.
        Pediatrics. 2009; 124: 1471-1473
        • Misra M.
        • Pacaud D.
        • Petryk A.
        • et al.
        Vitamin D deficiency in children and its management: Review of current knowledge and recommendations.
        Pediatrics. 2008; 122: 398-417
        • DeLucia M.C.
        • Mitnick M.E.
        • Carpenter T.O.
        Nutritional 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
        • Binkley N.
        • Novotny R.
        • Krueger D.
        • et al.
        Low vitamin D status despite abundant sun exposure.
        J Clin Endocrinol Metab. 2007; 92: 2130-2135
        • Lenders C.M.
        • Feldman H.A.
        • Von Scheven E.
        • et al.
        Relation of body fat indexes to vitamin D status and deficiency among obese adolescents.
        Am J Clin Nutr. 2009; 90: 459-467
        • Fischer P.R.
        • Thacher T.D.
        • Pettifor J.M.
        • et al.
        Vitamin D receptor polymorphisms and nutritional rickets in Nigerian children.
        J Bone Miner Res. 2000; 15: 2206-2210
        • Ames S.K.
        • Ellis K.J.
        • Gunn S.K.
        • et al.
        Vitamin D receptor gene Fok1 polymorphism predicts calcium absorption and bone mineral density in children.
        J Bone Miner Res. 1999; 14: 740-746
        • Binkley N.
        • Krueger D.
        • Lensmeyer G.
        25-hydroxyvitamin D measurement, 2009: A review for clinicians.
        J Clin Densitom. 2009; 12: 417-427