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.

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.2 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. SOURCES OF VITAMIN D Solar UV-B (wavelengths of 290-315 nm) irradiation is the primary source of vitamin D (other than diet supplements) for most people.1,3,4 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). For editorial Some foods are fortified in the United comment, States, including milk (100 IU per 8 oz) see page 297 and some cereals (100 IU per serving), orange juice (100 IU per 8 oz), some yogurts (100 IU per serving), and margarine.4-6 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.7-16 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.17 This is not surprising given that
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Mayo Clin Proc. 2006;81(3):353-373
1α(OH)D3 = 1α-hydroxyvitamin D3; 1,25(OH)2D = 1,25-dihydroxyvitamin α α D; 25(OH)D = 25-hydroxyvitamin D; BMD = bone mineral density; PTH = parathyroid hormone; RCT = randomized controlled trial; RECORD = Record Evaluation of Calcium or Vitamin D; VDR = vitamin D receptor


uring 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.1 At the same time, numerous reports have shown that relatively high proportions of people have inadequate
From the Vitamin D, Skin and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Mass. Dr Holick is an Academic Associate for Nichols Institute Diagnostics. This work was supported in part by National Institutes of Health grants MOIRR00533 and AR369637 and the UV Foundation. Individual reprints of this article are not available. Address correspondence to Michael F. Holick, PhD, MD, Vitamin D, Skin and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, 715 Albany St, Room M-1013, Boston, MA 02118 (e-mail: © 2006 Mayo Foundation for Medical Education and Research

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FIGURE 1. Cutaneous production of vitamin D and its metabolism and regulation for calcium homeostasis and cellular growth. 7-Dehydrocholesterol or provitamin D3 (proD3) in the skin absorbs solar UV-B radiation and is converted to previtamin D3 (preD3). D3 undergoes thermally induced (∆H) transformation to vitamin D3. Vitamin D from the diet or from the skin is metabolized in the liver by the vitamin D-25hydroxylase to 25-hydroxyvitamin D3 (25[OH]D3). 25(OH)D3 is converted in the kidney by the 25(OH)D3-1αhydroxylase to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. A variety of factors, including serum phosphorus 2– (PO4 ) and parathyroid hormone (PTH), regulate the renal production of 1,25(OH)2D3. 1,25(OH)2D regulates calcium metabolism through its interaction with its major target tissues, the bone and the intestine. From Osteoporos Int,21 with permission from Springer Science and Business Media.

compliance 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.6 VITAMIN D PHOTOBIOCHEMISTRY, METABOLISM, AND FUNCTIONS UV-B irradiation of skin triggers photolysis of 7-dehydrocholesterol (provitamin D3) to previtamin D3 in the plasma membrane of human skin keratinocytes.18-20 Once formed in the skin, cell plasma membrane previtamin D3 is rapidly converted to vitamin D3 by the skin’s temperature. Vitamin
354 Mayo Clin Proc. •

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, 1,25dihydroxyvitamin 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.19,20,22 Melanin skin pigmentation is an effective natural sunscreen, and increased skin pigment can greatly reduce UVB–mediated cutaneous synthesis of vitamin D3 by as much as 99%, similar to applying a sunscreen with a sun protection factor of 15.23,24 Keratinocytes are also capable of hydroxylating 25(OH)D to produce 1,25(OH)2D.25 The 1,25(OH)2D (from keratinocyte or renal sources) may regulate keratinocyte differentiation, melanocyte apoptosis, and melanin production,25-27 and this may be another mechanism for

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81(3):353-373 For personal use. examined the prevalence of vitamin D inadequacy reported as serum 25(OH)D levels below various values.7.42. Mayo Clin 355 March 2006. including elderly patients. vitamin D plays a central role in calcium and phosphorus homeostasis and skeletal health.36.57 and even higher in Europe (28%-100% of healthy and 70%-100% of hospitalized adults). . leading to formation of mature osteoclasts. Mass reproduce only with permission from Mayo Clinic Proceedings.1.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH regulating the cutaneous synthesis of vitamin D3 by negative feedback.7.37.39-47 It has been reported in healthy children. Vitamin D is primarily responsible for regulating the efficiency of intestinal calcium absorption. which included 30 studies published between January 1994 and April 2004. vitamin D is involved in bone formation.11 up to 57% in general medicine inpatients in the United States. patients with fat malabsorption syndromes. and progressive bone loss.3 (Figure 1). The serum 25(OH)D level is the standard clinical measure of vitamin D status.35-38 (Figure 2. the small intestine can absorb approximately 10% to 15% of dietary calcium. Circulating 1.3.14. In a low vitamin D state. is the active form of vitamin D.28 Thus. Although reliable and consistent evaluation of serum 25(OH)D levels remains an issue. when vitamin D levels (25[OH]D) are low. releasing calcium into the blood. When vitamin D levels are adequate.50 and middle-aged and elderly adults.1. This measurement is also useful for purposes of planning or monitoring vitamin D therapy.28 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)9.32. left). resorption.25(OH)2D reduces serum parathyroid hormone (PTH) levels directly by decreasing parathyroid gland activity and indirectly by increasing serum calcium. observational study conducted at 61 sites across North America showed that 52% of postmenopausal women receiving therapy for osteoporosis had 25(OH)D levels of less than 30 ng/mL (75 nmol/L). The 1. children and adults with increased skin pigmentation. The results of a recent cross-sectional. The increase in PTH restores calcium homeostasis by increasing tubular reabsorption of calcium in the kidney.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.51-56 Typically. rising to approximately 30% to 40%.1.55.mayoclinicproceedings.38. it should not be measured to determine vitamin D status.25(OH)2D regulates bone metabolism in part by interacting with the VDR in osteoblasts to release biochemical signals. The 1. even when using the same assay. and enhancing the production of 1.50 41% in outpatients aged 49 to 83 years.58 Vitamin D inadequacy is particularly common among patients with osteoporosis (Table 1). Recent reports have raised concerns about the degree of variability between assays and between laboratories.25(OH)2D. calcium absorption is insufficient to satisfy the calcium requirements not only for bone health but also for most metabolic functions and neuromuscular activity. calcium and phosphorus homeostasis becomes impaired.48 young adults. • and the benchmark high-performance liquid chromatography assays29 and liquid chromatography mass spectroscopy assays. EPIDEMIOLOGY OF VITAMIN D INADEQUACY Vitamin D inadequacy constitutes a largely unrecognized epidemic in many populations worldwide.41. In addition. Clinical assays of 25(OH)D include the Nichols Advantage Assay (chemiluminescence protein-binding assay.33 As noted previously. the prevalence of low 25(OH)D levels (<20 ng/mL [50 nmol/L]) is approximately 36% in otherwise healthy young adults aged 18 to 29 years.13.40.4 Testing of serum 25(OH)D is most useful in patients who are at risk of vitamin D deficiency. and mineralization and in maintaining neuromuscular function1. The body responds by increasing the production and release of PTH into the circulation (Figure 1). A recent systematic review by Gaugris et al39 concluded that the prevalence of inadequate 25(OH)D levels appears to be high in postmenopausal women and especially those with osteoporosis and a history of fracture.30.4 When vitamin D levels are inadequate.30 • www. increasing bone calcium mobilization from the bone. and efforts are in progress to improve and standardize assays to enhance accuracy and reproducibility at other laboratories. Since impaired calcium metabolism due to low serum 25(OH)D levels triggers secondary hyperparathyroidism.43-49.35 and calcium absorption is maximal.14 Although 1.3 ASSESSMENT OF VITAMIN D STATUS Serum 25(OH)D is the major circulating metabolite of vitamin D and reflects vitamin D inputs from cutaneous synthesis and dietary intake. This review. reliable laboratories currently exist.49 42% in black women aged 15 to 49 years.34-38 the optimal range of circulating 25(OH)D for skeletal health has been proposed as the range that reduces PTH levels to a minimum9.49. It usually is normal or even elevated in patients with vitamin D deficiency.1. the DiaSorin radioimmunoassay. infirm patients. and patients with osteoporosis.30 The chemiluminescence protein-binding assay and the radioimmunoassay are most commonly used to determine patient vitamin D status.1. increased bone turnover.49 especially African Americans. intestinal absorption of dietary calcium more than doubles.30. The osteoclasts release collagenases and hydrochloric acid to dissolve the matrix and mineral.

64 A study of 1546 African American women in the United States. Right. sunlight is insufficient to induce cutaneous vitamin D3 synthesis during the winter months.46 In a study of patients 50 years and older hospitalized for nontraumatic fractures. showed that more than 40% had serum 25(OH)D levels less than 15 ng/mL (37 nmol/L). The high prevalence of vitamin D inadequacy in that study was consistent across all age groups and North American geographic regions studied. .48 FACTORS THAT CONTRIBUTE TO VITAMIN D INADEQUACY Physical factors that attenuate UV-B exposure.50 A much 356 Mayo Clin Proc.8. with the proportion increasing to 94% during the winter months. with the highest prevalence reported in central and southern March 2006.59 Studies in the United Kingdom and South Africa reported that 13% to 33% of patients with hip fractures had histological evidence of osteomalacia that may have been caused by chronic vitamin D deficiency.mayoclinicproceedings. markedly reduce or completely eliminate the production of vitamin D3 in the skin.55 A global study of vitamin D status in postmenopausal women with osteoporosis showed that 24% had 25(OH)D levels less than 10 ng/mL (25 nmol/L). 97% had 25(OH)D levels less than 30 ng/mL (75 nmol/L). Left. and vitamin D deficiencies in both may be attributable to their cultural practice of wearing clothing that covers the entire body and avoiding direct sunlight.16. respectively. had serum 25(OH)D levels less than 20 ng/mL (50 nmol/L). rickets in Saudi children. A study of Asian adults in the United Kingdom showed that 82% had 25(OH)D levels less than 12 ng/mL (30 nmol/L) during the summer season. including clothing.3.3 Even children are at risk. For instance.67-69 The high prevalence of osteomalacia in Saudi Arabian women.66 Nevertheless.14 Vitamin D inadequacy is common even among patients with osteoporosis living at lower latitudes in highly sunny climates. A cross-sectional clinic-based study of 307 children (11-18 years old) in Boston reported that 52% of African American and Hispanic children had 25(OH)D levels of 20 ng/mL (50 nmol/L) or less. The percentage of subjects with secondary hyperparathyroidism (parathyroid hormone level >40 pg/mL) sorted by subgroups with serum 25(OH)D concentrations delineated by predefined cutoffs for analyses of 25(OH)D inadequacy.70. 53% of community-dwelling women with osteoporosis living in Southern California had 25(OH)D levels less than 30 ng/mL (75 nmol/L). latitude is not the only determinant of 25(OH)D levels. • higher proportion (84%) of elderly black adults in Boston.23. vitamin D inadequacy is common in schoolchildren. of white girls (9-11 years of age) in Maine also had 25(OH)D levels less than 20 ng/mL (50 nmol/L).60-63 Vitamin D inadequacy is also common among nonwhite populations and populations with low dietary or supplementary vitamin D intake or minimal exposure to sunlight.18 At latitudes above 37°N and below 37°S. From J Endocrinol Metab. sunscreens. Left and right. ranging in age from 15 to 49 years.30 with permission from The Endocrine Society. Percentage of subjects with secondary hyperparathyroidism by 25(OH)D level.71 Biological factors that inhibit cutaneous vitamin D synthesis and bioavailability include skin pigmentation. Mass.1.73 • www. and glass shielding. Copyright 2005. Even in sunny countries such as Lebanon.72.65.30 The prevalence of very low serum 25(OH)D levels (<12 ng/mL [30 nmol/L]) was 76% among patients with osteoporosis in another study. Relationship between serum 25-hydroxyvitamin D (25[OH]D) concentrations and mean ± SE (error bars) serum concentrations of parathyroid hormone in patients with osteoporosis receiving treatment.81(3):353-373 For personal use.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH FIGURE 2.7 Sullivan et al15 observed that at the end of winter and summer 48% and 17%. Mass reproduce only with permission from Mayo Clinic Proceedings.

9%.4 In adults.mayoclinicproceedings.4 Secondary hyperparathyroidism causes phosphaturia and hypophosphatemia.76 and age.84 Mayo Clin Proc.44 2003 Segal et al.85 Age does not alter dietary vitamin D absorption.74 body fat content. bone pain. and secondary hyperparathyroidism and resulting phosphaturia have more • www. multiple factors contribute to vitamin D inadequacy.43 2004 Glowacki et al.73 Certain drugs (eg. cystic fibrosis.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH TABLE 1. increasing the risk of osteoporosis.45 2003 Holick et al.81(3):353-373 For personal use. anticonvulsants. corticosteroids.76.46 2004 Simonelli et al.40 2003 Plotnikoff et al.42 2004 Harwood et al. including sprue.72. Mass reproduce only with permission from Mayo Clinic Proceedings. and osteomalacia may develop. This causes a widening of the epiphyseal plates at the end of the long bones in rachitic children and bulging of costochondral junctions (rachitic rosary). resulting in bowed legs or knocked knees. and Crohn disease. L = low sun/winter-spring. vitamin D will not be absorbed efficiently.30 2005 Population characteristics Elderly women referred to an osteoporosis center Various ethnic groups referred for chronic musculoskeletal pain Patients with primary hyperparathyroidism Female patients with hip fractures Postmenopausal osteoarthritic white women Patients with hip fracture at time of hospitalization Healthy population in osteoporosis study Postmenopausal women receiving antiresorptive or anabolic therapy for osteoporosis Community-dwelling women referred to osteoporosis clinic Patients hospitalized for nontraumatic fracture Location Italy Minnesota Italy United Kingdom Boston.75 Dietary sources of vitamin D are limited. including dietary deficiencies and decreased cutaneous synthesis due to reduced ability of the skin to synthesize vitamin D3.79.1.23. A 70-year-old produces approximately 4 times less vitamin D via cutaneous synthesis compared with a 20-year-old.78 Increased skin pigmentation can reduce cutaneous vitamin D3 production as much as 99. Vitamin D deficiency during skeletal maturation disrupts chondrocyte maturation and inhibits the normal mineralization of the growth plates. gravity causes bowing of the long bones in the lower extremities. and progressive loss of bone.18 In 357 March 2006. • SKELETAL CONSEQUENCES OF VITAMIN D INADEQUACY Chronic severe vitamin D deficiency in infants and children causes bone deformation due to poor mineralization. and cholestyramine) may adversely affect metabolism or bioavailability of vitamin D. and obtaining a sufficient amount from regular diet is often problematic for many people whose diet does not normally include the few foods that are naturally rich in vitamin D. Vitamin D Inadequacy in Osteoporosis: Summary of Reports Published in 2003 and 2004* Prevalence of low serum 25(OH)D (%) 27 76 33 93 27 70 22 60 67 52 Definition of low serum vitamin D (ng/mL) <5 <12 <8 <20 <12 <12 <15 <15 <18 <30 Reference Isaia et al.80 Recent studies have shown that body mass index and body fat content are inversely related to serum 25(OH)D levels and directly related to PTH levels. commonly known as rickets. but if an individual is taking cholestyramine. Patients with fat malabsorption syndromes.17 2004 Gomez-Alonso et al.86-89 Less severe vitamin D inadequacy prevents children and adolescents from attaining their optimal genetically programmed peak bone mass and in adults leads to secondary hyperparathyroidism.1. B = both low sun/winter-spring and high sun/summer-fall.41 2003 Carnevale et al. NA = not available.47 2005 L L 252 82 NA ≥50 53 97 <30 <30 *25(OH)D = 25-hydroxyvitamin D. medication use.78 Increasing age has been associated with lower 25(OH)D levels regardless of season.81-83 which is likely due to vitamin D sequestration in body fat compartments. rifampin. proximal muscle weakness.77.74.55. the epiphyseal plates are fused. Mass Israel Spain North America Southern California Minnesota Season B B B NA B B B L Sample size 700 150 62 150 68 96 268 1536 Mean age (y) 68 10-65 (range) 50 81 66 72 69 71 Blau et al. making the skeleton less rigid.84 Among elderly patients.77. are at especially high risk of vitamin D deficiency.75. When the rachitic child begins to stand. The resulting inadequate calcium-phosphorus product results in poor mineralization.75 fat malabsorption. . increased bone turnover.

358 Mayo Clin Proc.41. the authors concluded that daily vitamin D supplementation between 700 and 800 IU with or without calcium appears to reduce hip fracture risk by 26% and • www.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH Figure 3. This swelling could put outward pressure on the periosteal covering that is innervated with nocioceptors.81. clinical trials and observational studies have reported that dietary vitamin D supplementation (often given together with calcium) lowers fracture risk34.88 When 25(OH)D levels are less than approximately 10 ng/mL (25 nmol/L).50.53. Although the exact cause of the aching sensation that patients often complain of is unknown.91 Patients with osteomalacia are often misdiagnosed as having fibromyalgia. stratified by supplement use and residential status. Bischoff-Ferrari et al98 recently conducted a systematic review and meta-analysis of doubleblind randomized controlled trials (RCTs). increased risk of fragility fracture.30. Mean ± SD (error bars) serum 25-hydroxyvitamin D (25[OH]D) concentrations (shown as nmol/L and ng/mL) in women older than 70 years.81(3):353-373 For personal use. skeletal consequences. and (rarely) hypocalcemic tetany.7.90 (Figure 2). but not all. .30. osteoporosis. but equally devastating. osteomalacia is usually present.88-90 Some studies suggest that serum 25(OH)D levels greater than 30 ng/mL (75 nmol/L) may be required to maximize intestinal calcium absorption28 and prevent secondary hyperparathyroidism-induced skeletal conditions14.86.90 Moreover some. Chronic vitamin D inadequacy in adults can result in secondary hyperparathyroidism. Statistical justification was provided for pooling trials with higher vitamin D doses separately from those with lower doses.89. observational studies have linked vitamin D inadequacy (or lower vitamin D intake) to an increased risk of hip and other nonvertebral fractures.34-37. • Jell-O). the highest level of evidence. On the basis of the analysis of 3 RCTs for hip fracture risk involving 5572 subjects and 5 RCTs for nonvertebreal fracture risk involving 6098 subjects.mayoclinicproceedings. and increased fragility-fracture risk.87. subtle.91 Some. The result is increased skeletal porosity.89 This pain can be elicited on physical examination by applying minimal pressure with the thumb or forefinger on the sternum or anterior tibia. Adapted from J Clin Endocrinol Metab.4.61. but not all. or myocytis and treated inappropriately with nonsteroidal anti-inflammatory agents. decreased bone mineral density (BMD).87-89 The increase in PTHmediated osteoclastogenesis results in increased numbers and activity of osteoclasts.97 with permission from The Endocrine Society. defective bone March 2006. to assess the efficacy of vitamin D (vitamin D3 [cholecalciferol] or vitamin D2 [ergocalciferol]) supplementation with or without calcium supplementation vs calcium supplementation alone or placebo for preventing hip and nonvertebral fractures in elderly patients (≥60 years of age).92-96 (Figure 3). chronic fatigue syndrome. enhanced bone loss. Unlike patients with osteoporosis. releasing calcium and phosphorus into the extracellular space. increased bone turnover. patients with osteomalacia often complain of skeletal pain. The osteoclasts resorb bone via enzymatic degradation of the collagen matrix and secretion of hydrochloric acid.60. Mass reproduce only with permission from Mayo Clinic Proceedings.41.9. Copyright 1988. it is possible that the collagen-rich osteoid that is laid down on the periosteal surface of the skeleton may become swollen similar to the hydration of gelatin-based food products (eg.

Most intramuscular preparations are not very bioavailable. calcium alone. Data from a 359 March 2006. a double-blinded RCT randomized 249 healthy ambulatory postmenopausal women with usual daily intakes of 100 IU of vitamin D to receive 400 IU of vitamin D supplements or placebo daily. A separate systematic review and meta-analysis conducted several years earlier that included RCTs involving either vitamin D or its analogues reported a 37% reduction in the relative risk of vertebral fracture. Another randomized. double-blind. NEUROMUSCULAR FUNCTION The VDR has been identified in skeletal muscle tissue.000 IU of cholecalciferol (comparable to a 822-IU daily dose) or matching placebo disclosed no effect on fracture occurrence between groups. Thus.100 Many of the vitamin D supplementation studies reported herein included concurrent calcium supplementation.89. • vitamin D group had significantly reduced wintertime bone loss and improved net BMD of the spine.99. Mass reproduce only with permission from Mayo Clinic Proceedings. However.90. which is why they are no longer available in the United States.110 The earlier meta-analysis that pooled data from RCTs that included vitamin D analogues found a small nonsignificant BMD increase of 0. it is unknown whether the intramuscular vitamin D3 was completely bioavailable. At the end of 1 year.172 A prospective study • www. controlled trial with a factorial design examined the effect on fracture risk. Porthouse et al101 conducted an open-label RCT to assess whether 1000 mg of calcium daily with 800 IU of vitamin D3 supplementation reduced fracture risk among 3314 women 70 years and older with one or more risk factors for hip fracture.105. we cannot know if the lack of effect on fracture risk in the RECORD trial might be related to pretreatment levels of vitamin D and/or calcium. vitamin D inadequacy was associated with increased body sway.102 It is also possible that the benefits of vitamin D on fracture risk reduction (and BMD) may be greater in those with vitamin D deficiency or low calcium intake at baseline.4% relative to the control groups.81(3):353-373 For personal use.173 Additional supporting evidence comes from a study that investigated factors leading to fracture in postmenopausal women with osteoporosis.99.109 By contrast.mayoclinicproceedings. and bone pain are sometimes discounted or diagnosed as having fibromyalgia or chronic fatigue syndrome despite strong scientific evidence that they have vitamin D inadequacy.167-169 and low serum 25(OH)D levels have been associated with reversible myopathy in patients with osteomalacia. since 25(OH)D levels were not evaluated. muscle aches and pains. The incidence of hip and other clinical fractures did not differ significantly between groups after a median follow-up of 25 months. increased risk of falls. All participants also received 377 mg/d of calcium.106 Some randomized trials have also shown a benefit. therefore.104 and some studies have linked vitamin D inadequacy or low intake of vitamin D to low BMD. A population-based. In the RECORD trial. the observed benefits of vitamin D supplementation may be confounded or obscured by the effects of concurrent calcium supplements and cannot be ascribed to vitamin D alone.102 A total of 5292 patients were randomized to receive vitamin D with or without calcium.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH nonvertebral fracture risk by 23% vs calcium alone or placebo in ambulatory or institutionalized elderly persons.95 although this lower-quality trial did not meet the inclusion criteria for the meta-analysis described herein. No effect on fracture risk was observed in 2 trials that used a lower dose of 400 IU/d.103 However.91 Several studies support the hypothesis that vitamin D inadequacy contributes to age-related muscle weakness143.41. and fall-related fractures.100. compliance with the medication had declined to 63% after 24 months and may have been as low as 45% if nonresponders to the evaluation questionnaire were included.172-174 A compelling meta-analysis of RCTs of vitamin D supplementation showed a greater than 20% reduced risk of falls among ambulatory or institutionalized older individuals treated with supplements.120.89. Although the meta-analysis by BischoffFerrari et al98 reported that vitamin D supplementation with or without calcium supplementation reduced fracture risks. the factorial design of the Record Evaluation of Calcium or Vitamin D (RECORD) trial concluded that vitamin D supplementation with or without calcium supplementation had no significant effect on fracture risk reduction. 3-year cluster randomized intervention study involving 9605 community-dwelling elderly adults (≥66 years of age) found that 400 IU/d of vitamin D with 1000 mg of calcium produced a 16% fracture risk reduction.107.108 For example. or placebo.170 Patients with nonspecific muscle weakness.1%) had their serum baseline 25(OH)D levels measured.126.100 Two trials that failed to detect an effect on fracture risk were published soon after the meta-analysis was conducted. double-blinded. placebo-controlled trial of 9440 community-dwelling adults (75-100 years old) randomized to receive either an annual injection of 300. the authors found no significant differences in fracture rates among the 4 groups. only 60 participants (1.171 and falls.99. . however. The hierarchy of evidence for the role of vitamin D in BMD102-117 changes and fracture reduction is given in Table 2. another RCT reported no effect of vitamin D supplementation on bone loss or bone turnover markers in calcium-replete postmenopausal African American women.86. After a 24month follow-up. the Mayo Clin Proc.105. Decreased BMD is a major risk factor for fractures.

small trial No effect on TNF-α. IFN-γ. community controls Fracture vs no fracture Case vs control Cancer vs control Cancer vs control Small effect NHANES I NHS I and II—effect seen in earlier cohort Birth cohort.25(OH)2D interaction in black cases.81(3):353-373 • www.166 MS205 IHD mortality219 Type 1 DM incidence207 Rheumatoid arthritis208 Serum 25(OH)D60 Muscle function135 Serum 25(OH)D and serum 1.205.225 Small ↑ Small ↓ or no effect Approximately 20% ↓ Small ↑ Small ↓ Small ↓ in sway and reaction time ↓ number of fallers 25% ↓ with approximately 500 IU. • March 2006.25(OH)2D124 Serum 25(OH)D125 Serum 25(OH)D and serum 1. compared with controls ↑ risk with low levels No difference ↑ risk with less exposure Hemiplegic stroke patients Result Notes Effect seen with low baseline vitamin D Effect seen with low baseline 25(OH)D Low baseline 25(OH)D Effect seen with vitamin D or 1-H-vitamin D3 Single small study in fallers Benefit only with good calcium intake116 Unblinded study Benefits mostly seen with vitamin D deficiency at baseline Nonblinded Low baseline 25(OH)D.165. or IL-13 Very small double-blinded single study Exposure to UV-B Exposure to UV-A 2 Cohort studies Prospective epidemiological studies Serum 25(OH)D Serum 25(OH)D Serum 1. balance114 Fracture risk115 Fracture risk116 Falls126 Falls126 Sarcopenia127 Colon cancer164 Colon cancer202 Colorectal cancer164 Breast cancer risk132.25(OH)2D123 Serum 25(OH)D and serum 1. Finland. ↓ in white. ICU patients Small ↑ No effect Approximately 50% ↓ in falls in post–hip fracture post–hip fracture women 9% ↓ ↑ TGF-β1 BP ↓ to normal No effect on BP ↑ risk of hip fracture when low No effect on fracture. before diagnosis No difference in 25(OH)D 149 cases 61 cases Cancer vs control Cancer vs control MS case vs control (level 3 continued on next page) 360 Mayo Clin Proc.25(OH)2D128 Level of sunlight exposure during childhood and For personal use.25(OH)2D Vitamin D supplements Serum 25(OH)D Serum PTH Serum 25(OH)D Dietary vitamin D and calcium Serum 25(OH)D Dietary vitamin D and calcium Dietary vitamin D and sunlight exposure Latitude Dietary vitamin D Dietary vitamin D in first year of life Dietary vitamin D 3 Casecontrol studies Fracture cases and nonfracture controls D-deficient cases.100 1b RCTs Vitamin D (or analogue) alone Falls173 BMD changes100 Fracture risk94 Neuromuscular function118. .VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH TABLE 2. gait speed. Hierarchy of Evidence for Studies Relating Vitamin D to Pathologic Conditions* Level 1a Study type Metaanalyses Data source RCTs Treatment or predictor Vitamin D and calcium Outcome BMD100 Fracture risk99.mayoclinicproceedings.112 Fracture risk101.102 Falls43 BP201 Cytokines in patients with MS200 BP125 BP201 Fracture risk113 Fracture risk. “normal” controls Colorectal cancer cases (nested in cohort) Breast cancer cases at diagnosis. clinic controls Prostate cancer cases (nested in cohort) Prostate cancer cases (nested in cohort) MS cases.119 Falls119-121 CRP122 Vitamin D (or analogue) and calcium BMD changes111. poorer balance and gait speed when low ↑ risk of hip fracture when low No effect ↑ risk when low ↑ risk when high ↑ risk when low ↑ risk when low ↑ risk when low ↑ risk when low ↑ risk when low ↑ risk at higher latitudes No effect on MI or IHD ↓ risk with higher intake 33% ↓ risk in highest tertile of intake ↓ levels in women with hip fracture Reduced vitamin D deficiency ↑ risk with low 25(OH)D level ↑ race-1. 11-year follow-up Blood drawn at baseline. Mass reproduce only with permission from Mayo Clinic Proceedings.

Mass reproduce only with permission from Mayo Clinic Proceedings. mice. .146 EAE.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH TABLE 2. BMD = bone mineral density. mice147 IBD. Associations with most other diseases and conditions come from lower levels of evidence.mayoclinicproceedings. PTH = parathyroid hormone. • March 2006. community controls. geographic area Population-based. 1 county Cross-sectional surveys. mice149 IBD. There is some evidence from clinical trials that vitamin D (often given with calcium) may reduce the risk of falls and fractures.204 Cancer mortality 133. IFN-γ = interferon-γ.25(OH)2D 1α. MS = multiple sclerosis.25(OH)2D3 and analogues Vitamin D analogues Vitamin D and nicotine 1α. mice148 SLE153 Aortic allograft intimal and advential damage154 Heart allograft survival. MI = myocardial infarction. The most convincing evidence comes from randomized controlled trials.25(OH)2D Vitamin D analogue Vitamin D analogue Longer survival with treatment Regulates cell growth Antiproliferative effect Varying effects on serum calcium. community controls. mice234 Liver cancer156 177 Better walking speed and sit-to-stand time with higher levels Higher in areas with less sunlight Higher in areas with less sunlight Higher systolic and diastolic BP with higher levels No effect ↑ risk with low level. independently of BMD 98% <28 ng/mL 97% <30 ng/mL 5 1. depending on analogue used ↑ with treatment ↓ proliferation ↓ proliferation. Tromsø Population-based. mice Lyme arthritis. DM = diabetes mellitus.25(OH)2D = 1.81(3):353-373 • www. NOD = nonobese diabetic. NA = not applicable. NHANES III 4b Case series (and poorquality cohort and case-control studies) Expert opinion without explicit critical appraisal or based on physiology. NHS = Nurses’ Health Study.25(OH)2D 1α.25(OH)2D3 1. bench research. NHANES = National Health and Nutrition Examination Survey. heterotopic graft. TNF-α = tumor necrosis factor α. SLE = systemic lupus erythematosus. 1-H-vitamin D3 = 1 hydroxylated vitamin D3. IHD = ischemic heart disease. osteosarcoma. 25(OH)D = 25-hydroxyvitamin D.144. Mayo Clin Proc.25(OH)2D 1α.25 hydroxyvitamin D. RCT = randomized controlled trial. melanoma)3 Prostate cancer139 Aortic calcification140 Keratinocytes27 Keratinocytes and fibroblasts of patients with psoriasis141 DM (NOD mice) 361 For personal use.25(OH)2D 1α. no effect with prenatal use 70% ↓ risk with prenatal use. ↑ differentiation Protection against developing DM Prevents EAE Inhibits progression ↓ risk and severity ↑ effect with both Inhibits lupus nephritis ↓ damage Prolongs survival without bone loss or ↑ risk of infection Prolongs graft survival when used with cyclosporine Patients with inoperable liver cancer Up-regulates IL-4 IL-10 KO mice IL-2 KO mice IL-10 KO mice MRL/1 mice NOD mice Human *References are provided for examples of each type of study. nationwide Childhood-onset type 1 DM. KO = knockout. IBD = inflammatory bowel disease. or “first principles” Patients with nonvertebral fracture Patients with minimal trauma fracture Laboratory or animal studies Treatment or predictor Diabetic vs control Outcome Cod liver oil during pregnancy or first year of life130 Cod liver oil during pregnancy or first year of life131 Result 26% ↓ risk with use in first year of life. BP = blood pressure. 1α. IL = interleukin. rats155 Xenogenic pancreatic islets. Continued* Level 3 Study type Data source Childhood-onset type 1 DM.25(OH)2D Vitamin D intake Serum 25(OH)D NA NA Lower-extremity function143 Cancer mortality 132.25(OH)2D = 1α-25-hydroxyvitamin D.165.25(OH)2D3 1. CRP = C-reactive protein. EAE = experimental autoimmune encephalitis. no effect during first year Notes Norway Diabetic vs control Norway 4a Serum 25(OH)D Sunlight Sunlight Serum 1.25(OH)2D and calcium Vitamin D analogues Vitamin D analogue 1α. ICU = intensive care unit.166.25(OH)2D 1α.165 BP134 BP136 Periodontal disease137 Serum 25(OH)D inadequacy117 Serum 25(OH)D inadequacy47 Leukemia (mouse)138 Lung cancer cell growth150 Cancer cells proliferation (breast. ecological studies Older adults Breast cancer cases Ovarian cancer cases Population-based.25(OH)2D 1α. 1.

VDR ligands) have demonstrated antiproliferative. and various cells of the immune system. a study of community-dwelling elderly adults in Switzerland showed that treatment with 1. • www. rheumatoid arthritis.176.151. Ca + D = Ca plus vitamin D.119.185 and immune disorders. However. gonads.81(3):353-373 For personal use. hypertension. Similarly. Mass reproduce only with permission from Mayo Clinic Proceedings.182.183 Mounting biochemical and epidemiological evidence suggests that the VDR is also involved in mediating the noncalcemic effects of vitamin D and its analogues and may play a vital role in disease prevention and maintenance of extraskeletal health.177. 118.25(OH)2D is involved in non–genomicmediated intracellular signaling FIGURE 4. The presence of the VDR in other tissues and organs suggests that vitamin D may also be important in nonskeletal biological processes. Ca = calcium. 1.1.4. The VDR is a steroid hormone nuclear receptor that binds 1.176-178 Additionally. Relative to therapy with 1200 mg/d of calcium for 12 weeks.1.25[OH]2D) has been identified in tissues other than kidney150. prodifferentiative.120 These studies suggest that adequate serum 25(OH)D may prevent fractures not only by improving calcium homeostasis but also by improving musculoskeletal function.25(OH)2D and its synthetic analogues (collectively. that examined factors associated with falls in 637 institutionalized ambulatory subjects reported that a low baseline serum 25(OH)D level was significantly associated with increased risk of falling.2. Some of these include the heart.177 via paracrine or autocrine regulatory mechanisms. multiple sclerosis. and organs. including those not typically associated with calcium homeostasis and bone metabolism. skin.121.25(OH)2D may be important for regulating cell growth and cellular differentiation1. kidneys.179-181 (Figure 5).4. • March 2006.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH in muscle function and fall prevention is summarized in Table 2.192.177 Genetic variants of the gene encoding the VDR have also been associated with differential risk of developing various cancers184.188-191 Both 1. and immunomodulatory activities (which may be mediated by both the genomic and the nongenomic mechanisms) in several clinical and experimental settings.1-3 The VDR has been isolated from many cell types.mayoclinicproceedings. pancreas.174 with permission from The American Society for Bone and Mineral Research. the effects of vitamin D are not limited to mineral homeostasis and the maintenance of skeletal health. stomach.135 VITAMIN D AND EXTRASKELETAL HEALTH The small intestine.126 In a randomized. including type 1 diabetes mellitus. including psoriasis.188 and are being investigated for the potential treatment of many pathologic conditions.25(OH)2D with high affinity and mediates transcriptional gene regulation. brain.175 One population-based study reported that 25(OH)D levels between 16 and 38 ng/mL (40 and 94 nmol/L) were associated with better musculoskeletal function in the lower extremities of both active and sedentary ambulatory adults 60 years or older compared with levels less than 16 ng/mL (40 nmol/L). treatment with vitamin D plus calcium daily for 3 months reduced the risk of falling by 49% compared with calcium alone among elderly women in long-stay geriatric care174 (Figure 4).3 years) in long-term geriatric care.143 The hierarchy of evidence for the role of vitamin D 362 Mayo Clin Proc. cardiovascular heart disease.176.25(OH)2D3 and also 1α-hydroxyvitamin D3 (1α[OH]D3) significantly reduced the number of falls for individuals with calcium intake of more than 512 mg/d. and evidence is growing that extrarenal synthesis of 1.187 In addition. 85. Other recent evidence suggests that vitamin D inadequacy may be a factor in loss of muscle mass and muscle strength (sarcopenia). daily therapy with 800 IU of vitamin D and 1200 mg of calcium accounted for a 49% reduction in the relative risk of falls among older women (mean age.1.127. and bones are the primary organs and tissues responsive to vitamin D that are involved in mineral metabolism that affects skeletal health.193 Since the primary function of vitamin D is to modulate calcium homeostasis. Crohn disease. the use of analogues for the treatment of conditions other than osteoporosis or osteomalacia could trigger hypercalcemia or other unwanted adverse effects. tissues.176.186. the enzyme responsible for conversion of 25(OH)D to the biologically active form of vitamin D (1. Adapted from J Bone Miner Res.4. and many common cancers. . type 1 diabetes mellitus. double-blind trial.

4. prostate. breast.181 The antiproliferative • www.1. including lung.176.1. Mass reproduce only with permission from Mayo Clinic Proceedings.25[OH]2D).25-dihydroxyvitamin D (1. and lung to modulate cell growth and reduce risk of the cells becoming malignant. In addition.81(3):353-373 For personal use. The circulating levels of 1. This may help explain the epidemiological evidence that sun exposure at lower altitudes and higher serum levels of 25(OH)D are related to a decreased risk of a wide variety of chronic illnesses.176.198 by reducing angiogenesis. and breast. The kidneys serve as the endocrine organ to convert 25-hydroxyvitamin D (25[OH]D) to 1.194 Analogues that are able to effect antiproliferative.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH FIGURE 5.4. prostate. locally produce 1.177. and reducing cell proliferation156-158 and metastases.25(OH)2D in the colon.25(OH)2D inhibits proliferation and induces differentiation into normally functioning cells.179. Thus. prodifferentiative.25(OH)2D can also potentially influence the activity of other tissues and cells that have a vitamin D receptor (VDR) and have no function in regulating calcium homeostasis and bone health. • VITAMIN D AND CANCER Vitamin D is one of the most potent hormones for regulating cell growth. among others.mayoclinicproceedings. it has been suggested that most cells. 1.177. Endocrine and autocrine or paracrine functions of 1. active T and B lymphocytes.25(OH)2D carries out its calcium-regulating functions for bone health by stimulating intestinal calcium and phosphorus absorption.151.176. Mayo Clin Proc. Researching the development of VDR ligands with attenuated calcemic potential is a difficult challenge.153 increasing cell differentiation and apoptosis of cancer cells. and prostate. . 1.197 Some evidence suggests that 1. the heart skeletal muscle.25(OH)2D helps to regulate cell growth and prevent cancer progression1.177. a multitude of in vitro studies with human and animal cells have shown that most tissues and cells not only express the VDR but also express the same 1α-hydroxylase as the kidney. blood pressure. 363 March 2006.191. More than 1000 VDR ligands with various bioactivities have been synthesized.156. breast. colon. It has been speculated that when 25(OH)D levels are above 30 ng/mL this serves as the substrate for the external 25(OH)D3-1α-hydroxylase to produce 1. The hierarchy of evidence for the role of vitamin D and its analogues on these nonskeletal effects is summarized in Table 2. and immunomodulation changes while maintaining calcium homeostasis are of particular interest as potential treatments for nonskeletal diseases.25(OH)2D3 to help regulate a variety of cellular functions including growth and differentiation. These include.25(OH)2D.126.

Mass reproduce only with permission from Mayo Clinic Proceedings.125.209 postulated that roughly 25% of deaths due to breast cancer among women in northern Europe could be attributed to inadequate vitamin D levels.25(OH)2D completes this task. In a small blinded study of 18 hypertensive patients randomized to receive repeated exposure to artificial UV-A radiation (which cannot produce vitamin D3) or UV-B radiation (which leads to cutaneous vitamin D3 synthesis) treatment. and prostate cancers. possibly due to living at higher latitudes.163 This insightful observation went unnoticed until the 1980s. had March 2006.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH and prodifferentiative activity of VDR ligands was noted almost 3 decades ago.215 Ecological evidence also exists that African Americans.182.214 1.161. Evidence now exists to support the link between increased sunlight exposure and a lower incidence of many cancers. a new autocrine or paracrine function for vitamin D was revealed (Figure 5). Once 1.204 Grant166.164. colon.158. who have been shown to be at greater risk of vitamin D deficiency.176.1. Although some patients experienced remission.150. it was perplexing how increased exposure to sunlight. . and prostate cancer cells. When similar cells were transfected with a plasmid that contained the CYP27B gene.177.2. results of human trials for the treatment of preleukemia with VDR ligands were disappointing.199. the cellular proliferative activity decreased similarly to cells treated with 1. lung. who showed no change in serum • www.4.25(OH)2D. an increase in sun exposure or dietary vitamin D intake does not.214.165. one of the most important hormones for regulating blood pressure. and all patients eventually died. When the CYP27B transfected cells were treated with 25(OH)D3.180. there was no effect on the cancer cell’s proliferation activity.25(OH)2D3.162.mayoclinicproceedings. particularly since latitude is not always a strong predictor of vitamin D status. the UV-B treatment group showed an average 6mm Hg decrease in both systolic and diastolic blood pressure and a 180% increase in serum 25(OH)D levels vs the group exposed to UV-A. the treatment caused severe hypercalcemia.212 In one study. • tightly controls the amount of 1. a 1.1. Adding to these data are several retrospective and prospective observational studies that have reported decreases of 50% or greater in risk of large bowel cancer and prostate cancer when serum 25(OH)D levels are greater than 20 ng/mL (50 nmol/L) or vitamin D intake is increased.81(3):353-373 For personal use.182. This concept was supported by the observation that when a prostate cancer cell line LNCaP that did not express CYP27B was incubated with 25(OH)D3. osteosarcomas. higher vitamin D intake.181 Thus.25(OH)2D had one fifth the risk of breast cancer vs those in the lowest quartile. breast. when Garland et al132. and higher serum 25(OH)D levels could reduce risk of cancer in these tissues. Similar observations have been made in breast. and melanomas are responsive to the antiproliferative effects of 1.177. including the prostate.189 VITAMIN D AND CARDIOVASCULAR DISEASE Adding to the evidence of the effect of vitamin D on extraskeletal tissues are data that suggest that inadequate vitamin D and calcium and living at higher latitudes may be independent contributing factors in the pathogenesis and progression of hypertension and cardiovascular disease.202-204 Similar results have been observed for breast cancer. the cells were able to convert 25(OH)D3 to and that both men and women with greater sun exposure were less likely to die prematurely of cancer.182 and several epidemiological studies have reported that higher 25(OH)D levels are associated with reduced cancer incidence and decreased cancer-related mortality.25(OH)2D locally to regulate cell growth and differentiation.25(OH)2D3. it then induces the 25(OH)D-24-hydroxylase gene (CYP24B) to catabolize it to the biologically inactive calcitroic acid (Figure 1). and colon.176. However.124 Women in the National Health and Nutrition Examination Survey with self-reported high intake of vitamin D from supplements or high lifetime sun exposure had a significantly reduced risk of breast cancer. colon.25(OH)2D.201.177 Tanaka et al159 showed that mouse and human leukemic cells that expressed the VDR had growth inhibition and were stimulated to differentiate into mature macrophages when treated with 1α.161. Although it was recognized that most cells. colon. In 1998.160 Several in vitro studies have shown that breast.204 As early as 1941.1.25(OH)2D. people who live at higher latitudes in the United States were noted to have increased risks of breast.25(OH)2D it produces. CYP27B) to convert 25(OH)D to 1. and a multitude of other organs and tissues.202 reported increased breast and colon cancer risks for those living at higher latitudes in the United States.209-211 Such ecologic studies can be a weak form of evidence.2.213 This observation supports the hypothesis that increasing circulating concentrations of 25(OH)D provide most cells with the substrate to make 1. skin. Schwartz et al179 reported that normal prostate tissue and prostate cancer tissue from prostate biopsy specimens had the enzymatic machinery (25[OH]D-1α-hydroxylase. Suda et al138 were then able to show that leukemic mice survived longer if they were treated with 1α(OH)D3.2.166.25(OH)2D is involved in controlling the production of renin.4.176. also have a greater risk of hypertension and cardiovascular disease. women in the highest quartile of serum 1. It was known that the kidney 364 Mayo Clin Proc.25(OH)2D3. Although PTH and hypophosphatemia increase the renal production of 1.216 These studies do not directly provide a cause-and-effect relationship between vitamin D and cardiovascular health but suggest a provocative hypothesis for further research.25(OH)2D3 analogue.1.

216 Sowers et al134 also reported a positive association between 1. This suggested that hyperproliferative skin disorders such as psoriasis might be responsive to treatment with 1.200 Elevated transforming growth factor β1 levels have been associated with the stable phase of multiple sclerosis.25(OH)2D3.166.mayoclinicproceedings.141.205.141. reducing cytokine production and lymphocyte proliferation. 22 patients with prolonged critical illnesses were compared with matched controls and then randomized to daily vitamin D supplement of either ±200 IU or ±500 IU. • eration of human keratinocytes that express the VDR in vitro and accelerated their differentiation.24(OH)2D3. whereas reduced levels have been associated with relapsing-remitting multiple sclerosis. 74 years) found that vitamin D and calcium were more effective in reducing systolic blood pressure than calcium alone. .25(OH)2D acts as an immunomodulator.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH 25(OH)D levels or blood pressure. one observational with age-matched controls220 and a prospective cohort study of 34. are among the first-line treatments used for psoriasis. this study was confounded because the patients in general were at high risk of cardiovascular heart disease and there was no measure of vitamin D status to substantiate the “high intake.142. a model of human type 1 diabetes mellitus.225 However. from 1991 to 2001]) reported that higher intake of vitamin D was associated with a lower risk of developing multiple sclerosis.228 Two related observational studies229 (the Nurses’ Health Study [N=92. However.144 Zella and DeLuca145 have also shown that very large doses of vitamin D were able to suppress the development of insulitis and diabetes in the nonobese diabetic mouse. 1.223 VITAMIN D AND MULTIPLE SCLEROSIS As with previous epidemiological data reporting a latitudinal risk gradient for cancer and cardiovascular disease. the observed differences could be related to any number of other factors that were not measured.217 McCarty218 hypothesized that the excess of coronary mortality observed in winter may be related to inadequate levels of vitamin D and suggested a possible role for vitamin D in maintaining vascular health.486 postmenopausal women (55-69 years of age). some studies have reported contradictory findings.217 In one unblinded study. Lindén219 reported that vitamin D intake was elevated in patients with myocardial infarctions vs randomly selected age.163. with little or no adverse effects. A birth • www.and sex-matched controls who had no prior myocardial infarction or angina pectoris. The results demonstrated that a 500-IU/d dose of vitamin D reduced C-reactive protein levels by more than 25% in the critically ill patients vs the matched controls who did not receive supplementation. as with other ecological studies.221 found that 25(OH)D levels were not elevated in patients with myocardial infarctions and ischemic heart disease.25(OH)2D3. as with hypertension.1.142 In addition.223 Today.193. the administration of placebo-controlled. VITAMIN D AND TYPE I DIABETES MELLITUS 1. blood levels of 25(OH)D were not obtained. making it difficult to know the vitamin D status of the subjects who were studied.215 a similar risk gradient exists for developing multiple sclerosis.25(OH)2D prevents the development of experimentally induced type 1 diabetes mellitus.25(OH)2D3 inhibited the prolifMayo Clin Proc.201 A randomized. from 1980 to 2000] and the Nurses’ Health Study II [N=95.205.142. β-islet cells express the VDR and respond to 1. Although this evidence suggests that increased vitamin D is associated with reduced risk of hypertension. which have been implicated in the destruction of insulin-secreting β cells in the pancreas and the development of type 1 diabetes mellitus. Jorde and Bonaa136 reported no link between vitamin D intake and blood pressure. Furthermore. Elevated C-reactive protein levels have been associated with increased cardiovascular events.196 Smith et al27 showed that 1.204. and 365 March 2006. One double-blinded RCT involving patients with multiple sclerosis who were randomized to receive either vitamin D supplementation or placebo showed that patients who received supplementation had increased serum transforming growth factor β1 levels vs those who did not receive supplementation.222 Initial treatments with topical 1.231 In animals.25(OH)2D and vitamin D inadequacy and hypertension.224-226 Subjects who were born and/or lived below 35°N latitude for the first decade of life had decreased overall lifetime risks of developing multiple sclerosis.” Two other studies. which meant that they were not receiving enough vitamin D. Mass reproduce only with permission from Mayo Clinic Proceedings.193.230. However.206.81(3):353-373 For personal use.25(OH)2D by increasing insulin production.310. showed great improvements in reducing the severity and area of psoriatic lesions.209. In an observational study of vitamin D and myocardial infarction. double-blind clinical trial of 148 elderly women (mean age. contradictory findings suggest that increased vitamin D may be a causative factor or play no role in cardiovascular disease. 3 vitamin D analogues including calcipotriene. The authors noted that most participants older than 50 years were receiving less than 400 IU of vitamin D from their diet.227. VITAMIN D AND PSORIASIS One of the great successes of vitamin D therapy for treating an extraskeletal disorder is in the treatment of psoriasis.

84.107.92. and 600 IU/d for those older than 70 years.152 have shown that 1.97.236 Vitamin D supplementation and exposure to sunlight or simulated sunlight have been shown to increase serum 25(OH)D levels in elderly patients 11. • which vitamin D prevents transplantation-induced osteoporosis may be comparable to the mechanism by which it suppresses secondary hyperparathyroidism brought on by immunosuppressive agents such as corticosteroids and/ or cyclosporine. including those with inadequate sunlight exposure. established by the European Commission.247.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH cohort study involving 10. Children who regularly took the recommended supplemental dose of 2000 IU/d of vitamin D during their first year of life had a rate ratio of 0.28.74 VITAMIN D DOSING. osteoarthritis. independent of BMD. Many of these studies are epidemiological studies and animal models.000 IU of vitamin D2 may be necessary to boost 25(OH)D levels into the desired range of more than 30 to 50 ng/mL (75-125 nmol/L). The Institute of Medicine’s adequate intake for the United States and Canada is 200 IU/d for all children and adults younger than 51 years.235 Nagpal et al188 postulate that the mechanism by 366 Mayo Clin Proc.366 children conducted in Finland showed that higher dietary vitamin D supplementation was associated with reduced risk of type 1 diabetes mellitus.241 This recommendation is consistent with that of the US Food and Drug Administration’s daily recommended value of 400 IU/d (10 µg/d) of vitamin D3 regardless of age. a synthetic analogue of 1. Recent findings suggest that vitamin D intake is inversely associated with rheumatoid arthritis208 and that 1.94. More recently. systemic lupus erythematosus.000 women throughout 11 years and found that those whose daily vitamin D intake was less than 200 IU were 33% more likely to develop rheumatoid arthritis compared with women with higher intake levels.89.1. 0.05-0. . especially in elderly house-bound people.89) for type 1 diabetes mellitus compared with those who regularly received less than 2000 IU/d.25(OH)2D3 supplementation can inhibit disease progression in mouse models of human Lyme arthritis. These data do not support a direct cause-and-effect relationship but suggest that further studies are warranted. Dietrich et al137 reported that low serum levels of 25(OH)D may be associated with periodontal disease.1. 400 IU/d for people aged 51 to 70 years.000 IU/wk of vitamin D2 for 8 weeks. SUPPLEMENTATION. Abe et al153 were also able to alleviate symptoms in a mouse model of systemic lupus erythematosus without inducing hypercalcemia by using 22-oxa-1.147 Merlino et al208 tracked approximately 30. AND UV IRRADIATION AND/OR SENSIBLE SUN EXPOSURE Supplementation with vitamin D has been estimated to prevent vitamin D deficiency in approximately 98% of the general population. This is especially true in the winter or for children and adults not exposed to sunlight.245. Krall et al233 found that calcium and vitamin D supplementation was associated with a reduced risk of tooth loss in elderly patients.188 and both vascular and nonvascular March 2006. and periodontal disease. Stene et al130 reported a lower risk of type 1 diabetes mellitus in the children of mothers who took cod liver oil during their pregnancy.000 IU.102.25(OH)2D3.244 an intake of 400 IU/d may represent a minimum.242 Because it has been suggested that amounts up to 1000 IU/d of vitamin D3 may be needed to maintain a healthy 25(OH)D level of more than 30 ng/mL (75 nmol/L).16. then checking 25(OH)D levels.11 In some cases. including rheumatoid arthritis.155 Treatment of nonobese diabetic mice with a vitamin D analogue KH1060 in combination with cyclosporine achieved 100% early graft success of xenogenic islets.248 TREATMENT OF SEVERE VITAMIN D DEFICIENCY Although severe vitamin D deficiency (25[OH] levels <10 ng/mL [25 nmol/L]) is much less common than inadequacy. Mass reproduce only with permission from Mayo Clinic Proceedings.25(OH)2D3. VITAMIN D IN OTHER DISEASES A possible role of vitamin D has also been implicated in several other diseases. VDR ligands have been used experimentally to attenuate bone loss after organ transplantation.236 A report by the Scientific Committee for Food.000 IU/wk for 2 months have been administered without toxicity. The best method for treating vitamin D deficiency is an oral dose of 50.25(OH)2D3 can prevent and ameliorate symptoms of inflammatory bowel disease in a mouse model. the mechanism appears to involve pregnane X receptor–enhanced CYP24 gene expression. it does occur.5. For • www.207 Likewise. Cantorna et al148.4 and has only been observed from dietary intake when daily doses exceed 10.87. Experimental evidence also exits for an immunomodulatory role of VDR ligands in attenuating rejection of rat aortic allografts154.246 Doses of 4000 IU/d for 3 months and 50. and the effect in humans is unknown.234 In addition.243.21. inflammatory bowel disease. indicated that adults 65 years and older should receive 400 IU/d of vitamin D3 and suggested that the requirements of all adults. McAlindon et al232 observed that a higher intake of vitamin D and higher blood levels of 25(OH)D decreased progression of osteoarthritis in men and women by more than 60%.11. Vitamin D toxicity has not been reported from longterm exposure to sunlight1.237-240 (Figure 3). would be met by this dietary intake.22 (range.81(3):353-373 For personal use.mayoclinicproceedings. another once-weekly 8-week course of 50.

Some of the mechanisms by which vitamin D exerts its noncalcemic effects include apoptosis.248. and other autoimmune diseases (Table 2). hypertension. including cancer. evidentiary value varies.250-252 Vitamin D inadequacy is a global problem. severe vitamin D deficiency (25[OH]D.81(3):353-373 For personal use. with prospective cohort studies (such as the Framingham Study. the Nurses’ Health Study. osteomalacia. In adults. inadequate dietary intake and supplementation. inadequate vitamin D can result in secondary hyperparathyroidism.254.165.1. it should be appreciated that most melanomas occur on the least sun• www. antiangiogenesis. and immunomodulation (Figure 5) (Table 2). The putative nonmusculoskeletal effects of vitamin D may become better understood if appropriate trials are conducted.16.257 However.259 These skin cancers. and other factors. As indicated in Table 2. but at present inferences about such effects must be made with caution. This is because melanocytes are neurocrest cells and when they become malignant they express the Slug gene. Fortunately. sunscreen use.258. if detected early. and increased risk of fragility fractures. clinicians. vitamin D supplements are widely available and relatively inexpensive. results from nontrial studies are important because they identify associations and suggest hypotheses that can be tested more rigorously in RCTs. 1000 IU of vitamin D3 intake should be maintained. Similarly. especially if the patient is prone to vitamin D deficiency. the current level of evidence for associations of vitamin D with nonmusculoskeletal conditions is generally weaker than that for its calcemic and musculoskeletal effects (falls and fractures). The reported nonmusculoMayo Clin Proc. cardiovascular disease.253 However. including obesity. Alternatively. prodifferentiation. vitamin D inadequacy is not widely recognized as a problem by physicians and patients.249 Exposure to direct sunlight typically of no more than 5 to 10 minutes on the arms and legs between the hours of 10 AM and 3 PM during the spring. decreased BMD.255 Even among observational studies.256. Despite some negative studies.143 Many lines of research support the concept that inadequate vitamin D may be involved in the pathogenesis and/ or progression of several disorders. antiproliferation. Finally. <10 ng/mL [24. All types of non-RCT studies are subject to the risk of several biases. neuromuscular diseases. These observations highlight the need for greater awareness among researchers.mayoclinicproceedings. and patients of the high prevalence of vitamin D inadequacy and more aggressive screening for vitamin D inadequacy with a serum 25(OH)D determination. 10-29 ng/mL [24.238-240.107 fractures with vitamin D (given in combination with calcium in most trials). however. after correcting the deficiency. whereas bench research and expert opinion provide the least. • skeletal associations have come primarily from observational studies in humans or laboratory experiments (in vivo and in vitro). Cutaneous exposure to sunlight or artificial UV-B such as a tanning bed is also helpful. It is well documented that excessive exposure to sunlight. however. are usually easily treated and often cured. and skin pigmentation. results of a metaanalysis of RCTs suggest that vitamin D can reduce the risk of falls. 367 March 2006. Despite evidence of its profound importance to human health.150. the available supporting data are sometimes conflicting and generally represent a low level of evidence. Mass reproduce only with permission from Mayo Clinic Proceedings. and fall will prevent vitamin D inadequacy. is related to increased risk of squamous and basal cell carcinoma. Melanoma. randomized. and vitamin D inadequacy (25[OH]D. The presence of VDR in tissues other than bone and muscle suggests the possibility of important effects of vitamin D.000 IU every 2 weeks will sustain them in a vitamin D–sufficent state. especially the number of sunburning experiences. medication use.260 However.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH patients prone to developing vitamin D deficiency.76.65 CONCLUSION Vitamin D is important for calcium and phosphorus homeostasis and musculoskeletal health. covering all skin with clothing. particularly among high-risk populations such as elderly patients and patients with osteoporosis. especially in populations with low vitamin D status and low calcium intake at baseline. giving patients 50.4 nmol/L]) can impair or retard attainment of peak bone mass. Risk factors for low vitamin D include lack of exposure to sufficient sunlight. is one of the most aggressive and deadly forms of skin cancer. which are minimized by the design of RCTs: the qualitative and quantitative differences between observational and trial findings about hormone replacement therapy for postmenopausal women are probably the most noteworthy recent demonstration of the limitations of observational data. especially among elderly patients and patients with osteoporosis. which is responsible for its quick exit from skin metastasizing to various organs. age. the preponderance of evidence from RCTs supports a reduction in the risk of vertebral100 and nonvertebral92. In children. making it difficult to detect and treat. osteoarthritis. or the Study of Osteoporotic Fractures) yielding the most clinically useful information. summer.9-72. placebocontrolled. diabetes. .9 nmol/L]) manifests as rickets. we should not forget the important role that sensible sun exposure has in providing both young and old people with their vitamin D requirement. double-blind clinical trials (or meta-analyses of these trials) are considered to provide the highest level of evidence because randomization and blinding minimize the risk of bias in estimating treatment effects.

Sunscreens supress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab. 1987. Sahyoun NR. 10. 2005. 2004.10:94-111. Am J Clin Nutr. Heaney RP. San Diego. 15.113:1950-1957. Henderson SL. 16. type 1 diabetes. 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. J Clin Endocrinol Metab. Holick MF. Holick MF. Kuroki T. Feldman HA. Abe E. Kennedy et al259 reported that lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma. Furthermore. Bone. 2004. 9.81(3):353-373 • www. Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. J Clin Endocrinol Metab. Veronikis IE. Am J Clin Nutr. Chen TC. Endocrinology. Sullivan SS. Am J Clin Nutr.16. 8. 1989. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. suppl):1678S-1688S. and cardiovascular disease. Ide L.25-dihydroxyvitamin D3. Suda T. 19.249:559-563. cancers. ed. Koutkia P. MacLaughlin JA. Holick MF.216:1001-1003. Gunter EW. 14. deCosta BR.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH exposed areas. Lancet. Tangpricha V. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Allen M. 30. and Chang et al264 reported that a history of increased sun exposure was associated with reduced risk of non–Hodgkin lymphoma. 34.25dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. 22.90:3129. Clemens TL. 21. 2001. Segal E. 2002. 27. Binkley N. 2005. Osteoporos Int.30:771-777. 25. Osteoporos Int. in Australia and New Zealand. Bikle DD. Webb AR. 2004. Adams JS.9:87-98. 12.74:206-210. Hosomi J. 2. 2005. Altern Med Rev. Gallagher JC. Kauppinen-Mäkelin R. J Am Coll Nutr. Zinnman H. REFERENCES 1. Holick MF. 1998. Vol 1. 2004. 2004. Holick MF. Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites. 2005:609-630.7:439-443. Holick MF. Walworth NC. Chen TC.86:1212-1221. et al. 26. Emans SJ. 20. 4. 2002. 2nd ed. 25-OH-vitamin D assays [letter]. • March 2006. Holick MF. et al. Shao Q. Hosoi J.80(6. Kärkkäinen J. 2001. Holick M. Proc Natl Acad Sci U S A. Holick MF. Holick MF.90:3215-3224. 2005. Rieke SM.52:474-475. despite the fact that lifetime sun exposure did not diminish the number of melanocytic nevi or atypical nevi. et al. Chapuy MC. Dowell MS.105:971-974. Siris ES. 368 Mayo Clin Proc. Kinyamu HK. Holick MF.89:3152-3157. Halteman WA. 2003. Am J Clin Nutr. Holick MF. An international comparision of serum 25-hydroxyvitamin D measurements. The UV Advantage. Grant WB. Raz B. Balhorn KE. where the incidence of skin cancer is the highest in the world. et al. 1999. Science. J Invest Dermatol. DePeter KC. Jenkins M. Hale CA. Binkley N.1:74-76. Holick MF. 28. Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation. Adherence to vitamin D supplementation in elderly patients after hip fracture [letter]. 1992.mayoclinicproceedings. Krueger D. 1998. even though it is associated with increased risk of relatively benign skin cancer. Clair for assistance with preparation of the submitted manuscript. Effect of 1α. Osteoporos Int. 31. No substantiated scientific evidence exists to suggest that sensible suberythemal sun exposure significantly increases risk of any type of skin cancer and certainly not melanoma. In: Feldman D. These observations are consistent with the suggestion of Apperly163 that sun exposure seems to provide an immunity for most deadly cancers. Fraser WD. Tamir A.261.92:3124-3126. It is hoped that this message will be heard loud and clear and that this recommendation will also be adopted worldwide. J Clin Endocrinol Metab. Cowgill CS. 13. Vitamin D: role in skin and hair.79:362-371. Mass reproduce only with permission from Mayo Clinic Proceedings. Holick MF. Liu WW. 1997.22:142-146. Tähtelä R. Holick MF. Rafferty KA. Ish-Shalom S. Glendenning P. The vitamin D content of fortified milk and infant formula.90:3128-3129. 1994: vitamin D—new horizons for the 21st century.8(suppl 2):S24-S29. Vitamin D. the New Zealand Bone and Mineral Society in collaboration with the Australian College of Dermatologists and the Cancer Council of Australia have recommended a balance between avoiding an increased risk of skin cancer and achieving enough UV radiation to maintain adequate vitamin D levels. Calif: Elsevier Academic Press.262 Furthermore. 1995.22:477-501. J Am Diet Assoc. Lancet. 7. Berwick et al263 reported that sun exposure is associated with increased survival in patients with melanoma.79:890]. J Intern Med. 2001. Bendich A. Malabanan A. Indeed. Lips P. Outila TA. NewYork. 2003. Maamer M. Dawson-Hughes B. MacLaughlin JA. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin. Holick MF. 1982. J Clin Endocrinol Metab. Matsuoka LY. 1983. Lips P. 1998. 29. Holick MF. . 17. The negative publicity regarding sun exposure during the past 30 years has resulted in a vitamin D deficiency pandemic. Pols HA. Vitamin D: importance in the prevention of cancers. Prevalence of vitamin D deficiency among healthy adolescents. Holick MF. 1994. 2001.326:1178-1181.68:882-887. 2001. Oleksik A. Smith EL. 25-OH-vitamin D assays [letter]. Anderson RR. Am J Clin Nutr. 2004.9:394-397. Vitamin D status affects serum parathyroid hormone concentrations during winter in female adolescents: associations with forearm bone mineral density. Dawson-Hughes B.60:619-630. Endocr Rev. Karkkainen MU. J Clin Endocrinol Metab. Chen TC. I thank Dr Joseph West and Christine McCrary Sisk of Merck and Catherine St. 24.77:1478-1483. Holick MF. NY: iBooks. Tian XQ. 1986.158:531-537. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. Prevalence of vitamin D insufficiency in an adult normal population. 33. 32.351:805-806. Grace E. Curr Opin Endocrinol Diabetes. J Clin Endocrinol Metab. and osteoporosis [published correction appears in Am J Clin Nutr. Redefining vitamin D insufficiency [letter]. Lips P. Adolescent girls in Maine are at risk for vitamin D insufficiency. Fortification of orange juice with vitamin D: a novel approach to enhance vitamin D nutritional health. 23. 1982. Sunlight and vitamin D for bone health and prevention of autoimmune diseases. N Engl J Med.86:709-714. Calvo MS. Chapuy MC. 2005. 5. Välimäki MJ. Holick MF. Evolutionary importance for the membrane enhancement of the production of vitamin D3 in the skin of poikilothermic animals. Lamberg-Allardt CJ. Benefits and requirements of vitamin D for optimal health: a review.86:3008]. heart disease. Regulation of terminal differentiation of cultured mouse epidermal cells by 1 alpha. Preziosi P. 2003. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. 3. Wortsman For personal use. J Am Geriatr Soc. Gordon CM.67:342-348. 11. 6. Duong T. Arch Pediatr Adolesc Med. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. McCollum Award Lecture. Rosen CJ. Perez AA. Am J Clin Nutr. High prevalence of hypovitaminosis D in Finnish medical inand outpatients. 18. Looker AC. Löyttyniemi E. The important role that sensible sun exposure has in providing vitamin D for the world’s population needs to be reevaluated.64:1165-1168. Vitamin D requirements for humans of all ages: new increased requirements for women and men 50 years and older.

Harwood RH. 42. Petranick KM. Functional indices of vitamin D status and ramifications of vitamin D deficiency.338:777-783. Holick MF.3:1067-1070. 1995. 1984. Photobiology of vitamin D. Differences in vitamin D status between countries in young adults and the elderly. 49. 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. Holick MF. ed. Fernandez-Martin JL. Clin Med. Hollis BW. Blau EM. J Clin Endocrinol Metab. Wortsman J. The prevention and treatment of glucocorticoid-induced osteoporosis in clinical practice. Balhorn KE. Dawson-Hughes B.107:E53. Di Munno O. Adami S. 1997. J Lab Clin Med. van den Berg H. high bone turnover. Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients. 45. 43.121:1485-1488. Freany R. Aaron JE. Chen TC. Aksnes L. Shaw S. Gallagher JC. 2004.11:247-259. 1974. N Engl J Med. Totowa. 2005. Bruning AL. Maugeri D. CMAJ.321:1777-1783.28:181185.281:1505-1511. et al. Kolm P. 2004.14:577-582. Occult vitamin D deficiency in postmenopausal US women with acute hip fracture. 88:5109-5115. Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women. J Clin Endocrinol Metab. Holick MF. McKenna MJ.78:1463-1470. Am J Clin Nutr. 2003. Matsuoka LY. Greene A. 1989.65: 790-797. elderly population. Nesby-O’Dell S.21:1069-1074. Paris PW. Lo CW. Hosking DJ. Sahyoun N. Physiology.63(6. Decreased bioavailability of vitamin D in obesity [published correction appears in Am J Clin Nutr. Fernandez-Coto MT. Gaugris S. 52. Hypovitaminosis D in healthy schoolchildrren. Epstein S. Arunabh S. Coolidge JA. J Clin Invest. Choucair M. Dawson-Hughes B. Robert A. Vitamin D insufficiency in a population of healthy western Canadians [published correction appears in CMAJ.60:81-86. Taha SA. Treatment of vitamin D deficiency due to Crohn’s disease with tanning bed ultraviolet B radiation. Photochem Photobiol Sci.42:644-649. Osteoporos Int.80(6. Diaz-Lopez JB.4: 431-436. Daily duration of vitamin D synthesis in human skin with relation to latitude. Romagonoli E. Nolan J. Shaw NJ. 44. Holick MF. LeBoff MS. Brustad M. 1998. Body fat content and 25-hydroxyvitamin D levels in healthy women. Low 25-hydroxyvitamin D and normal serum calcium concentrations in Saudi Arabia: Riyadh region.274:16831686. et al. • March 2006. 2005. Walker-Bone K. Am J Med.88: 157-161. nonspecific musculoskeletal pain. Mayo Clin Proc. 1991. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey. 2004. . 48. 54.98:667-676. Dost SM.67:373-378. Clemens TL. Mass reproduce only with permission from Mayo Clinic Proceedings. N Engl J Med.93:69-77. 56. Webb AR.76:370-373. 63. Kelly M. Bombardieri S. multiracial.1:229233. Martinez P. NJ: Humana Press. 72.85:4125-4130. Gastroenterology. 85. Sahota O. Cogswell ME. J Clin Invest.85:S44-S48. Lu Z. Solomon L. Kurth H. Sedrani SH. 77. Chen TC. Troiano L. J Clin Endocrinol Metab. 1998. Romagnoli E. 55.mayoclinicproceedings. and solar ultraviolet. Heaney RP. 58. J Clin Endocrinol Metab. Carnevale V. Kline L. 1985. Scarnecchia L. Kimlin MG. Holick MF. pt 1):203-209. Oexmann MJ. Holick MF. Gaynor K. 80. 2005 [Epub ahead of print]. 53.76:1536-1538. J Bone Miner Res. et al. A randomised. Hanley DA. 2000. Lloyd-Jones DM. Abstract SU582. Wright J. LeBoff MS. Pollack S. Vitamin D status and secondary hyperparathyroidism: the importance of 25-hydroxyvitamin D cut-off levels. 2002. Curr Med Res Opin. Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes. Lowik MR. 82. El-Hajj Fuleihan G. suppl):1706S-1709S.135:332-337.13:724-730. 1988-1994. Ann Nutr Metab. Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. Mazzantini M.33:45-51. Serum vitamin D concentrations among elderly people in Europe. 41. Pini G. Giorgino R. total ozone. Simonelli C. Prevalence of severe hypovitaminosis D in patients with persistent. Lancet. 57. and Clinical Applications. Snijder MB. Engelsen O. Bevilacqua M. 83. controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study. altitude. Chen YT. Naves-Diaz ML.179:119-129. Am J Clin Nutr. et al. 67. Bell NH. Morancey J. 75.112:659662. Thomas MK. Koutkia P. 38. Low vitamin D status. Prevalence of vitamin D inadequacy in a minimal trauma fracture population.19(suppl 1):S342. Mosca M. Aging decreases the capacity of human skin to produce vitamin D3. Chen TC. et al. 65. Glowacki J. Dallal GE. Am J Clin Nutr. Hurwitz S. Masud T. 127:536-538. Chen Y. Pediatr Res. Brenneman SK. Bone Miner. Rini GB.90:4119-4123. 2003. 2004. 64. 2004. Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D. 40. Matsuoka LY. 66. aerosols and cloud thickness. Boonen S. Gundberg CM. Nabulsi M.126:452-457. Davison KS. Am J Clin Nutr. Kohlmeier L. Krall EA. 1992. Arch Dermatol. 1985. 2005. Rafferty KA. 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. Gomez-Alonso C. Thadhani RI. Osteoporos Int. 2004. 50. 47. Nguyen M. McKenna MJ. Visser M. 2005. Frequency of osteomalacia and osteoporosis in fractures of the proximal femur.167:850]. Anderson J. Vitamin D: Molecular Biology. et al.81(3):353-373 • www. Yeh J. A high prevalence of vitamin D insufficiency/deficiency in a minimal trauma fracture population [abstract]. 2004. Am J Med. 2003. 36. J Endocrinol. 71. Swanson L. et al.81:133-137. MacLaughlin J. Wortsman J. Osteomalacia and osteoporosis in femoral neck fracture. 1997.11:269-279.77:1342]. Bentkover JD.18:739-741. Pearce EN. Plotnikoff GA. Heaney RP. Lancet.76:187-192. Nutr Rev. Morancey JA. Vitamin D insufficiency among free-living healthy young adults. Compensation for the interracial variance in the cutaneous synthesis of vitamin D. 1985. 1973. J Clin Invest. 2003. Holick MF. ground cover. Pediatrics. Marshall T. 2005. Osteoporosis and vitamin-D deficiency among postmenopausal women with osteoarthritis undergoing total hip arthroplasty. Hollis BW. Soteriades E. Haddad JG Jr. Pal BR. Matsuoka LY. 1995. Tangpricha V. Gloth FM III. Age. Pascussi JM. Cannata-Andia JB. Living in low-latitude regions in the United States does not prevent poor vitamin D status.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH 35. 81. JAMA. Quigley JM. JAMA. 2005. Mayo Clin Proc. 2002. Vitamin D insufficiency and hyperparathyroidism in a low income.115:177-186. In: Holick MF. 74. 2002.66:454]. Hordon LD. Sen SS. 2003. J Bone Miner Res.346:207-210. Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women. 37.166:1517-1524. Vitamin D inadequacy among post-menopausal women: a systematic review. Caravella P. Chen TC. Hull R. Tobin JD. Lu Z. Hypovitaminosis D in medical inpatients. van Dam RM. Holick MF. Manfredi G. 79. Vitamin D insufficiency in North America. 25-Hydroxyvitamin D and total calcium: extraordinarily low plasma concentrations in Saudi mothers and their neonates. 68. Peacock M. Thornhill TS. Kinyamu HK. Isaia G. 46. 2002. 70. 62. Kidney Int Suppl. Weiss TW. Racial pigmentation and the cutaneous synthesis of vitamin D. Scanlon KS. Distribution analysis of vitamin D highlights differences in population subgroups: preliminary observations from a pilot study in UK adults. Br J Nutr. 2001. 2001. Age Ageing. Rucker D. Chen TC. Haddad JG. Lupus. Wood A. 76. 39. 1984. et al. Wortsman J. 2003. Mudgal S. et al. Gallagher JC. 1999. J Clin Endocrinol Metab. Swanson L. Lund E. Minisola S. 2003. Passeri G. Delle Sedie A. 51. 61. 73. 84. Hurwitz S. and bone fractures in centenarians. van der Wielen RP. Prevalence of vitamin D insufficiency in an osteoporosis population in Southern California [abstract].com 369 For personal use. Risk factors for osteoporosis in female patients with systemic lupus erythematosus. Franklin J. Estimations of the human ‘vitamin D’ UV exposure in the USA. vitamin D. Aloia JF. Sedrani SH. 59. 1990.72:690-693. 60. Vitamin D deficiency in homebound elderly persons.2:1104-1105. J Nutr. et al.85-A:23712377. 1989. Harris SS. Shary J. Wortsman J. Photochem Photobiol. Hanley DA. QJM. James C. 69. Johnson MA. Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage? Clin Endocrinol (Oxf). Park S. 1999. Evidence for alteration of the vitamin D-endocrine system in obese subjects. 1988. 2000.8(suppl 2):S3-S6. Abstract M373. Glowacki J. J Bone Joint Surg Am. Matsuoka LY. 2003. 2004. Lancet. 1999:17-37. Fick GH. Allan JA. Tannenbaum S. Simonelli C. et al. Am J Clin Nutr. 1995. 78. Schallhorn KA.19(suppl 1):S433. Fracture of the femoral neck in the elderly: bone ageing or disease? S Afr J Surg. Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors.

Porthouse J. The pharmacology of vitamin D. 1999. 96. Association between 25-hydroxy vitamin D levels.247:260-268. Cockayne S. BMJ. placebo-controlled clinical trial. 2005:995-1015. Wong JB. 95. Public Health Nutr.293:22572264. Vitamin D supplementation and fracture incidence in elderly persons: a randomized. 1992. 93. Tuohimaa P. vitamin D. et al. Sokoll LJ. The effects of calcitriol on falls and fractures and physical performance tests. Lips P. Papadimitropoulos E.365:1621-1628. Holick MF. 2000. Compston J. Dallal GE. including fortification strategies. • March 2006. Eriksen EF. Yeh J. Carbonelli MG. Giovannucci E. De Lorenzo A. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. Association between low levels of 1. 117. Lester GE.11:847-852. 1966. 1995. Ringsberg KA. Osteoporos Int. J Clin Endocrinol Metab. 106. Use of cod liver oil during pregnancy associated with lower risk of type I diabetes on the offspring [published correction appears in Diabetologia. For personal use. et al.3:73-77. et al. Gerdhem P. et al. Joner G. Willet WC. Mikkelsen K. 88. Mass reproduce only with permission from Mayo Clinic Proceedings. Effect of supplementation of calcium and vitamin D on bone mineral density and bone mineral content in peri. Randomized controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. 2003. Griffith L. Pharmacol Res. skin phenotype. 92.337:670-676. Am J Clin Nutr. Bone density parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women. Curr Med Res Opin.89:1572-1576. Chapuy P. 2002.6:235-239. Falconer G.330:1003-1006. 2000. Meunier PJ. Weinberg CR.1:201-204. Hakama M. 125. vitamin D-deficient patients.327:1637-1642. Vitamin D supplementation improves neuromuscular function in older people who fall. et al. Joner G. Cancer Causes Control. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. 1998. Poulsen L. Harkness M. Tenkanen L. Gallagher SJ. BMJ. Harris S. Gallagher JC. Cauley JA. Bouillon R. Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily.1451]. Schacht E. et al.23:570-578. Chen JS. Wedel H. Gallagher AP. Browner WS. 1991. 110. Helzlsouer K.67:644-650. J Clin Endocinol Metab.25-dihydroxyvitamin D and breast cancer risk. Glerup H. 2005. Comstock GW. Endocr Rev. Dawson-Hughes B. 104. et al. Rev Rhum Engl Ed. Avenell A. et al.165:1618-1623. Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population.78:1457-1459.and post-menopause women. Holick MF. case-control study. Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. De Pourcq L. Mazor Z. The effects of calcitriol therapy on serum interleukin-1.78:1128-1134. Nutrition and metabolic bone disease in old age. Candeloro N. Arch Intern Med. 2004. 2004.89-90:497-501. Cooper C. et al. Stene LC. RECORD): a randomised placebo-controlled trial. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). 2004. Helzlsouer KJ. 2004. Teppo L. Crozier SR.21:1355-1361. 2003. Mermerci B. Ann Intern Med. 2004. Nevitt MC. 127. Ponsonby AL. Johnell O. van der Mei IA. 1996. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. BMJ. Prostate cancer and prediagnostic levels of serum vitamin D metabolites (Maryland. milk consumption. Bauer D. Ahonen MH. Biochemical effects of calcium and vitamin D supplementation in elderly. Vitamin D deficiency and risk of hip fractures among disabled elderly stroke patients. Chapuy MC. Ann Intern Med. Khaw KT. physical activity. Willett WC. 105. 1996. Effect of annual intramuscular vitamin D supplementation on fracture risk in 9440 community-living older people: the Wessex Fracture Prevention Trial [abstract]. Age Ageing. Raphael HM.88:4623-4632. Mosekilde L. Stene LC. Bearne LM. Biogerontology. 2005. Tangrea J. Trivedi DP. 91. Dallal GE. 2005. 97. population-based. Foldspang A. 100. Tutkak H.43. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D. . Cancer Causes Control. Ensrud KE. 116. King C. Abstract 1220. Study of Osteoporotic Fractures Research Group. Vitamin D deficiency and aging: implications for general health and osteoporosis. 2005. Wells G. 115. Bone mineral density and the risk of incident nonspinal fractures in black and white women. JAMA.63:135-140. Diabetologia. ed. Wouters PJ. Malabanan AO. Shea B. 89. Sato Y. Osteoporos Int. Endogenous hormones and the risk of hip and vertebral fractures among older women. BMJ. Talwar SA.mayoclinicproceedings. Wells G. Visser M. Ooms ME. 2004. 2005. Osteoporosis Research Advisory Group. 112. Marshall D. Tugwell P.16:1425-1431. Bouter LM. 2000.52:230-236. Chapuy MC. controlled trial. Lancet. Lips P. N Engl J Med. Smith HE. et al. 2000. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. Vitamin D deficiency: what a pain it is [editorial]. Graafmans WC. Amsterdam. J Clin Endocrinol Metab. 122. 131. A Randomized controlled trial of vitamin D3 supplementation in African American women. Larsen ER.19(suppl 1):S57. Pietinen P. and risk of multiple sclerosis: case-control study. Van Roosbroeck D. Wiersinga A. 107.32:1673-1677. Exton-Smith AN. 101. Vanhove P. 87. Vieth R. Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited. Lips P. van Ginkel FC. N Engl J Med. J Bone Miner Res. Janowsky EC. Grant AM. Feskanich D. J Clin Endocrinol Metab. 119. et al. 130. 2003. Bezemer PD. 109.115:505-512. Am J Clin Nutr. 90. 33:589-595. Magnus P. and hip fractures: a prospective study among postmenopausal women. Deeg DJ. Guyatt G. Krall EA. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. 2nd ed. Norwegian Childhood Diabetes Study Group. Bischoff HA.50:637641. Ozoran K. Colditz GA. Turner AK. 99. March LM. BMJ.339:733-738. et al. Stahelin HB. Rosen C. Stanton BR. et al. Am J Epidemiol. VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Intern Med.312:1254-1259. 1997. Thomas JL. 98. JAMA. Cumming RG. et al. Cummings SR.327:316-317. Satoh K. 124. randomized. 123. Khaw KT. 2003.23:560-569. Calcium. Inanir A. Pollack S.145:926-934. Dawson-Hughes B. Dukas L. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. Sambrook PN. RECORD Trial Group. 1998. 1996. 2002. Doll R. 2005. Krall EA. Mayo Clin Proc. Glerup H. 126. Dwyer T. 2003. Bone turnover in prolonged critical illness: effect of vitamin D. J Int Med Res. Iacopino L. Vol 2. 108. et al. Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control. interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis. 2003.77:504-511. Aloia JF.8:615-625. Osteoporosis Methodology Group. 103. Di Daniele N. McQuillian C. 1992. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large. Hodkinson HM. 102. Endocr Rev. Sneyd MJ. Dhesi JK. Campbell MK.43:1093-1098.32:570-582. muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women.305:273-277. Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with low creatinine clearance of <65 ml/min. Calcium intake and fracture risk: results from the study of osteoporotic fractures.2:283-291. Dawson-Hughes B. J Clin Densitometr. Hollis BW. Vitamin D3 and calcium to prevent hip fractures in elderly women. 2005. Dukas L. van den Berghe G. 128. 2005. Past exposure to sun. Cummings SR. Meta-analyses of therapies for postmenopausal osteoporosis. In: Feldman D. a double-blind.293: 2102-2108.19:370-378. 2002. 2003. 129.326:469-475. Meta-analyses of therapies for postmenopausal osteoporosis. J Steroid Biochem Mol Biol.124:400-406. Osteoporosis Research Advisory Group.81(3):353-373 • www. Asoh T. 94. Vitamin D. Obrant KJ. IX: summary of meta-analyses of therapies for postmenopausal osteoporosis. 2001. Kondo I. 111. Duboeuf F. 118. institutionalized. J Am Geriatr Soc. 1997.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH 86. Lui LY.16:198-203. Finlay F. 370 Mayo Clin Proc. Severe generalized bone pain and osteoporosis in a premenopausal black female: effect of vitamin D replacement. United States). Bischoff-Ferrari HA. J Bone Miner Res. Anderson FH. Ulriksen J. 121. Dixon T. 2004. Arlot ME.2:999-1001. Lancet. N Engl J Med. 1988. Jackson SH. Lindpainter LS. 113. 120. Cranney A. Osteoporosis Methodology Group. Andreoli A. Dietrich T. Prevalence of vitamin D inadequacy in Scottish adults with nonverterbral fragility fractures. Netherlands: Elsevier Academic Press. Harris SS. 114.88:5766-5772. 2004. Akesson K. 1997. Hazard MC. Braun MM.

Am J Clin Nutr. 178.80:108-113. Trends Endocrinol Metab. Steroids. Laaksi I. Lefkowitz ES. Bischoff HA. Garland FC. Endocrinology. Binderup L.87:214-220. 183. Eur J Immunol. Waer M.444:921-925. 164. Cantorna MT. and ovarian cancer mortality rates in US women. Mathieu C. Pincus SH. Paul O. 154. Bemiss CJ. 142. 1. 182. Interleukin2 is one of the targets of 1. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Minne HW. Calcium and 1 alpha. DeLuca HF. Abe E. A vitamin D analog. 2004. Hollis BW. Smith EL. 25-Hydroxyvitamin D1α-hydroxylase in normal and malignant colon tissue. Lokeshwar BL. 146. Transplantation. Mawer EB. 1α. Role of vitamin D in skeletal muscle function. An estimate of premature cancer mortality in the U. Ray R. Target cells for 1. Herrath DV. Cantorna MT. 1. Dietrich T.109:87-92. Dawson-Hughes B. Br J Cancer. 2001.25-dihydroxyvitamin D3 displays strong antiproliferative and cytotoxic behavior in prostate cancer cells. Freedman LP. 174. 143. Haddad JG. et al. DeLuca HF.260: 8882-8891. A phase II study of the vitamin D analogue seocalcitol in patients with inoperable hepatocellular carcinoma. 1994.94:1867-1875. falls.64:357-406. Stahelin HB.402:249-254. Burnstein KL. February 1982. Garland CF.71:1530-1535. Vitamin D and autoimmune diabetes. Effect of vitamin D on falls: a meta-analysis.1:191-195. Bouillon R. Holick MF. 2003. Thomas GA. 1:626-629. Miyaura C. Abe J. Sunlight and mortality from breast.48:1053-1056. Morley JE. et al. 159. Zhao XY. trunk muscle strength.80(6. Schwartz GG. 2001. and non-melanoma skin cancer: a composite death certificate based case-control study. 167. Prolongation of allograft survival by 1.25 dihydroxyvitamin D 3. Williamsburg. suppl):1689S-1696S. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement.25dihydroxyvitamin D3 by a human small cell lung cancer cell line.119:2214-2220. Itri L. 2005.25-dihydroxyvitamin D3 receptors and hormonal responses in cloned human skeletal muscle cells. 2004. J Androl. 166. Germany: Walter de Gruyter. 173. Hahn TJ. Cancer Res. A novel approach for the evaluation and treatment of psoriasis: oral or topical use of 1. et al.7:391-395.19:516-528.14:423-430. J Vasc Res.291:1999-2006. Schwartz GG. Biochim Biophys Acta. Hirjik J. Whitlatch LW.89:909-916. 153. Bischoff-Ferrari HA. Feldman D. Raisanen-Sokolowski AK. 136. 179. colon. Baumgartner RN. Schott GD. Science. Poulsen L. Holick MF. Mechanisms of gene regulation by vitamin D3 receptor: a network of coactivator interactions. 1. Zhu Y.1:307-309. Lokeshwar BL. 1990. Overview of general physiologic features and functions of vitamin D. 1998. 145. 2000. Chen TC. J Nutr Sci Vitaminol (Tokyo). 1994. Mass reproduce only with permission from Mayo Clinic Proceedings. Mahon BD. Bobryshev YV. 172.63:936-941. 112:181-187.130:2648-2652. Steroids. Cantorna MT.80:752-758. Diabetologia. 139. Canfield 371 For personal use. Tangpricha V. 1982. Min C. 1985. Tanaka Y. Munsick C. Barrett-Connor E. 171.25-dihydroxyvitamin D3. Froicu M. Boland R. Vitamin D status. USA. Young JF. Garland C. Cancer Epidemiol Biomarkers Prev. 2002. J Bone Miner Res. an affinity labeling derivative of 1α.25-dihydroxyvitamin D3 can be a safe and effective therapy for psoriasis. Waer M. 2002. Garland CF. 1998.79:554-560. Vitamin D. Endocr Rev. 141. . Holick MF.164:273-288.69:1399-1407. In vivo upregulation of interleukin-4 is one mechanism underlying the immunoregulatory effects of 1. Koeffler HP.128:68-72. 175. 2003. 147. Muscle weakness in osteomalacia.34:386-398.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH 132. Prevention of immunological disorders in MRL/1 mice by a new synthetic analogue of vitamin D3: 22-oxa-1α. Samila SP. 1994. 2003. 2001. Chemical. Whitlatch LW. Cantorna MT.66:419-424. 135. and fractures among 237 postmenopausal women with osteoporosis. Mayer J. Irie H. 151. 157. Simpson RU. prostate.25-dihydroxyvitamin D3. 168. kidney. Bouillon R. 2000. Nakamura K. Clin Exp Immunol. 2000. 1998. J Biol Chem. 140. stomach. Pakkala IS. 1. Owens PE.25-dihydroxyvitamin D3. Roubenoff R. Redaelli C. Feldman D. Induction of differentiation of human myeloid leukemia cells by 1α. Vitamin D metabolite-binding proteins in human tissue. 148.25-dihydroxyvitamin D3 in the immune system. Arch Biochem Biophys.25-dihydroxyvitamin D3 in intestinal tract. et al. 1988. Bemiss C. Mahon BD. Cross HS. Cancer. et al. 1976. Vitam Horm. 2002. Grant WB. Nishii Y.25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. Wallace RB. Antiproliferative action of vitamin D. VA. 2000.137:231-243. 181. Lou YR. In: Norman AW.59:257262. Blau HM. Costa EM. Reid FA. Holick MF.25-dihydroxyvitamin D3 receptors and activities in muscle. 1988. • March 2006. inhibits adventitial inflammation and suppresses intimal lesions in rat aortic allografts.23:1133-1136. et al. and Clinical Endocrinology of Calcium Metabolism: Proceedings of the Fifth Workshop on Vitamin D. DeLuca H. Weaver V. Pfeifer M. 2003.88:216-222. 1997. 149. Glerup H. et al. DeLuca HF. 137. Rutgeerts O. J Am Acad Dermatol. Casteels K. Prevention of autoimmune diabetes in NOD mice by 1.204: 713-719. Chen TC. Bischoff-Ferrari HA. Am J Clin Nutr. Cancer Treat Rep. Humpal-Winter J. Rachez C. 165.25-Dihydroxyvitamin D33β-(2)-bromoacetate. 1986. Joshipura KJ. Holick MF.25-Dihydroxycholecalciferol and a human myeloid leukaemia cell line (HL-60). 1985. 158.25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes. 1976. Weigel NL. Cantorna MT. J Cell Biochem.357:16731674. Prev Med. 1979. et al. et al.25-dihydroxyvitamin D3 from 25hydroxyvitamin D3. Freedman DM. 2000. Laureys J. Mawer EB. Lemke JH. Rossof AH. Sarcopenia. Human prostate cells synthesize 1. Pakkala ST. Tanaka H.81(3):353-373 • www. Bonaa K. 176. Polek TC. 2000. Hayes ME.35:217-224. Vitamin D and prostate cancer. Am J Clin Nutr.206:1188-1190. Shekelle RB.S. Am J Clin Nutr. Vitamin D: a millenium perspective. 2002. 2004. 1941. Aortic calcification produced by vitamin D3 plus nicotine. Chen TC. Mayo Clin Proc. et al. body sway. Association between serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population. et al. 2003. Biochem J. Transplantation. Takita Y. Hofer H. Atkinson J. Relationship between 1.66:293-300. Evaluation of vitamin D analogs as therapeutic agents for prostate cancer. Am J Clin Nutr.36:21-31. 1997.377:135-138. and blood pressure: the Tromso study. Berlin. Bischoff-Ferrari HA. Suda T.246:9-21.25dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged ≥60 y. Dick W. 177. Flanagan JN. Calcium from dairy products. Giummelly P. 180. Criqui MH. Jorde R. Ylikomi T. Vitamin D and prostate cancer prevention and treatment. Nair KS. 161. 138.25-dihydroxyvitamin D3 and blood pressure in a geographically defined population. Gene. Grigdeit HG. 162. Henry A. and parathyroid. Nakano T. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. Constitutive synthesis of 1. 1. Apperly FL. 2001. Sowers MF.37:552-558. 1998. Biochemical. Identification of 1. Arch Biochem Biophys. Lancet.25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease.66:287-292. 150. Lartaud-Idjouadiene I. Persons KS. MC1288. 2003.25-Dihydroxyvitamin D3: in vivo and in vitro effects on human preleukemic and leukemic cells. J Cell Biochem. Bundred NJ. Hayry PJ. 23:9-17. 133. Recent Results Cancer Res. Dietrich T. Dancey J. vitamin D. 170.66:824828. Donovan L. 160. Zella JB. The relation of solar radiation to cancer mortality in North America. Dosemeci M. Dawson-Hughes B. Lancet. 169. J Nutr. Sunlight. 1990. 1 alpha.7:434-448. 1985. et al. 1α. Mantell DJ. Mikkelsen K. Mahon BD. J Nutr. Bareis P. vitamin D intake. skin. Schaefer K. Arnold AJ. J Clin Endocrinol Metab. 2002. pituitary. The role of vitamin D in prostate cancer. JAMA. 88:296-307. Hayes CE. ovarian. Gorham ED. 25-Hydroxyvitamin D3-1αhydroxlyase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis. Orav EJ. Miyaura C. Exp Clin Endocrinol Diabetes.18:343-351.19:614-622. 156. Dalhoff K. 2003. due to inadequate doses of solar ultraviolet-B radiation. Cantorna MT. Chen TC. Willett WC. J Cell Biochem. Walgate J. eds. Heys SE. Hullett DA. DeLuca HF. 152. Stumpf WE.mayoclinicproceedings. 155.25Dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo. 1982:59–64.25-dihydroxyvitamin D3. Abe E. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. J Lab Clin Med. Sar M. Occup Environ Med. Astrup L. et al. 2004. Swamy N. Lancet . Begerow B. 134. Int J Epidemiol. Wills MR. 2001. Calcif Tissue Int. 1986. et al. Niederhoffer N. Circ Res.89:252-257. 163. McGlynn K. 144.

Vitamin D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis [letter]. Dreon DM. Virtanen SM.25-dihydroxyvitamin D and risk of breast cancer. 205. Colditz GA. Tillmann HC.181-182:71-78. Vitamin D and myocardial infarction. Vitamin D intake and incidence of multiple sclerosis. 229. 2004. dietary supply data and latitude for European countries. 1971-1975 to 1992: National Health and Nutrition Examination Survey. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study.53:17111718. Bouillon R.3:85-94. 2004. 2002.67:457-466. Losy J.147:316-323. Neurology.134:238-246. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. 208. 231. Pfeifer M. Mathieu C. and dietary food intake to ischemic heart disease mortality among postmenopausal women. Holick MF. Stehle P. 1997. Cytokine profile in patients with multiple sclerosis following vitamin D supplementation.14:12-17. 201. 226. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Gange W. Sellers TA.22:139166. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Womens’s Health Study. Okamura WH. Hansen C. Lindén V. Perez A. 2002.889-890. 2004. Garland CF. Donner H et al. Gill RK. 213. Colon cancer and solar ultraviolet B radiation and prevention and treatment of colon cancer in mice with vitamin D and its Gemini analogs. ed. vitamin D. 216. 204. Effects of a short-term vitamin D3 and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. 86:1633-1637. Shaw EK. 2000. 198. Noncalcemic actions of vitamin D receptor ligands. Atherosclerosis. 190. Hernan MA. Feuring M. Sharon D. Wehler C. Pols HA. Chen WY. Ann Neurol. Schleithoff SS. Wu Y. Mass reproduce only with permission from Mayo Clinic Proceedings. et al. 187.49:504-507. 1995. 2004.8:399-406. Nagpal S. 111:452-456. 1. Retinoids 1998. Taylor D. McAlindon TE. Perrella O.134:1602-1610. Waer M. Vitamin D deficiency and secondary hyperparathyroidism are common complications in patients with peripheral arterial disease. Fryer AA. Nachtigall D. 2005. Bishop JE. Norman AW. Comstock GW. Vitamin D and type 1 diabetes [letter]. 2005. 2003. Clinical efficacy of 1. Trends Endocrinol Metab. 202. Bertone-Johnson ER. May BK. Clark SA. 200. Zhang SM. Massachusetts. Harris SS. Gorga F. 233.25(OH)2vitamin D3. 1994. 232. Leibowitz U. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Hoffman M. 2003. Cultured psoriatic fibroblasts from involved and uninvolved sites have a partial but not absolute resistance to the proliferation-inhibition activity of 1. Uitterlinden AG. 2002:267-276.mayoclinicproceedings.25-dihydroxyvitamin D3 and its analogues in the treatment of psoriasis. Cosman F. Cancer Epidemiol Biomarkers Prev. McDermott MF. Sepulveda JL. Embry AF.134:128-132. Minne HW. 2003. Norman AW. Van De Kerkhof PCM. function. Curtis J. Arthritis Rheum. 197. 221.20:407-416.89-90:187-193. et al. Gordon SA. Mathieu C. 191. Cruz J. Turner A. Lancet.81:135-140. Pani MA. 1989. BMJ. Merlino LA. Folsom AR. De Rosa T. et al. In: Holick MF. Laara E. 2005. Holick MF. French ME. vitamin D.17:663-669. 215. Omdahl JL. a vitamin D3 analog.33:2365.106:44-46. 218.81(3):353-373 • www. Zittermann A. and insulin secretion. et al. Eur Urol. 186. Holick MF. Curr Drug Targets. Ramachandran A. Brain. J Neuroimmunol. Bouillon R. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol. and the occurrence of colorectal cancer among women. Lancet. 1999. Mahon BD. Spina C. Holick MF. J Gen Intern Med. Curr Opin Cardiol. Biologic Effects of Light 2001: Proceedings of a Symposium. 2004. A multicountry ecologic study of risk and risk reduction factors for prostate cancer mortality.111:750-756. 2001.25-dihydroxyvitamin D3) for the treatment of psoriasis. J Steroid Biochem Mol Biol. Cantorna MT. 211. An ecologic study of the role of solar UV-B radiation in reducing the risk of cancer using cancer mortality data. Laureys J.41:105-112. 2002. Endocr Rev.125:353359. Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians Diabetologia. and cyclosporin prevents early graft failure and prolongs graft survival of xenogenic islets in nonobese diabetic mice. Lee S. Gorham ED. 196. Schwartz GG. Holick MF. Cambazard F. Helsing KJ. 1997. 1985.50:72-77. Fang Y. Structure-function relationships in the vitamin D endocrine system. Zhang Y. Falkenstein E.52:513-556. Hypponen E. 1999. Goossen J. 192. MacLaughlin JA. 193. Sharma AM.164:3-28. 228. van den Bemd GJ.20:373-382. et al. 2001. 1974. Seidel D. Krause R. 220. 2003. pt 1):150-156. Olek MJ. Am J Med.64:1022-1026. 2002. Pharmacol Rev. Bostick RM. Tartaglia G. Molecular tools for study of genomic and rapid signal transduction responses initiated by 1α. Schwartz GG. Li YC. O’Reilly E. Krall EA. Vitamin D and type 1 diabetes mellitus: state of the art. Steroids. Tenderich G. Ascherio A. Koo J. Profile of cerebrospinal fluid and serum cytokines in patients with relapsingremitting sclerosis: a correlation with clinical activity. Recent Results Cancer Res. Med Hypotheses.26:662-687. et al. Ultraviolet B and blood pressure [letter]. et al. Annu Rev Nutr. Neurology. Hypertension.2:1176-1178. J Steroid Biochem Mol Biol.111:983]. 223. Meyer KA. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Am J Epidemiol. Boston. 2005. Diabetes. 230. et al. 25-Hydroxyvitamin D1α-hydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. 1999. J Cell Biochem.149: 151-161. Transplant Proc. Mikuls TR. 79. 199.45:271-279. et al. 189. Vitamin D receptor gene polymorphisms in relation to Vitamin D related disease states. Calcium. A combination of KH1060.25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors. Wehling M. Whitlatch LW. Secondary hyperparathyroidism promotes the acute phase response—a rationale for supplemental vitamin D in prevention of vascular events in the elderly.16:200257. Christ M. 1996.26:55-58. 210. van der Mei I. van Leeuwen H. Ann Intern Med. Neuhausen SL.88:327-331. Munger KL. 224. Snowdon LR. 2000. Rathnachalam R. 1996. • March 2006. In vivo effect of interferon-beta 1a on interleukin-12 and TGF-beta(1) cytokines in patients with relapsing-remitting multiple sclerosis. Chang GT. Gysemans C. Dietary calcium. Cancer Epidemiol Biomarkers Prev. Proc Natl Acad Sci U S A. Young MV. Evolution and function of vitamin D. Alter M. Felson DT. 372 Mayo Clin Proc. 1977. 2001. et al. VDR genotypes and colorectal cancer [published correction appears in Int J For personal use. Guenther L. Michalowska-Wender G. Badenhoop K. Br J Dermatol. Dobnig H. Plasma 25-hydroxyvitamin D and 1. Körfe R.16:261-266. nongenomic effects. 1967. J Clin Endocrinol Metab. Vieth R. Multiple actions of steroid hormones—a focus on rapid. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized.40:971-975. Grant WB. Reunanen A. Int J Cancer. Obernosterer A. 207. Calcium and vitamin D supplements reduce tooth loss in the elderly. Smith E. Chen TC. Giovannucci EL.90:871-886. Garland FC. Begerow B. Bula CM. Serum 25-hydroxycholecalciferol in myocardial infarction. Fahrleitner A. 227. Martinez ME. 195. 212. . vehicle-controlled clinical trial.48:271-272. Efficacy and safety of topical calcitriol (1. gene expression. 194. van Meurs JB. and regulation. 2004. 214. Tangpricha V. Toxicology. 219. 2001. 1998.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH 184. 358:1500-1503. 2000. et al. 222.25-dihydroxyvitamin D3. Mehta JL. 206. Na S. Christakos S. Endocr Rev. Ultraviolet light may contribute to geographic and racial blood pressure differences. 2001.352:709-710. Ogunkolade BW. Jarvelin MR. 225. McMichael A. Carrieri PB. J Steroid Biochem Mol Biol. Rostand SG. Geographic variation of MS incidence in two prospective studies of US women. vitamin D. Schmidt-Gayk H. Vitamin D and vitamin D analogs in cancer treatment.62:60-65. 2002. Immunopharmacol Immunotoxicol. Garcia RI. Morris HA.97:111-120. 2002.88:1375-1382. 2004. Ponsonby AL. C-reactive protein and cardiovascular disease: a critical appraisal. Boston. Luscombe CJ. et al. 234. Buhring M. Vitamin D and breast cancer risk: the NHANES I epidemiologic follow-up study.30(2. et al.14:1991-1997. Berthold HK. Endocrinology. 2002. Knapp M. Geographical considerations in multiple sclerosis. 203. Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer. Hydroxylase enzymes of the vitamin D pathway: expression. Yao M. Am J Clin Nutr. Lancet.358:641-642. Vitamin D regulation of the renin-angiotensin system. Mass: Kluwer Academic Publishing. Br J Dermatol. Lendle F. 209. Dawson-Hughes B. Hopfenmuller W. 185. Provitera V. Kushi LH. 2005. Relation of calcium. 1998.82:5409-5412. McCarty MF. double-blind. 2002. 217. Acta Neurol Scand.3:647-650. Lancet . Harris SS. J Natl Cancer Inst. Slattery ML. 188. Grant WB. et al. John EM. 2005. 1996.

Am J Clin Nutr.45:261-267. Alfacalcidiol and calcitriol in the prevention of bone loss after organ transplantation. Hullet DA. Nat Genet. DC: National Academy Press. Holick MF. Shao Q. Arch Environ Health. Vitamin D. 254. N Engl J Med.345:66-67. Evidence-Based Medicine Working Group. Sackett DL. Cooper C. 2002. 1993. 2003. 2005. Berwick M. 1998. Harvey N. J Intern Med. Ben-Porat L. 258. 249. Biologic Effects of Light: Proceedings of a Symposium. Hjalgrim H.13:1238-1242. 2005. 236. Kennedy C. White MR. Vieth R. Popp-Snijders C. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. 2001. Cantorna MT. J Steroid Biochem Mol Biol. et al. Jacobus CH.pdf. N Engl J Med .gov/fdac. Hypervitaminosis D associated with drinking milk. Laupacis A. In: Grob JJ. 257. Chen TC. 262. and Fluoride. et al. and Prevention of Skin Diseases. 253.288:321333. 2004.291:1701-1712. Boston. Tangpricha V. Am J Clin Nutr. Available at: www. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Berlin. Javaid K. eds. 261. J Natl Cancer Inst. The melanocytes differentiation program predisposes to metastasis after neoplastic transformation. 1998. Lyytikäinen A. Accessibility verified January 31. Brunet J. 1992. Cheng S. atypical nevi. Spina C. et al. Davies KM. parathyroid hormone. Holick MF. 238. 2001. Ooms ME. 2002. J Invest Dermatol. 250. Navy. Shaw E. The evolution of the randomized controlled trial and its role in evidence-based decision making. Heaney RP. December 4. Garland FC. et al. Holick MF. JAMA.97:195-199. Limacher M. McAlister FA. Garland CF. Why the optimal requirement for vitamin D3 is probably much higher than what is officially recommended for adults. Kligman A. Vitamin D intoxication with an overthe-counter supplement [letter].17:168-171.imace. Am J Clin Nutr. Holick MF. 1. Sunscreens—a public health opportunity [editorial]. 259.329:1193-1194. 2006. J Nutr. Chel VGM.326:1173-1177. Tylavsky 373 For personal use. Calcif Tissue Int. Basel. 251.65:341-343. Ryder KA. Gupta PB. Decastro S. 2005. 242. Shao Q. Gorham ED. 1997:250-287. Sun exposure and mortality from melanoma. Yusuf S.135:2739S-2748S. Weinstock WA. Stern RS. November 1-3. recommended dietary allowances. In: Dietary Reference Intakes for Calcium.VITAMIN D INADEQUACY AND IMPLICATIONS FOR HEALTH 235. Oxford. Barger-Lux MJ. 255.S. Hollis BW. Redaelli C. 1990. Reference daily intakes. Garland CF. Vitamin D. 2003. 252. Family history of hematopoietic malignancy and risk of lymphoma. Turner A. Opinion on the tolerable upper intake level of vitamin D. Chang ET. Devereaux PJ.89-90:575-579.77:204-210. Kuperwasser C. 2005. United States Food and Drug Administration Web site. Lack of efficacy of common sunscreens in melanoma prevention.78:1047]. 241. 2004. Garland FC. Rossouw JE. The influence of painful sunburns and lifetime of sun exposure on the risk of actinic keratoses. Assaf AR. Matuulla-Nolte B. Koutkia P.mayoclinicproceedings. J Natl Cancer Inst. 2006. guidelines for determining whether a drug is exerting (more than) a class effect. Transplantation. Causes. The vitamin D epidemic and its health consequences. Willemze R. • March 2006. Ultraviolet irradiation corrects vitamin D deficiency and suppresses secondary hyperparathyroidism in the elderly. Users’ guides to the medical literature. 256. Photodermatol Photoimmunol Photomed. Chan PC. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. 2004. Chen TC. et al. Bavinck JN. 2001. . Wells GA.66:828-831. Germany: Walter De Gruyter.81(3):353-373 • www. 263. Epidemiology. eds. Bajdik CD. 239. Westlake S. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes Food and Nutrition Board Institute of Medicine. J Nutr. seborrheic warts. Sun-tanning bed radiation increases vitamin D synthesis in human skin in vivo. et al.73:288-294. Dennison E. 2005. Gorham ED. Occupational sunlight exposure and melanoma in the U. Biological Effects of Light. Prentice RL. Smedby KE. 1992:62-66. J Nutr. Mass reproduce only with permission from Mayo Clinic Proceedings. Holick MF. Mayo Clin Proc. Writing Group for the Women’s Health Initiative Investigators.120:1087-1093.97:14661474. Chen TC. et al. Available at: www.135:2735S-2738S. In: Holick MF. Mass: Kluwer Academic Publishers. Switzerland. and skin cancer. 246. XIX: applying clinical trial results: B. Vieth R.135:2728S-2734S. Magnesium. J Bone Miner Res. Sambrook P. 264. England: Blackwell Science. Schmidt-Gayk H. 240. melanocytic nevi. Accessibility verified February 13. 244. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol [published correction appears in Am J Clin Nutr. eds. Holick MF. and bone mass in adolescents. Diffey B.121-123. J Nutr 2005.fda.37:1047-1054. 248. JAMA. MacFarlane GD. Chen TC. 1999. Tanning is associated with optimal vitamin D status (serum 25-hydroxyvitamin D concentration) and higher bone mineral density. Scientific Committee on Food. Todd J. N Engl J Med. In: Holick MF. Developmental origins of osteoporotic fracture: the role of maternal vitamin D insufficiency.282:1371-1377. 1999. 260. Anderson GL. Women’s Health Initiative Steering Committee. Subliminal ultraviolet-B irradiation for the prevention of vitamin D deficiency in the elderly: a feasibility study. Serial UVB irradiation can influence secondary hyperparathyroidism in vitamin D deficiency. pdf/poster.25-Dihydroxyvitamin D3 prolongs graft survival without compromising host resistance to infection or bone mineral density. Jung EG. 2003. Chuck A. 1999. MacKie RM. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. 245. Armstrong BK. 243. 1999:151-158. Krause B.80: 1645-1649. 2003. Phosphorus. Gilchrest BA. 1998. 2005. 237. Washington.135:317-322. et al.254: 105-113. Anderson GL. Vitamin D. 247. de Gruijl FR.

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