High Prevalence of Vitamin D Inadequacy and Implications for Health

During the past decade, major advances have been made in vitamin D research that transcend the simple concept that vitamin D is important for the prevention of rickets in children and has little physiologic relevance for adults. Inadequate vitamin D, in addition to causing rickets, prevents children from attaining their genetically programmed peak bone mass, contributes to and exacerbates osteoporosis in adults, and causes the often painful bone disease osteomalacia. Adequate vitamin D is also important for proper muscle functioning, and controversial evidence suggests it may help prevent type 1 diabetes mellitus, hypertension, and many common cancers. Vitamin D inadequacy has been reported in approximately 36% of otherwise healthy young adults and up to 57% of general medicine inpatients in the United States and in even higher percentages in Europe. Recent epidemiological data document the high prevalence of vitamin D inadequacy among elderly patients and especially among patients with osteoporosis. Factors such as low sunlight exposure, age-related decreases in cutaneous synthesis, and diets low in vitamin D contribute to the high prevalence of vitamin D inadequacy. Vitamin D production from cutaneous synthesis or intake from the few vitamin D-rich or enriched foods typically occurs only intermittently. Supplemental doses of vitamin D and sensible sun exposure could prevent deficiency in most of the general population. The purposes of this article are to examine the prevalence of vitamin D inadequacy and to review the potential implications for skeletal and extraskeletal health. During the past decade, major advances have been made in vitamin D research that transcend the simple concept that vitamin D is important for the prevention of rickets in children and has little physiologic relevance for adults. Inadequate vitamin D, in addition to causing rickets, prevents children from attaining their genetically programmed peak bone mass, contributes to and exacerbates osteoporosis in adults, and causes the often painful bone disease osteomalacia. Adequate vitamin D is also important for proper muscle functioning, and controversial evidence suggests it may help prevent type 1 diabetes mellitus, hypertension, and many common cancers. Vitamin D inadequacy has been reported in approximately 36% of otherwise healthy young adults and up to 57% of general medicine inpatients in the United States and in even higher percentages in Europe. Recent epidemiological data document the high prevalence of vitamin D inadequacy among elderly patients and especially among patients with osteoporosis. Factors such as low sunlight exposure, age-related decreases in cutaneous synthesis, and diets low in vitamin D contribute to the high prevalence of vitamin D inadequacy. Vitamin D production from cutaneous synthesis or intake from the few vitamin D-rich or enriched foods typically occurs only intermittently. Supplemental doses of vitamin D and sensible sun exposure could prevent deficiency in most of the general population. The purposes of this article are to examine the prevalence of vitamin D inadequacy and to review the potential implications for skeletal and extraskeletal health. During the past decade, important advances in the study of vitamin D have been made. In addition to its important role in skeletal development and maintenance, evidence is mounting that vitamin D produces beneficial effects on extraskeletal tissues and that the amounts needed for optimal health are probably higher than previously thought.1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar At the same time, numerous reports have shown that relatively high proportions of people have inadequate levels of vitamin D. The extraskeletal health benefits of vitamin D and high prevalence of inadequate levels of vitamin D have been largely unrecognized by both physicians and patients.2Grant WB Holick MF Benefits and requirements of vitamin D for optimal health: a review.Altern Med Rev. 2005; 10: 94-111PubMed Google Scholar The purposes of this review article are to examine the prevalence of vitamin D inadequacy as defined by low serum 25-hydroxyvitamin D (25[OH]D), the major circulating form of vitamin D and standard indicator of vitamin D status, and to review the potential implications on both skeletal and extraskeletal health. Solar UV-B (wavelengths of 290-315 nm) irradiation is the primary source of vitamin D (other than diet supplements) for most people.1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar, 3Holick MF Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.Curr Opin Endocrinol Diabetes. 2002; 9: 87-98Crossref Scopus (243) Google Scholar, 4Holick MF Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].Am J Clin Nutr. 2004; 79: 362-371PubMed Google Scholar Dietary sources of vitamin D are limited. They include oily fish such as salmon (approximately 400 IU per 3.5 oz), mackerel, and sardines; some fish oils such as cod liver oil (400 IU/tsp); and egg yolks (approximately 20 IU). Some foods are fortified in the United States, including milk (100 IU per 8 oz) and some cereals (100 IU per serving), orange juice (100 IU per 8 oz), some yogurts (100 IU per serving), and margarine.4Holick MF Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].Am J Clin Nutr. 2004; 79: 362-371PubMed Google Scholar, 5Tangpricha V Koutkia P Rieke SM Chen TC Perez AA Holick MF Fortification of orange juice with vitamin D: a novel approach to enhance vitamin D nutritional health.Am J Clin Nutr. 2003; 77: 1478-1483PubMed Google Scholar, 6Holick MF Shao Q Liu WW Chen TC The vitamin D content of fortified milk and infant formula.N Engl J Med. 1992; 326: 1178-1181Crossref PubMed Google Scholar Milk is not vitamin D enriched in most European countries; however, margarine and some cereals are. There are 2 forms of vitamin D. Vitamin D2 (ergocalciferol) comes from irradiation of the yeast and plant sterol ergosterol, and vitamin D3 (cholecalciferol) is found in oily fish and cod liver oil and is made in the skin. Vitamin D represents vitamin D2 and vitamin D3. Vitamin D from cutaneous synthesis or dietary sources typically occurs only intermittently. Irregular intake of vitamin D, irrespective of the source, can lead to chronic vitamin D inadequacy. This condition has been reported across all age groups, geographic regions, and seasons.7Gordon CM DePeter KC Feldman HA Grace E Emans SJ Prevalence of vitamin D deficiency among healthy adolescents.Arch Pediatr Adolesc Med. 2004; 158: 531-537Crossref PubMed Scopus (387) Google Scholar, 8Outila TA Karkkainen MU Lamberg-Allardt CJ Vitamin D status affects serum parathyroid hormone concentrations during winter in female adolescents: associations with forearm bone mineral density.Am J Clin Nutr. 2001; 74: 206-210PubMed Google Scholar, 9Chapuy MC Preziosi P Maamer M et al.Prevalence of vitamin D insufficiency in an adult normal population.Osteoporos Int. 1997; 7: 439-443Crossref PubMed Scopus (853) Google Scholar, 10Kinyamu HK Gallagher JC Rafferty KA Balhorn KE Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites.Am J Clin Nutr. 1998; 67: 342-348PubMed Google Scholar, 11Malabanan A Veronikis IE Holick MF Redefining vitamin D insufficiency [letter].Lancet. 1998; 351: 805-806Abstract Full Text Full Text PDF PubMed Google Scholar, 12Kauppinen-Mäkelin R Tähtelä R Löyttyniemi E Kärkkäinen J Välimäki MJ High prevalence of hypovitaminosis D in Finnish medical in- and outpatients.J Intern Med. 2001; 249: 559-563Crossref PubMed Scopus (53) Google Scholar, 13Looker AC Dawson-Hughes B Calvo MS Gunter EW Sahyoun NR Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III.Bone. 2002; 30: 771-777Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 14Lips P Duong T Oleksik A et al.A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].J Clin Endocrinol Metab. 2001; 86: 1212-1221Crossref PubMed Scopus (380) Google Scholar, 15Sullivan SS Rosen CJ Halteman WA Chen TC Holick MF Adolescent girls in Maine are at risk for vitamin D insufficiency.J Am Diet Assoc. 2005; 105: 971-974Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 16Holick M Jenkins M The UV Advantage. iBooks, NewYork, NY2003Google Scholar Enhancing vitamin D levels by taking supplements is usually necessary to achieve the minimum recommended daily intakes; however, compliance is often problematic. In particular, some groups who may be at high risk of vitamin D inadequacy often do not follow regular daily dosing guidelines. Adherence to vitamin D supplementation recommendations is low among elderly patients with osteoporosis. One study showed that, despite receiving counseling on the importance of vitamin D and calcium supplementation, 76% of elderly patients with hip fractures did not comply with recommendations.17Segal E Zinnman H Raz B Tamir A Ish-Shalom S Adherence to vitamin D supplementation in elderly patients after hip fracture [letter].J Am Geriatr Soc. 2004; 52: 474-475Crossref PubMed Scopus (19) Google Scholar This is not surprising given thatcompliance declines as the number of medications increases, and elderly patients often take many medications. Similarly, achieving adequate vitamin D intake through milk consumption is unreliable among elderly patients because of the high prevalence of lactose intolerance among this population and the often low levels of vitamin D in the milk supply.6Holick MF Shao Q Liu WW Chen TC The vitamin D content of fortified milk and infant formula.N Engl J Med. 1992; 326: 1178-1181Crossref PubMed Google Scholar UV-B irradiation of skin triggers photolysis of 7-dehydrocholesterol (provitamin D3) to previtamin D3 in the plasma membrane of human skin keratinocytes.18Holick MF McCollum Award Lecture, 1994: vitamin D—new horizons for the 21st century.Am J Clin Nutr. 1994; 60: 619-630Crossref PubMed Scopus (0) Google Scholar, 19MacLaughlin JA Anderson RR Holick MF Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin.Science. 1982; 216: 1001-1003Crossref PubMed Google Scholar, 20Holick MF Tian XQ Allen M Evolutionary importance for the membrane enhancement of the production of vitamin D3 in the skin of poikilothermic animals.Proc Natl Acad Sci U S A. 1995; 92: 3124-3126Crossref PubMed Scopus (0) Google Scholar Once formed in the skin, cell plasma membrane previtamin D3 is rapidly converted to vitamin D3 by the skin's temperature. Vitamin D3 from the skin and vitamin D from the diet undergo 2 sequential hydroxylations, first in the liver to 25(OH)D and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D (1,25[OH]2D) (Figure 1). Excessive solar UV-B irradiation will not cause vitamin D intoxication because excess vitamin D3 and previtamin D3 are photolyzed to biologically inactive photoproducts.19MacLaughlin JA Anderson RR Holick MF Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin.Science. 1982; 216: 1001-1003Crossref PubMed Google Scholar, 20Holick MF Tian XQ Allen M Evolutionary importance for the membrane enhancement of the production of vitamin D3 in the skin of poikilothermic animals.Proc Natl Acad Sci U S A. 1995; 92: 3124-3126Crossref PubMed Scopus (0) Google Scholar, 22Webb AR deCosta BR Holick MF Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation.J Clin Endocrinol Metab. 1989; 68: 882-887Crossref PubMed Google Scholar Melanin skin pigmentation is an effective natural sunscreen, and increased skin pigment can greatly reduce UV-B-mediated cutaneous synthesis of vitamin D3 by as much as 99%, similar to applying a sunscreen with a sun protection factor of 15.23Clemens TL Adams JS Henderson SL Holick MF Increased skin pigment reduces the capacity of skin to synthesise vitamin D3.Lancet. 1982; 1: 74-76Abstract PubMed Google Scholar, 24Matsuoka LY Ide L Wortsman J MacLaughlin JA Holick MF Sunscreens supress cutaneous vitamin D3 synthesis.J Clin Endocrinol Metab. 1987; 64: 1165-1168Crossref PubMed Google Scholar Keratinocytes are also capable of hydroxylating 25(OH)D to produce 1,25(OH)2D.25Bikle DD Vitamin D: role in skin and hair.in: Feldman D 2nd ed. Vitamin D. Vol 1. Elsevier Academic Press, San Diego, Calif2005: 609-630Google Scholar The 1,25(OH)2D (from keratinocyte or renal sources) may regulate keratinocyte differentiation, melanocyte apoptosis, and melanin production,25Bikle DD Vitamin D: role in skin and hair.in: Feldman D 2nd ed. Vitamin D. Vol 1. Elsevier Academic Press, San Diego, Calif2005: 609-630Google Scholar, 26Hosomi J Hosoi J Abe E Suda T Kuroki T Regulation of terminal differentiation of cultured mouse epidermal cells by 1 alpha, 25-dihydroxyvitamin D3.Endocrinology. 1983; 113: 1950-1957Crossref PubMed Google Scholar, 27Smith EL Walworth NC Holick MF Effect of 1α,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions.J Invest Dermatol. 1986; 86: 709-714Abstract Full Text PDF PubMed Google Scholar and this may be another mechanism for regulating the cutaneous synthesis of vitamin D3 by negative feedback. The 1,25(OH)2D ligand binds with high affinity to the vitamin D receptor (VDR) and triggers an increase in intestinal absorption of both calcium and phosphorus. In addition, vitamin D is involved in bone formation, resorption, and mineralization and in maintaining neuromuscular function1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar, 3Holick MF Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.Curr Opin Endocrinol Diabetes. 2002; 9: 87-98Crossref Scopus (243) Google Scholar (Figure 1). Circulating 1,25(OH)2D reduces serum parathyroid hormone (PTH) levels directly by decreasing parathyroid gland activity and indirectly by increasing serum calcium. The 1,25(OH)2D regulates bone metabolism in part by interacting with the VDR in osteoblasts to release biochemical signals, leading to formation of mature osteoclasts. The osteoclasts release collagenases and hydrochloric acid to dissolve the matrix and mineral, releasing calcium into the blood.1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar, 3Holick MF Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.Curr Opin Endocrinol Diabetes. 2002; 9: 87-98Crossref Scopus (243) Google Scholar, 4Holick MF Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].Am J Clin Nutr. 2004; 79: 362-371PubMed Google Scholar When vitamin D levels are inadequate, calcium and phosphorus homeostasis becomes impaired. Vitamin D is primarily responsible for regulating the efficiency of intestinal calcium absorption. In a low vitamin D state, the small intestine can absorb approximately 10% to 15% of dietary calcium. When vitamin D levels are adequate, intestinal absorption of dietary calcium more than doubles, rising to approximately 30% to 40%.1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar, 3Holick MF Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.Curr Opin Endocrinol Diabetes. 2002; 9: 87-98Crossref Scopus (243) Google Scholar, 4Holick MF Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].Am J Clin Nutr. 2004; 79: 362-371PubMed Google Scholar, 28Heaney RP Dowell MS Hale CA Bendich A Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D.J Am Coll Nutr. 2003; 22: 142-146Crossref PubMed Google Scholar Thus, when vitamin D levels (25[OH]D) are low, calcium absorption is insufficient to satisfy the calcium requirements not only for bone health but also for most metabolic functions and neuromuscular activity. The body responds by increasing the production and release of PTH into the circulation (Figure 1). The increase in PTH restores calcium homeostasis by increasing tubular reabsorption of calcium in the kidney, increasing bone calcium mobilization from the bone, and enhancing the production of 1,25(OH)2 D.1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar, 3Holick MF Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.Curr Opin Endocrinol Diabetes. 2002; 9: 87-98Crossref Scopus (243) Google Scholar Serum 25(OH)D is the major circulating metabolite of vitamin D and reflects vitamin D inputs from cutaneous synthesis and dietary intake. The serum 25(OH)D level is the standard clinical measure of vitamin D status.1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar, 14Lips P Duong T Oleksik A et al.A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].J Clin Endocrinol Metab. 2001; 86: 1212-1221Crossref PubMed Scopus (380) Google Scholar Although 1,25(OH)2D is the active form of vitamin D, it should not be measured to determine vitamin D status. It usually is normal or even elevated in patients with vitamin D deficiency.1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar, 3Holick MF Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.Curr Opin Endocrinol Diabetes. 2002; 9: 87-98Crossref Scopus (243) Google Scholar, 4Holick MF Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].Am J Clin Nutr. 2004; 79: 362-371PubMed Google Scholar Testing of serum 25(OH)D is most useful in patients who are at risk of vitamin D deficiency, including elderly patients, infirm patients, children and adults with increased skin pigmentation, patients with fat malabsorption syndromes, and patients with osteoporosis. This measurement is also useful for purposes of planning or monitoring vitamin D therapy. Clinical assays of 25(OH)D include the Nichols Advantage Assay (chemiluminescence protein-binding assay, the DiaSorin radioimmunoassay, and the benchmark high-performance liquid chromatography assays29Binkley N Krueger D Cowgill CS et al.Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization.J Clin Endocrinol Metab. 2004; 89: 3152-3157Crossref PubMed Scopus (322) Google Scholar and liquid chromatography mass spectroscopy assays.30Holick MF Siris ES Binkley N et al.Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.J Clin Endocrinol Metab. 2005; 90: 3215-3224Crossref PubMed Scopus (407) Google Scholar The chemiluminescence protein-binding assay and the radioimmunoassay are most commonly used to determine patient vitamin D status. Recent reports have raised concerns about the degree of variability between assays and between laboratories, even when using the same assay.29Binkley N Krueger D Cowgill CS et al.Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization.J Clin Endocrinol Metab. 2004; 89: 3152-3157Crossref PubMed Scopus (322) Google Scholar, 30Holick MF Siris ES Binkley N et al.Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.J Clin Endocrinol Metab. 2005; 90: 3215-3224Crossref PubMed Scopus (407) Google Scholar, 31Lips P Chapuy MC Dawson-Hughes B Pols HA Holick MF An international comparision of serum 25-hydroxyvitamin D measurements.Osteoporos Int. 1999; 9: 394-397Crossref PubMed Scopus (236) Google Scholar, 32Holick MF 25-OH-vitamin D assays [letter].J Clin Endocrinol Metab. 2005; 90: 3128-3129Crossref PubMed Scopus (25) Google Scholar, 33Glendenning P Fraser WD 25-OH-vitamin D assays [letter].J Clin Endocrinol Metab. 2005; 90: 3129Crossref PubMed Google Scholar Although reliable and consistent evaluation of serum 25(OH)D levels remains an issue, reliable laboratories currently exist, and efforts are in progress to improve and standardize assays to enhance accuracy and reproducibility at other laboratories.30Holick MF Siris ES Binkley N et al.Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.J Clin Endocrinol Metab. 2005; 90: 3215-3224Crossref PubMed Scopus (407) Google Scholar, 32Holick MF 25-OH-vitamin D assays [letter].J Clin Endocrinol Metab. 2005; 90: 3128-3129Crossref PubMed Scopus (25) Google Scholar, 33Glendenning P Fraser WD 25-OH-vitamin D assays [letter].J Clin Endocrinol Metab. 2005; 90: 3129Crossref PubMed Google Scholar As noted previously, vitamin D plays a central role in calcium and phosphorus homeostasis and skeletal health. Since impaired calcium metabolism due to low serum 25(OH)D levels triggers secondary hyperparathyroidism, increased bone turnover, and progressive bone loss,1Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.Am J Clin Nutr. 2004; 80: 1678S-1688SCrossref PubMed Google Scholar, 34Lips P Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications.Endocr Rev. 2001; 22: 477-501Crossref PubMed Scopus (867) Google Scholar, 35Heaney RP Functional indices of vitamin D status and ramifications of vitamin D deficiency.Am J Clin Nutr. 2004; 80: 1706S-1709SPubMed Google Scholar, 36McKenna MJ Freany R Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D.Osteoporos Int. 1998; 8: S3-S6Crossref PubMed Google Scholar, 37Krall EA Sahyoun N Tannenbaum S Dallal GE Dawson-Hughes B Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women.N Engl J Med. 1989; 321: 1777-1783Crossref PubMed Google Scholar, 38Kinyamu HK Gallagher JC Balhorn KE Petranick KM Rafferty KA Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes [published correction appears in Am J Clin Nutr. 1997;66:454].Am J Clin Nutr. 1997; 65: 790-797PubMed Google Scholar the optimal range of circulating 25(OH)D for skeletal health has been proposed as the range that reduces PTH levels to a minimum9Chapuy MC Preziosi P Maamer M et al.Prevalence of vitamin D insufficiency in an adult normal population.Osteoporos Int. 1997; 7: 439-443Crossref PubMed Scopus (853) Google Scholar, 11Malabanan A Veronikis IE Holick MF Redefining vitamin D insufficiency [letter].Lancet. 1998; 351: 805-806Abstract Full Text Full Text PDF PubMed Google Scholar, 35Heaney RP Functional indices of vitamin D status and ramifications of vitamin D deficiency.Am J Clin Nutr. 2004; 80: 1706S-1709SPubMed Google Scholar and calcium absorption is maximal.28Heaney RP Dowell MS Hale CA Bendich A Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D.J Am Coll Nutr. 2003; 22: 142-146Crossref PubMed Google Scholar Several studies have shown that PTH levels plateau to a minimum steady-state level as serum 25(OH)D levels approach and rise above approximately 30 ng/mL (75 nmol/L)9Chapuy MC Preziosi P Maamer M et al.Prevalence of vitamin D insufficiency in an adult normal population.Osteoporos Int. 1997; 7: 439-443Crossref PubMed Scopus (853) Google Scholar, 30Holick MF Siris ES Binkley N et al.Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.J Clin Endocrinol Metab. 2005; 90: 3215-3224Crossref PubMed Scopus (407) Google Scholar, 35Heaney RP Functional indices of vitamin D status and ramifications of vitamin D deficiency.Am J Clin Nutr. 2004; 80: 1706S-1709SPubMed Google Scholar, 36McKenna MJ Freany R Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D.Osteoporos Int. 1998; 8: S3-S6Crossref PubMed Google Scholar, 37Krall EA Sahyoun N Tannenbaum S Dallal GE Dawson-Hughes B Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women.N Engl J Med. 1989; 321: 1777-1783Crossref PubMed Google Scholar, 38Kinyamu HK Gallagher JC Balhorn KE Petranick KM Rafferty KA Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes [published correction appears in Am J Clin Nutr. 1997;66:454].Am J Clin Nutr. 1997; 65: 790-797PubMed Google Scholar (Figure 2, left). Vitamin D inadequacy constitutes a largely unrecognized epidemic in many populations worldwide.39Gaugris S Heaney RP Boonen S Kurth H Bentkover JD Sen SS Vitamin D inadequacy among post-menopausal women: a systematic review.QJM. 2005; 98: 667-676Crossref PubMed Scopus (89) Google Scholar, 40Isaia G Giorgino R Rini GB Bevilacqua M Maugeri D Adami S Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors.Osteoporos Int. 2003; 14: 577-582Crossref PubMed Scopus (143) Google Scholar, 41Plotnikoff GA Quigley JM Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.Mayo Clin Proc. 2003; 78: 1463-1470Abstract Full Text Full Text PDF PubMed Google Scholar, 42Carnevale V Manfredi G Romagonoli E et al.Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage?.Clin Endocrinol (Oxf). 2004; 60: 81-86Crossref PubMed Scopus (23) Google Scholar, 43Harwood RH Sahota O Gaynor K Masud T Hosking DJ A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.Age Ageing. 2004; 33: 45-51Crossref PubMed Scopus (82) Google Scholar, 44Glowacki J Hurwitz S Thornhill TS Kelly M LeBoff MS Osteoporosis and vitamin-D deficiency among postmenopausal women with osteoarthritis undergoing total hip arthroplasty.J Bone Joint Surg Am. 2003; 85–A: 2371-2377PubMed Google Scholar, 45Gomez-Alonso C Naves-Diaz ML Fernandez-Martin JL Diaz-Lopez JB Fernandez-Coto MT Cannata-Andia JB Vitamin D status and secondary hyperparathyroidism: the importance of 25-hydroxyvitamin D cut-off levels.Kidney Int Suppl. 2003; 85: S44-S48Crossref PubMed Google Scholar, 46Blau EM Brenneman SK Bruning AL Chen Y Prevalence of vitamin D insufficiency in an osteoporosis population in Southern California [abstract].J Bone Miner Res. 2004; 19 (Abstract SU582.): S342Google Scholar, 47Simonelli C Weiss TW Morancey J Swanson L Chen YT Prevalence of vitamin D inadequacy in a minimal trauma fracture population.Curr Med Res Opin. 2005; 21: 1069-1074Crossref PubMed Scopus (46) Google Scholar It has been reported in healthy children,7Gordon CM DePeter KC Feldman HA Grace E Emans SJ Prevalence of vitamin D deficiency among healthy adolescents.Arch Pediatr Adolesc Med. 2004; 158: 531-537Crossref PubMed Scopus (387) Google Scholar, 8Outila TA Karkkainen MU Lamberg-Allardt CJ Vitamin D status affects serum parathyroid hormone concentrations during winter in female adolescents: associations with forearm bone mineral density.Am J Clin Nutr. 2001; 74: 206-210PubMed Google Scholar, 13Looker AC Dawson-Hughes B Calvo MS Gunter EW Sahyoun NR Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III.Bone. 2002; 30: 771-777Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 15Sullivan SS Rosen CJ Halteman WA Chen TC Holick MF Adolescent girls in Maine are at risk for vitamin D insufficiency.J Am Diet Assoc. 2005; 105: 971-974Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 48El-HajjFuleihan G Nabulsi M Choucair M et al.Hypovitaminosis D in healthy schoolchildrren.Pediatrics. 2001; 107: E53Crossref PubMed Google Scholar young adults,38Kinyamu HK Gallagher JC Balhorn KE Petranick KM Rafferty KA Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women