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* Dr Holick is an Academic Associate for Nichols Institute Diagnostics.
Michael F. Holick
Correspondence
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
* Dr Holick is an Academic Associate for Nichols Institute Diagnostics.
Affiliations
Vitamin D, Skin and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Mass
During the past decade, major advances have been made in vitamin D research that transcend the simple concept that vitamin D is important for the prevention of rickets in children and has little physiologic relevance for adults. Inadequate vitamin D, in addition to causing rickets, prevents children from attaining their genetically programmed peak bone mass, contributes to and exacerbates osteoporosis in adults, and causes the often painful bone disease osteomalacia. Adequate vitamin D is also important for proper muscle functioning, and controversial evidence suggests it may help prevent type 1 diabetes mellitus, hypertension, and many common cancers. Vitamin D inadequacy has been reported in approximately 36% of otherwise healthy young adults and up to 57% of general medicine inpatients in the United States and in even higher percentages in Europe. Recent epidemiological data document the high prevalence of vitamin D inadequacy among elderly patients and especially among patients with osteoporosis. Factors such as low sunlight exposure, age-related decreases in cutaneous synthesis, and diets low in vitamin D contribute to the high prevalence of vitamin D inadequacy. Vitamin D production from cutaneous synthesis or intake from the few vitamin D-rich or enriched foods typically occurs only intermittently. Supplemental doses of vitamin D and sensible sun exposure could prevent deficiency in most of the general population. The purposes of this article are to examine the prevalence of vitamin D inadequacy and to review the potential implications for skeletal and extraskeletal health.
During the past decade, important advances in the study of vitamin D have been made. In addition to its important role in skeletal development and maintenance, evidence is mounting that vitamin D produces beneficial effects on extraskeletal tissues and that the amounts needed for optimal health are probably higher than previously thought.
At the same time, numerous reports have shown that relatively high proportions of people have inadequate levels of vitamin D. The extraskeletal health benefits of vitamin D and high prevalence of inadequate levels of vitamin D have been largely unrecognized by both physicians and patients.
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.
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
Dietary sources of vitamin D are limited. They include oily fish such as salmon (approximately 400 IU per 3.5 oz), mackerel, and sardines; some fish oils such as cod liver oil (400 IU/tsp); and egg yolks (approximately 20 IU). Some foods are fortified in the United States, including milk (100 IU per 8 oz) and some cereals (100 IU per serving), orange juice (100 IU per 8 oz), some yogurts (100 IU per serving), and margarine.
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
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.
A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
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.
This is not surprising given thatcompliance declines as the number of medications increases, and elderly patients often take many medications. Similarly, achieving adequate vitamin D intake through milk consumption is unreliable among elderly patients because of the high prevalence of lactose intolerance among this population and the often low levels of vitamin D in the milk supply.
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.
Once formed in the skin, cell plasma membrane previtamin D3 is rapidly converted to vitamin D3 by the skin's temperature. Vitamin D3 from the skin and vitamin D from the diet undergo 2 sequential hydroxylations, first in the liver to 25(OH)D and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D (1,25[OH]2D) (Figure 1). Excessive solar UV-B irradiation will not cause vitamin D intoxication because excess vitamin D3 and previtamin D3 are photolyzed to biologically inactive photoproducts.
Melanin skin pigmentation is an effective natural sunscreen, and increased skin pigment can greatly reduce UV-B-mediated cutaneous synthesis of vitamin D3 by as much as 99%, similar to applying a sunscreen with a sun protection factor of 15.
Effect of 1α,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions.
and this may be another mechanism for regulating the cutaneous synthesis of vitamin D3 by negative feedback.
FIGURE 1Cutaneous 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 (δH) transformation to vitamin D3. Vitamin D from the diet or from the skin is metabolized in the liver by the vitamin D-25-hydroxylase to 25-hydroxyvitamin D3 (25[OH]D3). 25(OH)D3 is converted in the kidney by the 25(OH)D3-1α-hydroxylase to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. A variety of factors, including serum phosphorus (PO2−4) 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,
The 1,25(OH)2D ligand binds with high affinity to the vitamin D receptor (VDR) and triggers an increase in intestinal absorption of both calcium and phosphorus. In addition, vitamin D is involved in bone formation, resorption, and mineralization and in maintaining neuromuscular function
(Figure 1). Circulating 1,25(OH)2D reduces serum parathyroid hormone (PTH) levels directly by decreasing parathyroid gland activity and indirectly by increasing serum calcium. The 1,25(OH)2D regulates bone metabolism in part by interacting with the VDR in osteoblasts to release biochemical signals, leading to formation of mature osteoclasts. The osteoclasts release collagenases and hydrochloric acid to dissolve the matrix and mineral, releasing calcium into the blood.
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
When vitamin D levels are inadequate, calcium and phosphorus homeostasis becomes impaired. Vitamin D is primarily responsible for regulating the efficiency of intestinal calcium absorption. In a low vitamin D state, the small intestine can absorb approximately 10% to 15% of dietary calcium. When vitamin D levels are adequate, intestinal absorption of dietary calcium more than doubles, rising to approximately 30% to 40%.
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
Thus, when vitamin D levels (25[OH]D) are low, calcium absorption is insufficient to satisfy the calcium requirements not only for bone health but also for most metabolic functions and neuromuscular activity. The body responds by increasing the production and release of PTH into the circulation (Figure 1). The increase in PTH restores calcium homeostasis by increasing tubular reabsorption of calcium in the kidney, increasing bone calcium mobilization from the bone, and enhancing the production of 1,25(OH)2 D.
Serum 25(OH)D is the major circulating metabolite of vitamin D and reflects vitamin D inputs from cutaneous synthesis and dietary intake. The serum 25(OH)D level is the standard clinical measure of vitamin D status.
A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
Although 1,25(OH)2D is the active form of vitamin D, it should not be measured to determine vitamin D status. It usually is normal or even elevated in patients with vitamin D deficiency.
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
Testing of serum 25(OH)D is most useful in patients who are at risk of vitamin D deficiency, including elderly patients, infirm patients, children and adults with increased skin pigmentation, patients with fat malabsorption syndromes, and patients with osteoporosis. This measurement is also useful for purposes of planning or monitoring vitamin D therapy. Clinical assays of 25(OH)D include the Nichols Advantage Assay (chemiluminescence protein-binding assay, the DiaSorin radioimmunoassay, and the benchmark high-performance liquid chromatography assays
The chemiluminescence protein-binding assay and the radioimmunoassay are most commonly used to determine patient vitamin D status. Recent reports have raised concerns about the degree of variability between assays and between laboratories, even when using the same assay.
Although reliable and consistent evaluation of serum 25(OH)D levels remains an issue, reliable laboratories currently exist, and efforts are in progress to improve and standardize assays to enhance accuracy and reproducibility at other laboratories.
As noted previously, vitamin D plays a central role in calcium and phosphorus homeostasis and skeletal health. Since impaired calcium metabolism due to low serum 25(OH)D levels triggers secondary hyperparathyroidism, increased bone turnover, and progressive bone loss,
Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes [published correction appears in Am J Clin Nutr. 1997;66:454].
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)
Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes [published correction appears in Am J Clin Nutr. 1997;66:454].
FIGURE 2Left, 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. Right, Percentage of subjects with secondary hyperparathyroidism by 25(OH)D level. 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. Left and right, From J Endocrinol Metab,
A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.
Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes [published correction appears in Am J Clin Nutr. 1997;66:454].
Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994.
A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.
Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994.
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. This review, which included 30 studies published between January 1994 and April 2004, examined the prevalence of vitamin D inadequacy reported as serum 25(OH)D levels below various values. The results of a recent cross-sectional, 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).
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), with the highest prevalence reported in central and southern Europe.
A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
Vitamin D inadequacy is common even among patients with osteoporosis living at lower latitudes in highly sunny climates. For instance, 53% of community-dwelling women with osteoporosis living in Southern California had 25(OH)D levels less than 30 ng/mL (75 nmol/L).
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.
A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.
Vitamin D inadequacy is also common among nonwhite populations and populations with low dietary or supplementary vitamin D intake or minimal exposure to sunlight. 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, with the proportion increasing to 94% during the winter months.
A study of 1546 African American women in the United States, ranging in age from 15 to 49 years, showed that more than 40% had serum 25(OH)D levels less than 15 ng/mL (37 nmol/L).
Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994.
Even children are at risk. 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.
observed that at the end of winter and summer 48% and 17%, respectively, of white girls (9-11 years of age) in Maine also had 25(OH)D levels less than 20 ng/mL (50 nmol/L). Even in sunny countries such as Lebanon, vitamin D inadequacy is common in schoolchildren.
Physical factors that attenuate UV-B exposure, including clothing, sunscreens, and glass shielding, markedly reduce or completely eliminate the production of vitamin D3 in the skin.
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.
The high prevalence of osteomalacia in Saudi Arabian women, rickets in Saudi children, 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.
Dietary sources of vitamin D are limited, 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. Patients with fat malabsorption syndromes, including sprue, cystic fibrosis, and Crohn disease, are at especially high risk of vitamin D deficiency.
Among elderly patients, multiple factors contribute to vitamin D inadequacy, including dietary deficiencies and decreased cutaneous synthesis due to reduced ability of the skin to synthesize vitamin D3. A 70-year-old produces approximately 4 times less vitamin D via cutaneous synthesis compared with a 20-year-old.
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
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, increased bone turnover, and progressive loss of bone, increasing the risk of osteoporosis.
Vitamin D deficiency during skeletal maturation disrupts chondrocyte maturation and inhibits the normal mineralization of the growth plates. 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).
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
Secondary hyperparathyroidism causes phosphaturia and hypophosphatemia. The resulting inadequate calcium-phosphorus product results in poor mineralization, making the skeleton less rigid. When the rachitic child begins to stand, gravity causes bowing of the long bones in the lower extremities, resulting in bowed legs or knocked knees.
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
In adults, the epiphyseal plates are fused, and secondary hyperparathyroidism and resulting phosphaturia have moresubtle, but equally devastating, skeletal consequences. Chronic vitamin D inadequacy in adults can result in secondary hyperparathyroidism, increased bone turnover, enhanced bone loss, increased risk of fragility fracture, and (rarely) hypocalcemic tetany.
The increase in PTH-mediated osteoclastogenesis results in increased numbers and activity of osteoclasts. The osteoclasts resorb bone via enzymatic degradation of the collagen matrix and secretion of hydrochloric acid, releasing calcium and phosphorus into the extracellular space. The result is increased skeletal porosity, defective bone mineralization, decreased bone mineral density (BMD), osteoporosis, and increased fragility-fracture risk.
Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis [published correction appears in Am J Clin Nutr. 2004;79:].
Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994.
A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial [published correction appears in J Clin Endocrinol Metab. 2001;86:3008].
This pain can be elicited on physical examination by applying minimal pressure with the thumb or forefinger on the sternum or anterior tibia. Although the exact cause of the aching sensation that patients often complain of is unknown, 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, Jell-O). This swelling could put outward pressure on the periosteal covering that is innervated with nocioceptors.
Patients with osteomalacia are often misdiagnosed as having fibromyalgia, chronic fatigue syndrome, or myocytis and treated inappropriately with nonsteroidal anti-inflammatory agents.
Some, but not all, observational studies have linked vitamin D inadequacy (or lower vitamin D intake) to an increased risk of hip and other nonvertebral fractures.
Moreover some, but not all, clinical trials and observational studies have reported that dietary vitamin D supplementation (often given together with calcium) lowers fracture risk
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.
Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study.
recently conducted a systematic review and meta-analysis of double-blind randomized controlled trials (RCTs), the highest level of evidence, 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). Statistical justification was provided for pooling trials with higher vitamin D doses separately from those with lower doses. 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, 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 nonvertebral fracture risk by 23% vs calcium alone or placebo in ambulatory or institutionalized elderly persons. No effect on fracture risk was observed in 2 trials that used a lower dose of 400 IU/d. A population-based, 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,
Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study.
although this lower-quality trial did not meet the inclusion criteria for the meta-analysis described herein. 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.
Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
et al.
Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
FIGURE 3Mean ± SD (error bars) serum 25-hydroxyvitamin D (25[OH]D) concentrations (shown as nmol/L and ng/mL) in women older than 70 years, stratified by supplement use and residential status. Adapted from J Clin Endocrinol Metab,
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. The incidence of hip and other clinical fractures did not differ significantly between groups after a median follow-up of 25 months. Another randomized, double-blinded, controlled trial with a factorial design examined the effect on fracture risk.
Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial.
A total of 5292 patients were randomized to receive vitamin D with or without calcium, calcium alone, or placebo. After a 24-month follow-up, the authors found no significant differences in fracture rates among the 4 groups. However, 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. Data from a randomized, double-blind, placebo-controlled trial of 9440 community-dwelling adults (75-100 years old) randomized to receive either an annual injection of 300,000 IU of cholecalciferol (comparable to a 822-IU daily dose) or matching placebo disclosed no effect on fracture occurrence between groups.
Effect of annual intramuscular vitamin D supplementation on fracture risk in 9440 community-living older people: the Wessex Fracture Prevention Trial [abstract].
However, since 25(OH)D levels were not evaluated, it is unknown whether the intramuscular vitamin D3 was completely bioavailable. Most intramuscular preparations are not very bioavailable, which is why they are no longer available in the United States.
Decreased BMD is a major risk factor for fractures,
Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
et al.
Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
For example, 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. All participants also received 377 mg/d of calcium. At the end of 1 year, the vitamin D group had significantly reduced wintertime bone loss and improved net BMD of the spine.
By contrast, however, another RCT reported no effect of vitamin D supplementation on bone loss or bone turnover markers in calcium-replete postmenopausal African American women.
The earlier meta-analysis that pooled data from RCTs that included vitamin D analogues found a small nonsignificant BMD increase of 0.4% relative to the control groups.
Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
et al.
Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
Many of the vitamin D supplementation studies reported herein included concurrent calcium supplementation; therefore, 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. Although the meta-analysis by Bischoff-Ferrari et al
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.
Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial.
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. In the RECORD trial, only 60 participants (1.1%) had their serum baseline 25(OH)D levels measured. Thus, 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. The hierarchy of evidence for the role of vitamin D in BMD
Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial.
Effect of annual intramuscular vitamin D supplementation on fracture risk in 9440 community-living older people: the Wessex Fracture Prevention Trial [abstract].
The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis.
Effect of supplementation of calcium and vitamin D on bone mineral density and bone mineral content in peri- and post-menopause women; a double-blind, randomized, controlled trial.
Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women.
References are provided for examples of each type of study. The most convincing evidence comes from randomized controlled trials. There is some evidence from clinical trials that vitamin D (often given with calcium) may reduce the risk of falls and fractures. Associations with most other diseases and conditions come from lower levels of evidence. 1α,25(OH)2D = 1α-25-hydroxyvitamin D; 1,25(OH)2D = 1,25 hydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; 1-H-vitamin D3 = 1 hydroxylated vitamin D3; BMD = bone mineral density; BP = blood pressure; CRP = C-reactive protein; DM = diabetes mellitus; EAE = experimental autoimmune encephalitis; IBD = inflammatory bowel disease; ICU = intensive care unit; IFN-γ = interferon-γ; IHD = ischemic heart disease; IL = interleukin; KO = knockout; MI = myocardial infarction; MS = multiple sclerosis; NA = not applicable; NHANES = National Health and Nutrition Examination Survey; NHS = Nurses' Health Study; NOD = nonobese diabetic; PTH = parathyroid hormone; RCT = randomized controlled trial; SLE = systemic lupus erythematosus; TNF-α = tumor necrosis factor α.
Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
et al.
Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
et al.
Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
Osteoporosis Methodology Group, Osteoporosis Research Advisory Group
et al.
Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
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.
The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis.
Effect of supplementation of calcium and vitamin D on bone mineral density and bone mineral content in peri- and post-menopause women; a double-blind, randomized, controlled trial.
Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial.
A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study.
Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly 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.
Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study.
Use of cod liver oil during pregnancy associated with lower risk of type I diabetes on the offspring [published correction appears in Diabetologia. 2000;43;1451].
Induction of differentiation of human myeloid leukemia cells by 1α,25-dihydroxyvitamin D3.
in: Norman AW Schaefer K Herrath DV Grigdeit HG Vitamin D, Chemical, Biochemical, and Clinical Endocrinology of Calcium Metabolism: Proceedings of the Fifth Workshop on Vitamin D, Williamsburg, VA, USA, February 1982. Walter de Gruyter,
Berlin, Germany1982: 59-64
1α,25-Dihydroxyvitamin D3-3β-(2)-bromoacetate, an affinity labeling derivative of 1α,25-dihydroxyvitamin D3 displays strong antiproliferative and cytotoxic behavior in prostate cancer cells.
Effect of 1α,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions.
A novel approach for the evaluation and treatment of psoriasis: oral or topical use of 1,25-dihydroxyvitamin D3 can be a safe and effective therapy for psoriasis.
A combination of KH1060, a vitamin D3 analog, and cyclosporin prevents early graft failure and prolongs graft survival of xenogenic islets in nonobese diabetic mice.