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1.  Clinical Utility of Vitamin D Testing 
Executive Summary
This report from the Medical Advisory Secretariat (MAS) was intended to evaluate the clinical utility of vitamin D testing in average risk Canadians and in those with kidney disease. As a separate analysis, this report also includes a systematic literature review of the prevalence of vitamin D deficiency in these two subgroups.
This evaluation did not set out to determine the serum vitamin D thresholds that might apply to non-bone health outcomes. For bone health outcomes, no high or moderate quality evidence could be found to support a target serum level above 50 nmol/L. Similarly, no high or moderate quality evidence could be found to support vitamin D’s effects in non-bone health outcomes, other than falls.
Vitamin D
Vitamin D is a lipid soluble vitamin that acts as a hormone. It stimulates intestinal calcium absorption and is important in maintaining adequate phosphate levels for bone mineralization, bone growth, and remodelling. It’s also believed to be involved in the regulation of cell growth proliferation and apoptosis (programmed cell death), as well as modulation of the immune system and other functions. Alone or in combination with calcium, Vitamin D has also been shown to reduce the risk of fractures in elderly men (≥ 65 years), postmenopausal women, and the risk of falls in community-dwelling seniors. However, in a comprehensive systematic review, inconsistent results were found concerning the effects of vitamin D in conditions such as cancer, all-cause mortality, and cardiovascular disease. In fact, no high or moderate quality evidence could be found concerning the effects of vitamin D in such non-bone health outcomes. Given the uncertainties surrounding the effects of vitamin D in non-bone health related outcomes, it was decided that this evaluation should focus on falls and the effects of vitamin D in bone health and exclusively within average-risk individuals and patients with kidney disease.
Synthesis of vitamin D occurs naturally in the skin through exposure to ultraviolet B (UVB) radiation from sunlight, but it can also be obtained from dietary sources including fortified foods, and supplements. Foods rich in vitamin D include fatty fish, egg yolks, fish liver oil, and some types of mushrooms. Since it is usually difficult to obtain sufficient vitamin D from non-fortified foods, either due to low content or infrequent use, most vitamin D is obtained from fortified foods, exposure to sunlight, and supplements.
Clinical Need: Condition and Target Population
Vitamin D deficiency may lead to rickets in infants and osteomalacia in adults. Factors believed to be associated with vitamin D deficiency include:
darker skin pigmentation,
winter season,
living at higher latitudes,
skin coverage,
kidney disease,
malabsorption syndromes such as Crohn’s disease, cystic fibrosis, and
genetic factors.
Patients with chronic kidney disease (CKD) are at a higher risk of vitamin D deficiency due to either renal losses or decreased synthesis of 1,25-dihydroxyvitamin D.
Health Canada currently recommends that, until the daily recommended intakes (DRI) for vitamin D are updated, Canada’s Food Guide (Eating Well with Canada’s Food Guide) should be followed with respect to vitamin D intake. Issued in 2007, the Guide recommends that Canadians consume two cups (500 ml) of fortified milk or fortified soy beverages daily in order to obtain a daily intake of 200 IU. In addition, men and women over the age of 50 should take 400 IU of vitamin D supplements daily. Additional recommendations were made for breastfed infants.
A Canadian survey evaluated the median vitamin D intake derived from diet alone (excluding supplements) among 35,000 Canadians, 10,900 of which were from Ontario. Among Ontarian males ages 9 and up, the median daily dietary vitamin D intake ranged between 196 IU and 272 IU per day. Among females, it varied from 152 IU to 196 IU per day. In boys and girls ages 1 to 3, the median daily dietary vitamin D intake was 248 IU, while among those 4 to 8 years it was 224 IU.
Vitamin D Testing
Two laboratory tests for vitamin D are available, 25-hydroxy vitamin D, referred to as 25(OH)D, and 1,25-dihydroxyvitamin D. Vitamin D status is assessed by measuring the serum 25(OH)D levels, which can be assayed using radioimmunoassays, competitive protein-binding assays (CPBA), high pressure liquid chromatography (HPLC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). These may yield different results with inter-assay variation reaching up to 25% (at lower serum levels) and intra-assay variation reaching 10%.
The optimal serum concentration of vitamin D has not been established and it may change across different stages of life. Similarly, there is currently no consensus on target serum vitamin D levels. There does, however, appear to be a consensus on the definition of vitamin D deficiency at 25(OH)D < 25 nmol/l, which is based on the risk of diseases such as rickets and osteomalacia. Higher target serum levels have also been proposed based on subclinical endpoints such as parathyroid hormone (PTH). Therefore, in this report, two conservative target serum levels have been adopted, 25 nmol/L (based on the risk of rickets and osteomalacia), and 40 to 50 nmol/L (based on vitamin D’s interaction with PTH).
Ontario Context
Volume & Cost
The volume of vitamin D tests done in Ontario has been increasing over the past 5 years with a steep increase of 169,000 tests in 2007 to more than 393,400 tests in 2008. The number of tests continues to rise with the projected number of tests for 2009 exceeding 731,000. According to the Ontario Schedule of Benefits, the billing cost of each test is $51.7 for 25(OH)D (L606, 100 LMS units, $0.517/unit) and $77.6 for 1,25-dihydroxyvitamin D (L605, 150 LMS units, $0.517/unit). Province wide, the total annual cost of vitamin D testing has increased from approximately $1.7M in 2004 to over $21.0M in 2008. The projected annual cost for 2009 is approximately $38.8M.
Evidence-Based Analysis
The objective of this report is to evaluate the clinical utility of vitamin D testing in the average risk population and in those with kidney disease. As a separate analysis, the report also sought to evaluate the prevalence of vitamin D deficiency in Canada. The specific research questions addressed were thus:
What is the clinical utility of vitamin D testing in the average risk population and in subjects with kidney disease?
What is the prevalence of vitamin D deficiency in the average risk population in Canada?
What is the prevalence of vitamin D deficiency in patients with kidney disease in Canada?
Clinical utility was defined as the ability to improve bone health outcomes with the focus on the average risk population (excluding those with osteoporosis) and patients with kidney disease.
Literature Search
A literature search was performed on July 17th, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1998 until July 17th, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Observational studies that evaluated the prevalence of vitamin D deficiency in Canada in the population of interest were included based on the inclusion and exclusion criteria listed below. The baseline values were used in this report in the case of interventional studies that evaluated the effect of vitamin D intake on serum levels. Studies published in grey literature were included if no studies published in the peer-reviewed literature were identified for specific outcomes or subgroups.
Considering that vitamin D status may be affected by factors such as latitude, sun exposure, food fortification, among others, the search focused on prevalence studies published in Canada. In cases where no Canadian prevalence studies were identified, the decision was made to include studies from the United States, given the similar policies in vitamin D food fortification and recommended daily intake.
Inclusion Criteria
Studies published in English
Publications that reported the prevalence of vitamin D deficiency in Canada
Studies that included subjects from the general population or with kidney disease
Studies in children or adults
Studies published between January 1998 and July 17th 2009
Exclusion Criteria
Studies that included subjects defined according to a specific disease other than kidney disease
Letters, comments, and editorials
Studies that measured the serum vitamin D levels but did not report the percentage of subjects with serum levels below a given threshold
Outcomes of Interest
Prevalence of serum vitamin D less than 25 nmol/L
Prevalence of serum vitamin D less than 40 to 50 nmol/L
Serum 25-hydroxyvitamin D was the metabolite used to assess vitamin D status. Results from adult and children studies were reported separately. Subgroup analyses according to factors that affect serum vitamin D levels (e.g., seasonal effects, skin pigmentation, and vitamin D intake) were reported if enough information was provided in the studies
Quality of Evidence
The quality of the prevalence studies was based on the method of subject recruitment and sampling, possibility of selection bias, and generalizability to the source population. The overall quality of the trials was examined according to the GRADE Working Group criteria.
Summary of Findings
Fourteen prevalence studies examining Canadian adults and children met the eligibility criteria. With the exception of one longitudinal study, the studies had a cross-sectional design. Two studies were conducted among Canadian adults with renal disease but none studied Canadian children with renal disease (though three such US studies were included). No systematic reviews or health technology assessments that evaluated the prevalence of vitamin D deficiency in Canada were identified. Two studies were published in grey literature, consisting of a Canadian survey designed to measure serum vitamin D levels and a study in infants presented as an abstract at a conference. Also included were the results of vitamin D tests performed in community laboratories in Ontario between October 2008 and September 2009 (provided by the Ontario Association of Medical Laboratories).
Different threshold levels were used in the studies, thus we reported the percentage of subjects with serum levels of between 25 and 30 nmol/L and between 37.5 and 50 nmol/L. Some studies stratified the results according to factors affecting vitamin D status and two used multivariate models to investigate the effects of these characteristics (including age, season, BMI, vitamin D intake, skin pigmentation, and season) on serum 25(OH)D levels. It’s unclear, however, if these studies were adequately powered for these subgroup analyses.
Study participants generally consisted of healthy, community-dwelling subjects and most excluded individuals with conditions or medications that alter vitamin D or bone metabolism, such as kidney or liver disease. Although the studies were conducted in different parts of Canada, fewer were performed in Northern latitudes, i.e. above 53°N, which is equivalent to the city of Edmonton.
Adults
Serum vitamin D levels of < 25 to 30 nmol/L were observed in 0% to 25.5% of the subjects included in five studies; the weighted average was 3.8% (95% CI: 3.0, 4.6). The preliminary results of the Canadian survey showed that approximately 5% of the subjects had serum levels below 29.5 nmol/L. The results of over 600,000 vitamin D tests performed in Ontarian community laboratories between October 2008 and September 2009 showed that 2.6% of adults (> 18 years) had serum levels < 25 nmol/L.
The prevalence of serum vitamin D levels below 37.5-50 nmol/L reported among studies varied widely, ranging from 8% to 73.6% with a weighted average of 22.5%. The preliminary results of the CHMS survey showed that between 10% and 25% of subjects had serum levels below 37 to 48 nmol/L. The results of the vitamin D tests performed in community laboratories showed that 10% to 25% of the individuals had serum levels between 39 and 50 nmol/L.
In an attempt to explain this inter-study variation, the study results were stratified according to factors affecting serum vitamin D levels, as summarized below. These results should be interpreted with caution as none were adjusted for other potential confounders. Adequately powered multivariate analyses would be necessary to determine the contribution of risk factors to lower serum 25(OH)D levels.
Seasonal variation
Three adult studies evaluating serum vitamin D levels in different seasons observed a trend towards a higher prevalence of serum levels < 37.5 to 50 nmol/L during the winter and spring months, specifically 21% to 39%, compared to 8% to 14% in the summer. The weighted average was 23.6% over the winter/spring months and 9.6% over summer. The difference between the seasons was not statistically significant in one study and not reported in the other two studies.
Skin Pigmentation
Four studies observed a trend toward a higher prevalence of serum vitamin D levels < 37.5 to 50 nmol/L in subjects with darker skin pigmentation compared to those with lighter skin pigmentation, with weighted averages of 46.8% among adults with darker skin colour and 15.9% among those with fairer skin.
Vitamin D intake and serum levels
Four adult studies evaluated serum vitamin D levels according to vitamin D intake and showed an overall trend toward a lower prevalence of serum levels < 37.5 to 50 nmol/L with higher levels of vitamin D intake. One study observed a dose-response relationship between higher vitamin D intake from supplements, diet (milk), and sun exposure (results not adjusted for other variables). It was observed that subjects taking 50 to 400 IU or > 400 IU of vitamin D per day had a 6% and 3% prevalence of serum vitamin D level < 40 nmol/L, respectively, versus 29% in subjects not on vitamin D supplementation. Similarly, among subjects drinking one or two glasses of milk per day, the prevalence of serum vitamin D levels < 40 nmol/L was found to be 15%, versus 6% in those who drink more than two glasses of milk per day and 21% among those who do not drink milk. On the other hand, one study observed little variation in serum vitamin D levels during winter according to milk intake, with the proportion of subjects exhibiting vitamin D levels of < 40 nmol/L being 21% among those drinking 0-2 glasses per day, 26% among those drinking > 2 glasses, and 20% among non-milk drinkers.
The overall quality of evidence for the studies conducted among adults was deemed to be low, although it was considered moderate for the subgroups of skin pigmentation and seasonal variation.
Newborn, Children and Adolescents
Five Canadian studies evaluated serum vitamin D levels in newborns, children, and adolescents. In four of these, it was found that between 0 and 36% of children exhibited deficiency across age groups with a weighted average of 6.4%. The results of over 28,000 vitamin D tests performed in children 0 to 18 years old in Ontario laboratories (Oct. 2008 to Sept. 2009) showed that 4.4% had serum levels of < 25 nmol/L.
According to two studies, 32% of infants 24 to 30 months old and 35.3% of newborns had serum vitamin D levels of < 50 nmol/L. Two studies of children 2 to 16 years old reported that 24.5% and 34% had serum vitamin D levels below 37.5 to 40 nmol/L. In both studies, older children exhibited a higher prevalence than younger children, with weighted averages 34.4% and 10.3%, respectively. The overall weighted average of the prevalence of serum vitamin D levels < 37.5 to 50 nmol/L among pediatric studies was 25.8%. The preliminary results of the Canadian survey showed that between 10% and 25% of subjects between 6 and 11 years (N= 435) had serum levels below 50 nmol/L, while for those 12 to 19 years, 25% to 50% exhibited serum vitamin D levels below 50 nmol/L.
The effects of season, skin pigmentation, and vitamin D intake were not explored in Canadian pediatric studies. A Canadian surveillance study did, however, report 104 confirmed cases1 (2.9 cases per 100,000 children) of vitamin D-deficient rickets among Canadian children age 1 to 18 between 2002 and 2004, 57 (55%) of which from Ontario. The highest incidence occurred among children living in the North, i.e., the Yukon, Northwest Territories, and Nunavut. In 92 (89%) cases, skin pigmentation was categorized as intermediate to dark, 98 (94%) had been breastfed, and 25 (24%) were offspring of immigrants to Canada. There were no cases of rickets in children receiving ≥ 400 IU VD supplementation/day.
Overall, the quality of evidence of the studies of children was considered very low.
Kidney Disease
Adults
Two studies evaluated serum vitamin D levels in Canadian adults with kidney disease. The first included 128 patients with chronic kidney disease stages 3 to 5, 38% of which had serum vitamin D levels of < 37.5 nmol/L (measured between April and July). This is higher than what was reported in Canadian studies of the general population during the summer months (i.e. between 8% and 14%). In the second, which examined 419 subjects who had received a renal transplantation (mean time since transplantation: 7.2 ± 6.4 years), the prevalence of serum vitamin D levels < 40 nmol/L was 27.3%. The authors concluded that the prevalence observed in the study population was similar to what is expected in the general population.
Children
No studies evaluating serum vitamin D levels in Canadian pediatric patients with kidney disease could be identified, although three such US studies among children with chronic kidney disease stages 1 to 5 were. The mean age varied between 10.7 and 12.5 years in two studies but was not reported in the third. Across all three studies, the prevalence of serum vitamin D levels below the range of 37.5 to 50 nmol/L varied between 21% and 39%, which is not considerably different from what was observed in studies of healthy Canadian children (24% to 35%).
Overall, the quality of evidence in adults and children with kidney disease was considered very low.
Clinical Utility of Vitamin D Testing
A high quality comprehensive systematic review published in August 2007 evaluated the association between serum vitamin D levels and different bone health outcomes in different age groups. A total of 72 studies were included. The authors observed that there was a trend towards improvement in some bone health outcomes with higher serum vitamin D levels. Nevertheless, precise thresholds for improved bone health outcomes could not be defined across age groups. Further, no new studies on the association were identified during an updated systematic review on vitamin D published in July 2009.
With regards to non-bone health outcomes, there is no high or even moderate quality evidence that supports the effectiveness of vitamin D in outcomes such as cancer, cardiovascular outcomes, and all-cause mortality. Even if there is any residual uncertainty, there is no evidence that testing vitamin D levels encourages adherence to Health Canada’s guidelines for vitamin D intake. A normal serum vitamin D threshold required to prevent non-bone health related conditions cannot be resolved until a causal effect or correlation has been demonstrated between vitamin D levels and these conditions. This is as an ongoing research issue around which there is currently too much uncertainty to base any conclusions that would support routine vitamin D testing.
For patients with chronic kidney disease (CKD), there is again no high or moderate quality evidence supporting improved outcomes through the use of calcitriol or vitamin D analogs. In the absence of such data, the authors of the guidelines for CKD patients consider it best practice to maintain serum calcium and phosphate at normal levels, while supplementation with active vitamin D should be considered if serum PTH levels are elevated. As previously stated, the authors of guidelines for CKD patients believe that there is not enough evidence to support routine vitamin D [25(OH)D] testing. According to what is stated in the guidelines, decisions regarding the commencement or discontinuation of treatment with calcitriol or vitamin D analogs should be based on serum PTH, calcium, and phosphate levels.
Limitations associated with the evidence of vitamin D testing include ambiguities in the definition of an ‘adequate threshold level’ and both inter- and intra- assay variability. The MAS considers both the lack of a consensus on the target serum vitamin D levels and assay limitations directly affect and undermine the clinical utility of testing. The evidence supporting the clinical utility of vitamin D testing is thus considered to be of very low quality.
Daily vitamin D intake, either through diet or supplementation, should follow Health Canada’s recommendations for healthy individuals of different age groups. For those with medical conditions such as renal disease, liver disease, and malabsorption syndromes, and for those taking medications that may affect vitamin D absorption/metabolism, physician guidance should be followed with respect to both vitamin D testing and supplementation.
Conclusions
Studies indicate that vitamin D, alone or in combination with calcium, may decrease the risk of fractures and falls among older adults.
There is no high or moderate quality evidence to support the effectiveness of vitamin D in other outcomes such as cancer, cardiovascular outcomes, and all-cause mortality.
Studies suggest that the prevalence of vitamin D deficiency in Canadian adults and children is relatively low (approximately 5%), and between 10% and 25% have serum levels below 40 to 50 nmol/L (based on very low to low grade evidence).
Given the limitations associated with serum vitamin D measurement, ambiguities in the definition of a ‘target serum level’, and the availability of clear guidelines on vitamin D supplementation from Health Canada, vitamin D testing is not warranted for the average risk population.
Health Canada has issued recommendations regarding the adequate daily intake of vitamin D, but current studies suggest that the mean dietary intake is below these recommendations. Accordingly, Health Canada’s guidelines and recommendations should be promoted.
Based on a moderate level of evidence, individuals with darker skin pigmentation appear to have a higher risk of low serum vitamin D levels than those with lighter skin pigmentation and therefore may need to be specially targeted with respect to optimum vitamin D intake. The cause-effect of this association is currently unclear.
Individuals with medical conditions such as renal and liver disease, osteoporosis, and malabsorption syndromes, as well as those taking medications that may affect vitamin D absorption/metabolism, should follow their physician’s guidance concerning both vitamin D testing and supplementation.
PMCID: PMC3377517  PMID: 23074397
2.  Vitamin D status among Adult Saudi Females visiting Primary Health Care Clinics 
Background
Vitamin D plays an important role in diverse physiological functions in addition to its role in bone health. Vitamin D deficiency is very common in elderly people, but there are few reports on its prevalence in young adults.
Method
A cross-sectional study was carried out on a total of 465 young adult Saudi females aged 19 to 40 years old who were selected from primary health care centers of King Abdulaziz medical city, Riyadh, KSA. A questionnaire was used to identify socio-demographic characteristics and risk factors such as sunlight exposure and dietary intake. 25-hydroxy vitamin D [25(OH)D], Parathyroid hormone (PTH) and bone biochemical parameter were measured. The cutoff values for Vitamin D were defined as follows: deficient (<25nmol/L), insufficient (25–75 nmol/L) and normal (≥ 75 nmol/L).
Result
Overall, hypovitaminosis D were identified in all participants, with a mean level of 18.34 ±8.2 nmol/L. Of all the participants, 79.1% exhibited severe vitamin D deficiency (serum 25(OH) D < 25 nmol/L), while 20.9% exhibited vitamin D insufficiency (serum 25(OH) D between 25–50 nmol/L). There was a significant inverse correlation between serum 25 (OH) D concentrations and PTH, where secondary hyperparathyroidism was evident in 61.4% of participants with deficient vitamin D compared to 39.2% of participants with insufficient vitamin D.
Conclusion
Despite the abundant sunlight in Saudi Arabia, the prevalence of hypovitaminosis D among young healthy Saudi females is 100%. This finding should be considered a public health problem. Case identification, health education and prevention should be encouraged.
PMCID: PMC3616941  PMID: 23580892
Vitamin D; prevalence; women; Saudi; secondary hyperparathyroidism; sunlight; dietary supplement
3.  Prevalence of Vitamin D Deficiency and Its Related Factors Among University Students in Shiraz, Iran 
Backgrounds:
Vitamin D deficiency is a public health concern even in sunny areas, so we decided to assess the prevalence of vitamin D deficiency and its related factors among university students in Shiraz.
Methods:
This cross-sectional study was carried out on 254 (128 male and 126 female) university students. Demographic questionnaires and a questionnaire on exposure to sun light and sun protection were completed by the participants. Serum 25OH-vitamin D was measured using a radioimmunoassay kit. Data analysis was done using Statistical Package for Social Sciences (SPSS) software # 16. A P value less than 0.05 was considered as significant.
Results:
Mean ± standard deviation (SD) of serum 25OH-vitamin D was 49.29 ± 12.87 (nmol/l) and 27.46 ± 10.37 (nmol/l) among male and female students, respectively. 51.2% of female students were vitamin D insufficient and 44% of them had vitamin D deficiency. Prevalence of vitamin D insufficiency and marginal status among male students were 49.5 and 48%, respectively. Serum vitamin D of female students was significantly less than the males (P < 0.001). Serum vitamin D was negatively correlated to sun protection score (P < 0.001, r = 0.50), but there was no correlation between serum vitamin D and sun exposure.
Conclusions:
Vitamin D deficiency especially among female students is alarmingly prevalent. Increasing use of sunscreen lotion and clothing style could be the main factors inhibiting endogenous vitamin D synthesis which results in its deficiency.
PMCID: PMC4085935  PMID: 25013702
Sun protection; university students; vitamin D status
4.  Vitamin D deficiency among healthy adolescents in Al Ain, United Arab Emirates 
BMC Public Health  2013;13:33.
Background
Although vitamin D deficiency has been studied in various adult populations, there are few data on the prevalence of this nutritional deficiency among healthy adolescents in the United Arab Emirates (UAE). This study was conducted to determine the prevalence of vitamin D deficiency and to examine its correlates in adolescents aged 15 to 18 years.
Methods
This was a cross-sectional study in urban schools. Healthy adolescents (N=315) from a sample of 8 schools were randomly selected from the 142 schools in Al Ain, Abu Dhabi Emirate. Outcomes measured included serum concentrations of 25-hydroxy vitamin D (25OHD), plasma lipids, blood sugar, blood pressure and anthropometric data, nutrition and lifestyle variables.
Results
Fourty-one participants (19.7%) were vitamin D deficient (serum 25OHD level ≤15 ng/mL [≤37.5 nmol/L]. Using a cutoff level of 25(OH) D of ≤20 ng/ml [≤50 nmol/l] 143 participants (45.4%) were vitamin D insufficient. Overall 65.1% of study participants were either vitamin D deficient or insufficient. The prevalence of vitamin D deficiency varied between boys (10%) and girls (28%). In a final multivariate model, serum 25(OH) D concentrations were inversely correlated with female gender, consumption of fast food per week, and body mass index and positively correlated with physical activity scores after adjustment for age.
Conclusions
Vitamin D deficiency and insufficiency were highly prevalent in adolescents, and more common in girls.
doi:10.1186/1471-2458-13-33
PMCID: PMC3610121  PMID: 23311702
Vitamin D deficiency; Adolescents; United Arab Emirates
5.  Relationship between 25-Hydroxy Vitamin-D and Obesity in 2-7 years old Children Referred to a Paediatric Hospital in Iran 
Background: Obesity is increasing in children and it can cause many complications in adulthood, such as Diabetes mellitus (DM) and metabolic syndrome. In observational studies, vitamin-D was one of the factors which were found to be associated with obesity.
Aims: To determine the association between body mass index (BMI) and serum level of vitamin-D in children who were outpatients at Taleghani Paediatric Hospital, Iran.
Settings and Design: This was a cross-sectional observational study done on 215 children who were 2 to 7 y old, who were referred to Taleghani Hospital in winter (1391 solar calendar) 2013.
Materials and Methods: In this cross-sectional study, anthropometric indices: weight, height and waist circumference were measured by using identical instruments. BMI was also determined as per CDC 2000 criteria. Vitamin-D levels were estimated by ELISA.
Statistical Analysis: Vitamin-D levels which were less than 20 nmol/L were considered as a deficiency, levels which were 20-30 nmol\L were considered as inadequate and those which were equal to or greater than 30 nmol\L were considered as sufficient. t-test, ANOVA and Pearson’s correlation coefficient at a significant level of 0.05 were applied and data were analysed by using SPSS (version 16).
Results: One hundred and twenty five children (47.4%) were males and the rest were females. One hundred eighty four children (85.6%) had vitamin-D deficiency and only 31 had adequate levels of vitamin-D. The prevalence of obesity and overweight were 27%, but considering the vitamin-D status, it was found to be insignificant. However, there was a linear relationship between waist circumference and serum vitamin-D (p<0.01). The means and standard deviations of serum vitamin-D levels in girls and boys were 22.76 ±11.62 and 23.46 ± 9.30 nmol/L and this difference was not significant. Vitamin-D levels found in the three ethnic groups of Fars, Turkmen and Sistani showed significant differences (p<0.002).
Conclusions: There was a high prevalence of vitamin-D deficiency in 2 to 7 year olds. There was no significant relationship between BMI and vitamin-D, but it was recorded in ethnic groups, and there was a correlation between waist circumference and vitamin-D levels. More exposure to sunlight and prescription of vitamin supplements were recommended.
doi:10.7860/JCDR/2014/8282.4810
PMCID: PMC4225948  PMID: 25386496
BMI; Vitamin-D
6.  The Causal Effect of Vitamin D Binding Protein (DBP) Levels on Calcemic and Cardiometabolic Diseases: A Mendelian Randomization Study 
PLoS Medicine  2014;11(10):e1001751.
In this study, Richards and colleagues undertook a Mendelian randomization study to determine whether vitamin D binding protein (DBP) levels have a causal effect on common calcemic and cardiometabolic diseases. They concluded that DBP has no demonstrable causal effect on any of the diseases or traits investigated here, except Vit D levels.
Please see later in the article for the Editors' Summary
Background
Observational studies have shown that vitamin D binding protein (DBP) levels, a key determinant of 25-hydroxy-vitamin D (25OHD) levels, and 25OHD levels themselves both associate with risk of disease. If 25OHD levels have a causal influence on disease, and DBP lies in this causal pathway, then DBP levels should likewise be causally associated with disease. We undertook a Mendelian randomization study to determine whether DBP levels have causal effects on common calcemic and cardiometabolic disease.
Methods and Findings
We measured DBP and 25OHD levels in 2,254 individuals, followed for up to 10 y, in the Canadian Multicentre Osteoporosis Study (CaMos). Using the single nucleotide polymorphism rs2282679 as an instrumental variable, we applied Mendelian randomization methods to determine the causal effect of DBP on calcemic (osteoporosis and hyperparathyroidism) and cardiometabolic diseases (hypertension, type 2 diabetes, coronary artery disease, and stroke) and related traits, first in CaMos and then in large-scale genome-wide association study consortia. The effect allele was associated with an age- and sex-adjusted decrease in DBP level of 27.4 mg/l (95% CI 24.7, 30.0; n = 2,254). DBP had a strong observational and causal association with 25OHD levels (p = 3.2×10−19). While DBP levels were observationally associated with calcium and body mass index (BMI), these associations were not supported by causal analyses. Despite well-powered sample sizes from consortia, there were no associations of rs2282679 with any other traits and diseases: fasting glucose (0.00 mmol/l [95% CI −0.01, 0.01]; p = 1.00; n = 46,186); fasting insulin (0.01 pmol/l [95% CI −0.00, 0.01,]; p = 0.22; n = 46,186); BMI (0.00 kg/m2 [95% CI −0.01, 0.01]; p = 0.80; n = 127,587); bone mineral density (0.01 g/cm2 [95% CI −0.01, 0.03]; p = 0.36; n = 32,961); mean arterial pressure (−0.06 mm Hg [95% CI −0.19, 0.07]); p = 0.36; n = 28,775); ischemic stroke (odds ratio [OR] = 1.00 [95% CI 0.97, 1.04]; p = 0.92; n = 12,389/62,004 cases/controls); coronary artery disease (OR = 1.02 [95% CI 0.99, 1.05]; p = 0.31; n = 22,233/64,762); or type 2 diabetes (OR = 1.01 [95% CI 0.97, 1.05]; p = 0.76; n = 9,580/53,810).
Conclusions
DBP has no demonstrable causal effect on any of the diseases or traits investigated here, except 25OHD levels. It remains to be determined whether 25OHD has a causal effect on these outcomes independent of DBP.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Vitamin D deficiency is an increasingly common public health concern. According to some estimates, more than a billion people worldwide may be vitamin D deficient. Indeed, many people living in the US and Europe (in particular, elderly people, breastfed infants, people with dark skin, and obese individuals) have serum (circulating) 25-hydroxy-vitamin D (25OHD) levels below 50 nmol/l, the threshold for vitamin D deficiency. Vitamin D helps the body absorb calcium, a mineral that is essential for healthy bones. Consequently, vitamin D deficiency can lead to calcemic diseases such as rickets (a condition that affects bone development in children), osteomalacia (soft bones in adults), and osteoporosis (a condition in which the bones weaken and become susceptible to fracture). We get most of our vitamin D needs from our skin, which makes vitamin D after exposure to sunlight. Vitamin D is also found naturally in oily fish and eggs, and is added to some other foods, including cereals and milk, but some people need to take vitamin D supplements to avoid vitamin D deficiency.
Why Was This Study Done?
Observational studies have reported that the low levels of serum 25OHD and serum vitamin D binding protein (DBP, a key determinant of serum 25OHD level) are both associated with the risk of several common diseases and traits. Such studies have implicated vitamin D deficiency in cardiometabolic disease (cardiovascular diseases that affect the heart and/or blood vessels and metabolic diseases that affect the cellular chemical reactions needed to sustain life), in some cancers, and in Alzheimer disease. But observational studies cannot prove that vitamin D deficiency or DBP levels actually cause any of these diseases. So, for example, an observational study might report an association between vitamin D deficiency and type 2 diabetes (a metabolic disease), but the individuals who develop type 2 diabetes might share another unknown characteristic that is actually responsible for disease development (a confounding factor). Alternatively, type 2 diabetes might reduce circulating vitamin D levels (reverse causation). Here, the researchers undertake a Mendelian randomization study to determine whether circulating DBP levels have causal effects on calcemic and cardiometabolic diseases. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if low DBP levels lead to low serum 25OHD levels, and vitamin D levels have a causal effect on common diseases, genetic variants associated with low DBP levels should be associated with the development of common diseases.
What Did the Researchers Do and Find?
The researchers analyzed the association between a genetic variant called single nucleotide polymorphism (SNP) rs2282679, which is known to alter DBP levels, and calcemic and cardiometabolic diseases and related traits in 2,254 participants in the Canadian Multicentre Osteoporosis Study (CaMos). The researchers report that there was a strong association between SNP rs2282679 and both serum DBP and 25OHD levels among the CaMos participants. However, there were no significant associations (associations unlikely to have occurred by chance) between SNP rs2282679 and calcium level, osteoporosis, or several cardiometabolic diseases, including heart attacks and diabetes. Moreover, when the researchers examined publically available genome-wide association study data collected by several international consortia investigating genetic influences on disease, they found no significant associations between rs2282679 and a wide range of calcemic and cardiometabolic diseases.
What Do These Findings Mean?
In this Mendelian randomization study, DBP level had no demonstrable causal effect on any of the calcemic or cardiometabolic diseases or traits investigated, except 25OHD level. Because most of the participants in CaMos and the international consortia were of European descent, these findings are applicable only to people of European ancestry. Moreover, like all Mendelian randomization studies, the reliability of these findings depends on several assumptions made by the researchers. Notably, although this study strongly suggests that DBP level does not have a causal influence on several common diseases, it remains to be determined whether 25OHD has a causal effect on any calcemic or cardiometabolic outcomes independent of DBP level.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001751.
The UK National Health Service Choices website provides information about vitamin D and about how to get vitamin D from sunshine; “Behind the Headlines” articles describe a recent observational study that reported an association between vitamin D deficiency and Alzheimer disease and the media coverage of this study, other health claims made for vitamin D, and a randomized control trial that questioned the role of vitamin D in disease
The US National Institutes of Health Office of Dietary Supplements provides information about vitamin D (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about the vitamin D status of the US population
MedlinePlus has links to further information about vitamin D (in English and Spanish)
Information about the Canadian Multicentre Osteoporosis Study is available
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001751
PMCID: PMC4211663  PMID: 25350643
7.  Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts 
PLoS Medicine  2013;10(2):e1001383.
A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.
Background
Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.
Methods and Findings
We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects.
Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).
Conclusions
On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Obesity—having an unhealthy amount of body fat—is increasing worldwide. In the US, for example, a third of the adult population is now obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Although there is a genetic contribution to obesity, people generally become obese by consuming food and drink that contains more energy than they need for their daily activities. Thus, obesity can be prevented by having a healthy diet and exercising regularly. Compared to people with a healthy weight, obese individuals have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. They also have a higher risk of vitamin D deficiency, another increasingly common public health concern. Vitamin D, which is essential for healthy bones as well as other functions, is made in the skin after exposure to sunlight but can also be obtained through the diet and through supplements.
Why Was This Study Done?
Observational studies cannot prove that obesity causes vitamin D deficiency because obese individuals may share other characteristics that reduce their circulating 25-hydroxy vitamin D [25(OH)D] levels (referred to as confounding). Moreover, observational studies cannot indicate whether the larger vitamin D storage capacity of obese individuals (vitamin D is stored in fatty tissues) lowers their 25(OH)D levels or whether 25(OH)D levels influence fat accumulation (reverse causation). If obesity causes vitamin D deficiency, monitoring and treating vitamin D deficiency might alleviate some of the adverse health effects of obesity. Conversely, if low vitamin D levels cause obesity, encouraging people to take vitamin D supplements might help to control the obesity epidemic. Here, the researchers use bi-directional “Mendelian randomization” to examine the direction and causality of the relationship between BMI and 25(OH)D. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants do not change over time and are inherited randomly, they are not prone to confounding and are free from reverse causation. Thus, if a lower vitamin D status leads to obesity, genetic variants associated with lower 25(OH)D concentrations should be associated with higher BMI, and if obesity leads to a lower vitamin D status, then genetic variants associated with higher BMI should be associated with lower 25(OH)D concentrations.
What Did the Researchers Do and Find?
The researchers created a “BMI allele score” based on 12 BMI-related gene variants and two “25(OH)D allele scores,” which are based on gene variants that affect either 25(OH)D synthesis or breakdown. Using information on up to 42,024 participants from 21 studies, the researchers showed that the BMI allele score was associated with both BMI and with 25(OH)D levels among the study participants. Based on this information, they calculated that each 10% increase in BMI will lead to a 4.2% decrease in 25(OH)D concentrations. By contrast, although both 25(OH)D allele scores were strongly associated with 25(OH)D levels, neither score was associated with BMI. This lack of an association between 25(OH)D allele scores and obesity was confirmed using data from more than 100,000 individuals involved in 46 studies that has been collected by the GIANT (Genetic Investigation of Anthropometric Traits) consortium.
What Do These Findings Mean?
These findings suggest that a higher BMI leads to a lower vitamin D status whereas any effects of low vitamin D status on BMI are likely to be small. That is, these findings provide evidence for obesity as a causal factor in the development of vitamin D deficiency but not for vitamin D deficiency as a causal factor in the development of obesity. These findings suggest that population-level interventions to reduce obesity should lead to a reduction in the prevalence of vitamin D deficiency and highlight the importance of monitoring and treating vitamin D deficiency as a means of alleviating the adverse influences of obesity on health.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001383.
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish); a data brief provides information about the vitamin D status of the US population
The World Health Organization provides information on obesity (in several languages)
The UK National Health Service Choices website provides detailed information about obesity and a link to a personal story about losing weight; it also provides information about vitamin D
The International Obesity Taskforce provides information about the global obesity epidemic
The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)
The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish)
MedlinePlus has links to further information about obesity and about vitamin D (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Overview and details of the collaborative large-scale genetic association study (D-CarDia) provide information about vitamin D and the risk of cardiovascular disease, diabetes and related traits
doi:10.1371/journal.pmed.1001383
PMCID: PMC3564800  PMID: 23393431
8.  Vitamin D status among population of Qassim Region, Saudi Arabia 
Objectives
The objectives of this study were to assess serum 25OHD level among healthy Saudi population of Qassim region, besides socio-demographic characters, dietary habits, sun exposure and common symptoms of vitamin D deficiency were also evaluated.
Subjects and Methods
One hundred and eighty healthy males and females subjects above the age of 18 years were randomly selected from five primary health care centers of Qassim region. A predesigned structured questionnaire was administered by the doctor working in Primary Health Care Center and blood sample was obtained for measuring vitamin D (serum 25 OHD) level. Vitamin D sufficiency was defined as serum level of 25 OHD 30ng/ml or above. A level ranging 20 to 29 ng/ml was considered as vitamin D insufficiency, whereas below 20ng/ml as vitamin D deficiency.
Results
Out of 180 study participants, 51(28.3%) subjects were vitamin D deficient, 71 (39.4%) were vitamin insufficient and 58 (32.2%) had normal vitamin D level. Commonest symptom of vitamin D deficiency was bone pain (20%) and fatigue (11.1%).
Conclusion
Vitamin D inadequacy is a major public health problem in Saudi population. The prevalence of vitamin D deficiency/insufficiency among healthy Saudi population residing in Qassim region is 67.8%. If the issue is not urgently addressed it could lead to serious health consequences.
PMCID: PMC3521830  PMID: 23267289
Vitamin D; Qassim Region; Saudi Arabia
9.  Lower vitamin D status is more common among Saudi adults with diabetes mellitus type 1 than in non-diabetics 
BMC Public Health  2014;14:153.
Background
Vitamin D deficiency is an increasingly recognized comorbidity in patients with type 1 diabetes mellitus (DMT1), suggesting that vitamin D deficiency might play a role in DMT1. We aimed to determine and compare the vitamin D status of Saudi adults with and without DMT1.
Methods
A total of 60 Saudi adults with DMT1 from the Diabetes Clinics and 60 non-DM, healthy controls were included in the study. The mean age for those with DMT1 was 25.9 ± 16.1 years versus 36.7 ± 3.6 years among the controls. We measured serum 25-hydroxy vitamin D (25OHD), calcium, cholesterol, blood glucose, HDL, and triglycerides and compared the results between the DMT1 group and control subjects.
Results
Both the DMT1 and healthy groups had vitamin D deficiency. The mean levels of 25OHD were significantly lower in the DMT1 adults than in the controls (28.1 ± 1.4 nmol/L versus 33.4 ± 1.6 nmol/L). In the DMT1 adults, 66.7% were mildly, 31.7% moderately, and 3.3% severely vitamin D deficient as compared with 41.7% (mildly), 31.7% (moderately), and 5% (severely) in the control group. Overall, 100% of the DMT1 adults and 78% of the healthy children were vitamin D deficient.
Conclusion
The prevalence of vitamin D deficiency among DMT1 adults was relatively high. Therefore, screening for vitamin D deficiency and supplementation for this population should be warranted.
doi:10.1186/1471-2458-14-153
PMCID: PMC3929135  PMID: 24517121
Vitamin D; Vitamin D Deficiency; Type 1 diabetes
10.  Vitamin D levels in an Australian population 
BMC Public Health  2014;14(1):1001.
Background
Levels of vitamin D in the population have come under increasing scrutiny, however there are only a few studies in Australia which measure levels in the general population. The aim of this study was to measure the levels of vitamin D within a large population cohort and examine the association with seasons and selected demographic and health risk factors.
Methods
A longitudinal cohort study of 2413 participants in the northwest suburbs of Adelaide, South Australia conducted between 2008 and 2010 was used to examine serum levels of 25-hydroxy vitamin D (25(OH)D) in relation to demographic characteristics (age, sex, income, education and country of birth), seasons, the use of vitamin D supplements and selected health risk factors (physical activity, body mass index and smoking). Both unadjusted and adjusted mean levels of serum 25(OH)D were examined, as were the factors associated with the unadjusted and adjusted prevalence of serum 25(OH)D levels below 50 and 75 nmol/L.
Results
Overall, the mean level of serum 25(OH)D was 69.2 nmol/L with 22.7% of the population having a serum 25(OH)D level below 50 nmol/L, the level which is generally recognised as vitamin D deficiency. There were significantly higher levels of 25(OH)D among males compared to females (t = 4.65, p < 0.001). Higher levels of 25(OH)D were also measured in summer and autumn compared with winter and spring. Generally, mean levels of 25(OH)D were lower in those classified as obese. Smokers and those undertaking no or less than 150 minutes/week of physical activity also had lower levels of serum vitamin D. Obesity (as classified by body mass index), season and undertaking an insufficient level of physical activity to obtain a health benefit were significantly associated with the prevalence of vitamin D deficiency.
Conclusions
Vitamin D deficiency is prevalent in South Australia, affecting almost one quarter of the population and levels are related to activity, obesity and season even when adjusted for confounding factors. Improved methods of addressing vitamin D levels in population are required.
doi:10.1186/1471-2458-14-1001
PMCID: PMC4194387  PMID: 25256413
Vitamin D; Population; Cohort study; Risk factors; Demographic factors
11.  Vitamin D deficiency in children living in Jeddah, Saudi Arabia 
Objective:
Vitamin D deficiency is an unrecognized epidemic and a common health problem worldwide. This study was conducted to evaluate the vitamin D status in children living in Jeddah, Saudi Arabia and to study its relation to various variables.
Materials and Methods:
A cross-sectional study was conducted in the pediatric clinic in Jeddah Clinic Hospital-Kandarah, Jeddah, KSA, from October through December 2010, in which 510 healthy children aged 4–15 years were enrolled. Serum calcium, phosphorus, alkaline phosphatase and 25-hydroxyvitamin D [25(OH)D] were measured. Dietary vitamin D intake and duration of daily sunlight exposure were determined. 25(OH)D levels <20 ng/mL and <7 ng/mL were defined as relative and severe vitamin D deficiency, respectively.
Results:
The mean concentration of 25(OH)D was 13.07 ± 7.81 ng/mL. Seventy subjects (13.72%) had normal 25(OH)D level ranging 20–70 ng/mL. Three hundred (58.82%) had relative 25(OH)D deficiency and 140 (27.45%) had severe deficiency (P=0.000). 220 (43.14%) subjects were males and 290 (56.86%) were females having a statistically significant higher incidence of 25(OH)D deficiency (P=0.019). 54.9% were Saudis, 27.45% were Yemenis and 11.76% were Egyptians. Saudis and Yemenis were more subjected to 25(OH)D deficiency in comparison to Egyptians and other nationalities (P=0.01). There were significant inverse correlations between 25(OH)D levels and bony aches (P=0.000). 56.25% of asymptomatic children had vitamin D deficiency (P=0.000). Duration of sunlight exposure and daily intake of vitamin D had significant effects on serum level of vitamin D (P=0.000).
Conclusions:
A high prevalence of vitamin D deficiency in children living in Jeddah was observed in this study. Vitamin D supplementation of food products can prevent vitamin D deficiency in these children.
doi:10.4103/2230-8210.93746
PMCID: PMC3313746  PMID: 22470865
Bony aches; children; fracture; vitamin D
12.  A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate Cancer 
PLoS Medicine  2007;4(3):e103.
Background
Vitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.
Methods and Findings
During 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7–10, metastatic, and fatal prostate cancer) and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (<20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (<32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and 1,25(OH)2D were below (versus above) the median had a significantly increased risk of aggressive prostate cancer (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.2–3.4), although the interaction between the two vitamin D metabolites was not statistically significant (pinteraction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction < 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of total (OR = 1.9, 95% CI 1.1–3.3) and aggressive prostate cancer (OR = 2.5, 95% CI 1.1–5.8). Among men with plasma 25(OH)D levels above the median, the ff genotype was no longer associated with risk. Conversely, among men with the ff genotype, high plasma 25(OH)D level (above versus below the median) was related to significant 60%∼70% lower risks of total and aggressive prostate cancer.
Conclusions
Our data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of low 25(OH)D status.
Results of this study by Haojie Li and colleagues suggest that vitamin D deficiency is common among men in the US, and that vitamin D status and genetic variation in theVDR gene affect prostate cancer risk.
Editors' Summary
Background.
Prostate cancer occurs when cells in the prostate gland (part of the male reproductive system) accumulate genetic changes that allow them to grow into a disorganized mass of cells. Patients whose disease is diagnosed when these cells are still relatively normal can survive for many years, but for patients with aggressive cancers—ones containing fast-growing cells that can migrate around the body—the outlook is poor. Factors that increase prostate cancer risk include increasing age, having a family history of prostate cancer, and being African American. Also, there are hints that some environmental or dietary factors affect prostate cancer risk. One of these factors is vitamin D, of which high levels are found in seafood and dairy products, but which can also be made naturally by the body—more specifically, by sunlight-exposed skin. One reason researchers think vitamin D might protect against prostate cancer is that this cancer is more common in sun-starved northern countries (where people often have a vitamin D deficiency) than in sunny regions. Prostate cancer is also more common in African American men than in those of European descent (when exposed to the same amount of sunlight, individuals with darker skin make less vitamin D than those with lighter skin). Once in the human body, vitamin D is converted into the vitamin D metabolite 25-hydroxyvitamin D3 (25[OH]D) and then into the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D). This binds to vitamin D receptors (VDRs) and inhibits cell proliferation and migration.
Why Was This Study Done?
The effect of 1,25(OH)2D on cells and the observation that related chemicals slow prostate cancer growth in rodents suggest that vitamin D protects against prostate cancer. But circulating levels of vitamin D metabolites in human male populations do not always reflect how many men develop prostate cancer. This lack of correlation may partly be because different forms of the VDR gene exist. One area of variation in the VDR gene is called the FokI polymorphism. Because everyone carries two copies of the VDR gene, individuals may have a FokI FF, FokI Ff, or FokI ff genotype. The f variant (or allele) codes for a receptor that is less responsive to 1,25(OH)2D than the receptor encoded by the FokI F allele. So levels of vitamin D sufficient to prevent cancer in one person may be insufficient in someone with a different FokI genotype. In this study, the researchers have investigated how levels of 25(OH)D and 1,25(OH)2D in combination with different VDR FokI alleles are influencing prostate cancer risk.
What Did the Researchers Do and Find?
The researchers identified 1,066 men who developed prostate cancer between enrollment into the US Physicians' Health Study in 1982 and 2000, and 1,618 cancer-free men of the same ages and smoking levels as “controls.” They measured vitamin D metabolite levels in many of the blood samples taken from these men in 1982 and determined their FokI genotype. Two-thirds of the men had insufficient blood levels of vitamin D metabolites in the winter/spring; almost one-third had a vitamin D deficiency. Men whose blood levels of both metabolites were below average were twice as likely to develop aggressive prostate cancer as those in whom both levels were above average. Compared with men with high blood levels of 25(OH)D and the FokI FF or Ff genotype, men with low 25(OH)D levels and the FokI ff genotype were 2.5 times as likely to develop aggressive prostate cancer. However, men with the ff genotype were not at higher risk if they had sufficient 25(OH)D levels. Among men with the ff genotype, sufficient 25(OH)D levels might therefore protect against prostate cancer, especially against the clinically aggressive form.
What Do These Findings Mean?
These findings confirm that many US men have suboptimal levels of circulating vitamin D. This vitamin is essential for healthy bones, so irrespective of its effects on prostate cancer, vitamin D supplements might improve overall health. In addition, this large and lengthy study reveals an association between low levels of the two vitamin D metabolites and aggressive prostate cancer that is consistent with vitamin D helping to prevent the progression of prostate cancer. It also indicates that the VDR FokI genotype modifies the prostate cancer risk associated with different blood levels of vitamin D. Together, these results suggest that improving vitamin D status through increased exposure to sun and vitamin D supplements might reduce prostate cancer risk, particularly in men with the FokI ff genotype. Because the study participants were mainly of European descent, the researchers caution that these results may not apply to other ethnic groups and note that further detailed studies are needed to understand fully how vitamin D affects prostate cancer risk across the population.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040103.
MedlinePlus encyclopedia has pages on prostate cancer and on vitamin D
Information for patients and physicians is available from the US National Cancer Institute on prostate cancer and on cancer prevention
The Prostate Cancer Foundation's information on prostate cancer discusses the effects of nutrition on the disease
Patient information on prostate cancer is available from Cancer Research UK
Cancerbackup also has patient information on prostate cancer
doi:10.1371/journal.pmed.0040103
PMCID: PMC1831738  PMID: 17388667
13.  Prevalence of Vitamin D Insufficiency in Qatar: a Systematic Review 
Qatar has a high burden of chronic diseases including obesity, cardiovascular disease and type 2 diabetes mellitus. Low serum vitamin D levels have been implicated in the development and progression of a range of these chronic conditions. The prevalence of vitamin D insufficiency or deficiency in the general population of Qatar has still not been investigated. The aim of this study was to carry out a systematic review of published studies documenting the prevalence of vitamin D insufficiency or deficiency in the Qatari population. A search strategy was developed for online databases (PubMed, Ovid MEDLINE, Embase and Embase Classic) between 1980 to the last week of August 2012, and bibliographies of the included studies were further searched for additional reports. Search terms used were QATAR and VITAMIN D. Studies reporting the serum levels of vitamin D in several Qatari sub-populations were identified. Weighted-average vitamin D serum levels and prevalence of low vitamin D status (<75 nmol/L) were calculated. Subgroup analysis was carried out by age. The quality of each study was evaluated according to four criteria: national representativeness, representation of males and females, the sample size, and the sampling protocol. A total of 16 relevant publications were identified, and 8 of these (reporting from 7 unique studies) met our inclusion and exclusion criteria with a total number of 1,699 Qatari subjects. The pooled sample size weighted-average vitamin D concentration (±SD) was 45.3±14.3 nmol/L (95% CI: 44.6-46.0; range 29.2-66.9 nmol/L). The weighted-average prevalence of low vitamin D status was 90.4% (95% CI: 90.1-91.0; range 83%-91%). Age was inversely correlated with vitamin D levels and directly with its insufficiency/deficiency prevalence. There have only been a few studies on the prevalence of low vitamin D in Qatar a very high prevalence of vitamin D insufficiency/deficiency in Qatar that increases with age has been suggested. The present report underlines the need to develop a nationally representative study to further evaluate vitamin D status in Qatar. Given the growing evidence of the role of vitamin D in chronic disease, this study could help develop public health strategies for disease prevention in Qatar.
doi:10.4081/jphr.2012.e36
PMCID: PMC4140375  PMID: 25170469
Qatar; vitamin D; prevalence; prevention; public health; systematic review
14.  The correlation between third-trimester maternal and newborn-serum 25-hydroxy-vitamin D in a selected South Australian group of newborn samples 
BMJ Open  2011;1(2):e000236.
Background
Although vitamin D insufficiency is prevalent in the community, only a few population-based studies have measured serum 25-hydroxy-vitamin D (25OHD) levels during pregnancy and in newborns. Maternal vitamin D deficiency has been linked to pregnancy complications, as well as hypocalcaemia and rickets in the newborn. Here, the authors report third-trimester maternal and newborn-serum 25OHD concentrations in 101 neonates whose serum samples were sent for testing.
Methods
The newborn 25OHD levels were correlated with the third-trimester maternal serum 25OHD levels using a least-square regression analysis. All samples were measured using an enzyme immunoassay (EIA). Ten randomly selected newborn serum samples were also measured using liquid chromatography/tandem mass spectrometry LC-MSMS, and correlated with the EIA method.
Results
Out of 99 mothers of the newborns, only 19, 42 and 68 had their 25OHD level measured in the first, second and third trimester respectively. The mean maternal age was 30 years, while the mean maternal third-trimester 25OHD concentration was 48 nmol/l. Of the newborns, 53% were female, and 85% were term deliveries. The mean newborn-serum 25OHD was 68 nmol/l. Neonatal 25OHD was related to maternal third-trimester levels measured by EIA (r=0.3; newborn 25OHD=0.42(maternal 25OHD)+44.2; p=0.02). EIA and LC-MSMS concentrations for newborns correlated significantly over a range between 20 and 103 nmol/l by EIA (r=0.9; EIA=1.04(LCMSMS)+10.1; p<0.00 (slope); p=0.18 (intercept)). The mean 25OHD concentration in women who suffered pre-eclampsia and premature rupture of membranes were 45 and 39 nmol/l respectively.
Conclusions
Newborn-serum 25OHD concentrations depend on the maternal circulating plasma 25OHD level at least during the third trimester. Neonatal 25OHD levels obtained by EIA correlated well with LC-MSMS. Although the EIA values for neonates were greater than LC-MSMS values, this difference was not statistically significant.
Article summary
Article focus
There is evidence that maternal vitamin D status affects fetal and neonatal development.
Despite the evidence, testing for vitamin D during pregnancy is not offered to many women in our community.
We hypothesise that the maternal vitamin D status especially the 3rd trimester maternal serum levels determines the neonatal vitamin D status.
Key messages
Despite National Guidelines, women in the third trimester of pregnancy are vitamin D deficient.
Maternal vitamin D status determines the neonatal vitamin D status.
Women with very low levels of vitamin D may be more likely to develop pregnancy and birth comlications.
Strengths & limitations
Strengths
Access to 100 newborn samples from a teaching hospital.
Validation of enzyme immunoassay with HPLC—mass spectrometry for neonatal vitamin D.
Limitations
Numbers of women with pregnancy and birth complications are too small to make a strong statement regarding direct effects of vitamin D.
No follow-up data available for the neonates (ie, developemental milestones etc).
doi:10.1136/bmjopen-2011-000236
PMCID: PMC3191602  PMID: 22021888
15.  Incidence of vitamin B12 / D3 deficiency among company executives 
The present cross-sectional and interventional study was carried out to assess the incidence of vitamin B12 / vitamin D deficiency in male office executives in the tropical city of Mumbai, India. A total of 75 senior executives were surveyed and subjected to analysis of blood levels of vitamin D (25 Hydroxy Cholecalciferol) by RIA method and vitamin B12 by CLIA method. The same was performed in a reputed analytical laboratory with NABL accreditation. History of smoking, exposure to sunlight, exercise, dietary habits, consumption of vitamin supplements, medication etc. was obtained.
The results revealed 65% executives with vitamin B12 deficiency (less than 193 pg/ml) and 28% executives with vitamin D deficiency (less than 7.6 ng/ml). The prevalence of low levels of vitamin B12 is lower (58%) in those who give history of regular exercise than others. The prevalence of vitamin D deficiency is lower (25%) in those who give history of regular exercise than in others (46.2%). Prevalence of vitamin D deficiency is higher (47%) in those whose workday day started earlier than in those whose workday started later (12%).
In the second phase of the survey, 58 executives with low B12/ D3 values, were given vitamin B12/D3 oral supplements for a period of three months along with counseling for lifestyle modification. A modified questionnaire was then circulated and the subjects analyzed for B12/D3 values. Significant improvements in serum B12 and D3 values were seen after the oral therapy, sun exposure and dietary modifications.
doi:10.4103/0019-5278.34535
PMCID: PMC3168103  PMID: 21938222
Alfacalcidol; mecobalamine
16.  Vitamin D status in apparently healthy adults in Kashmir Valley of Indian subcontinent 
Postgraduate Medical Journal  2007;83(985):713-716.
Background
The worldwide prevalence of vitamin D deficiency is reported to be high.
Objectives
To assess the vitamin D status in apparently healthy adults in Kashmir valley by measuring serum 25‐hydroxyvitamin D (25 (OH) D).
Methods
92 healthy natives (64 men and 28 non‐pregnant/non‐lactating women, aged 18–40 years), residing in Kashmir for at least last 5 years and not having any suggestion of systemic disease, were selected for this study. The samples were collected throughout the year in both summer and winter months. Vitamin D deficiency was defined as a serum 25 (OH) D concentration of <50 nmol/l and graded as mild (25–50 nmol/l), moderate (12.5–25 nmol/l) and severe (<12.5 nmol/l).
Results
Body mass index, total energy intake, and other nutritional parameters were comparable among subjects in different groups. Overall 76 (83%) of the subjects studied had vitamin D deficiency—25%, 33%, and 25% had mild, moderate, and severe deficiency, respectively. 49 of the 64 males and all but 1 of the 28 females were vitamin D deficient. The prevalence of vitamin D deficiency ranged from 69.6% in the employed group to 100% in the household group. Vitamin D deficiency was equally prevalent in subjects from rural and urban areas. Serum calcium and phosphorus values were comparable in subjects with and without vitamin D deficiency, while daily intake and urinary excretion of calcium were significantly lower in the former. Vitamin D deficient subjects had a significantly lower mean weekly exposure to sunlight.
Conclusions
In spite of abundant sunlight, healthy individuals in Kashmir valley are vitamin D deficient, particularly women. Serum 25 (OH) D concentrations are significantly related to sun exposure.
doi:10.1136/pgmj.2007.059113
PMCID: PMC2659966  PMID: 17989271
vitamin D; deficiency; 25 (OH) D; prevalence; sun‐exposure
17.  The High Prevalence of Vitamin D Insufficiency across Australian Populations Is Only Partly Explained by Season and Latitude 
Environmental Health Perspectives  2007;115(8):1132-1139.
Background
Inadequate sun exposure and dietary vitamin D intake can result in vitamin D insufficiency. However, limited data are available on actual vitamin D status and predictors in healthy individuals in different regions and by season.
Methods
We compared vitamin D status [25-hydroxyvitamin D; 25(OH)D] in people < 60 years of age using data from cross-sectional studies of three regions across Australia: southeast Queensland (27°S; 167 females and 211 males), Geelong region (38°S; 561 females), and Tasmania (43°S; 432 females and 298 males).
Results
The prevalence of vitamin D insufficiency (≤ 50 nmol/L) in women in winter/spring was 40.5% in southeast Queensland, 37.4% in the Geelong region, and 67.3% in Tasmania. Season, simulated maximum daily duration of vitamin D synthesis, and vitamin D effective daily dose each explained around 14% of the variation in 25(OH)D. Although latitude explained only 3.9% of the variation, a decrease in average 25(OH)D of 1.0 (95% confidence interval, 0.7–1.3) nmol/L for every degree increase in latitude may be clinically relevant. In some months, we found a high insufficiency or even deficiency when sun exposure protection would be recommended on the basis of the simulated ultraviolet index.
Conclusion
Vitamin D insufficiency is common over a wide latitude range in Australia. Season appears to be more important than latitude, but both accounted for less than one-fifth of the variation in serum 25(OH)D levels, highlighting the importance of behavioral factors. Current sun exposure guidelines do not seem to fully prevent vitamin D insufficiency, and consideration should be given to their modification or to pursuing other means to achieve vitamin D adequacy.
doi:10.1289/ehp.9937
PMCID: PMC1940076  PMID: 17687438
25(OH)D; behavior; latitude; UV index; UVR; vitamin D; vitamin D index
18.  Plasma concentrations of 25-hydroxyvitamin D among Jordanians: Effect of biological and habitual factors on vitamin D status 
Background
Vitamin D is cutaneously synthesized following sun exposure (vitamin D3) as well as it is derived from dietary intake (vitamin D3 and D2). Vitamin D2 and D3 are metabolized in the liver to 25-hydroxyvitamin D (25(OH)D). This metabolite is considered the functional indicator of vitamin D stores in humans. Since Jordan latitude is 31°N, cutaneous synthesis of vitamin D3 should be sufficient all year round. However, many indications reveal that it is not the case. Thus, this study was conducted to determine the 25(OH)D status among Jordanians.
Methods
Three hundred healthy volunteers were enrolled in a cross sectional study; 201 females and 99 males. 25(OH)D and calcium concentrations were measured by enzyme linked immunosorbent assay and spectroscopy techniques, respectively. All participants filled a study questionnaire that covered age, sex, height, weight, diet, and dress style for females. Females were divided according to their dress style: Western style, Hijab (all body parts are covered except the face and hands), and Niqab (all body parts are covered including face and hands).
Results
The average plasma 25(OH)D levels in males and females were 44.5 ± 10.0 nmol/l and 31.1 ± 12.0 nmol/l, respectively. However, when female 25(OH)D levels were categorized according to dress styles, the averages became 40.3, 31.3 and 28.5 nmol/l for the Western style, Hijab and Niqab groups, respectively. These 25(OH)D levels were significantly less than those of males (p < 0.05, 0.001, 0.001, respectively). In addition, the plasma 25(OH)D levels of the Western style group was significantly higher than those of Hijab and Niqab groups (p < 0.001). Furthermore, dairy consumption in males was a positive significant factor in vitamin D status. Even though calcium concentrations were within the reference range, the Hijab and Niqab-dressed females have significantly less plasma calcium levels than males (p < 0.01).
Conclusions
Very low plasma 25(OH)D levels in females wearing Hijab or Niqab are highly attributed to low sunlight or UVB exposure. In addition, most of males (76%) and Western style dressed females (90%) have 25(OH)D concentrations below the international recommended values (50 nmol/l), suggesting that although sun exposure should be enough, other factors do play a role in these low concentrations. These findings emphasize the importance of vitamin D supplementation especially among conservatively dressed females, and determining if single nucleotide polymorphisms of the genes involved in vitamin D metabolism do exist among Jordanians.
doi:10.1186/1472-6890-11-8
PMCID: PMC3163511  PMID: 21816088
(25-OHD); Vitamin D2; Vitamin D3; Diet; Dress Styles; Hypovitaminosis D; Jordan
19.  Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial 
PLoS Medicine  2008;5(10):1-12.
Background
Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.
Methods and Findings
This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.
Conclusions
Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.
Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)
Angela Cheung and colleagues investigate whether vitamin K1 can prevent bone loss among postmenopausal women with osteopenia.
Editors' Summary
Background.
Osteoporosis is a bone disease in which the bones gradually become less dense and more likely to break. In the US, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis. In both conditions, insufficient new bone is made and/or too much old bone is absorbed. Although bone appears solid and unchanging, very little bone in the human body is more than 10 y old. Old bone is continually absorbed and new bone built using calcium, phosphorous, and proteins. Because the sex hormones control calcium and phosphorous deposition in the bones and thus bone strength, the leading cause of osteoporosis in women is reduced estrogen levels after menopause. In men, an age-related decline in testosterone levels can cause osteoporosis. Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Treatments can slow down or reverse bone loss (antiresorptive therapies) and some (bone formation therapies) can even make bone and build bone tissue.
Why Was This Study Done?
Although regular exercise and a healthy diet can help to keep bones strong, other ways of preventing osteoporosis are badly needed. Recently, the lay media has promoted vitamin K supplements as a way to reduce bone loss in postmenopausal women. Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of proteins called carboxylation. This modification is essential for the activity of three bone-building proteins. In addition, there is some evidence that low bone density and fractures are associated with a low vitamin K intake. However, little is known about the long-term benefits or harms of vitamin K supplements. In this study, the researchers investigate whether a high-dose daily vitamin K supplement can safely reduce bone loss, bone turnover, and fractures in postmenopausal women with osteopenia in a randomized controlled trial called the “Evaluation of the Clinical Use of Vitamin K Supplementation in Post-Menopausal Women With Osteopenia” (ECKO) trial.
What Did the Researchers Do and Find?
In the study, 440 postmenopausal women with osteopenia were randomized to receive 5mg of vitamin K1 (the type of vitamin K in North American food; the recommended daily adult intake of vitamin K1 is about 0.1 mg) or an inactive tablet (placebo) daily for 2 y; 261 of the women continued their treatment for 2 y to gather information about the long-term effects of vitamin K1 supplementation. All the women had regular bone density scans of their lower back and hips and were examined for fractures and for changes in bone turnover. After 2 y and after 4 y, lower back and hip bone density measurements had decreased by similar amounts in both treatment groups. The women who took vitamin K1 had 10-fold higher amounts of vitamin K1 in their blood than the women who took placebo and lower amounts of a bone formation marker; the levels of a bone resorption marker were similar in both groups. Over the 4-y period, fewer women in the vitamin K group had fractures (nine versus 20 women in the placebo group), and fewer had cancer (three versus 12). Finally, vitamin K supplementation was well tolerated over the 4-y period and adverse health effects were similar in the two treatment groups.
What Do These Findings Mean?
These findings indicate that a high daily dose of vitamin K1 provides no protection against the age-related decline in bone density in postmenopausal women with osteopenia, but that vitamin K1 supplementation may protect against fractures and cancers in these women. The apparent contradiction between the effects of vitamin K1 on bone density and on fractures could mean that vitamin K1 supplements strengthen bone by changing factors other than bone density, e.g., by changing its fine structure rather than making it denser. However, because so few study participants had fractures, the difference in the fracture rate between the two treatment groups might have occurred by chance. Larger studies are therefore needed to examine the effect of vitamin K1 on fractures (and on cancer) and, until these are done, high-dose vitamin K1 supplementation should not be recommended for the prevention of osteoporosis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050196.
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides detailed information about osteoporosis (in English and Spanish) and links to other resources, including an interactive web tool called Check Up On Your Bones
MedlinePlus provides links to additional information about osteoporosis (in English and Spanish)
The MedlinePlus Encyclopedia has a page about vitamin K
The UK Food Standards Agency provides information about vitamin K
Full details about the ECKO trial are available on the ClinicalTrials.gov Web site
The Canadian Task Force for Preventive Health Care provides recommendations on the prevention of osteoporosis and osteoporotic fractures in postmenopausal women
Osteoporosis Canada provides information on current topics related to osteoporosis
doi:10.1371/journal.pmed.0050196
PMCID: PMC2566998  PMID: 18922041
20.  Relationship between vitamin D and IL-23, IL-17 and macrophage chemoattractant protein-1 as markers of fibrosis in hepatitis C virus Egyptians 
World Journal of Hepatology  2012;4(8):242-247.
AIM: To assess vitamin D in hepatitis C patients and its relationship to interleukin (IL)-23, IL-17, and macrophage chemoattractant protein-1 (MCP-1).
METHODS: The study was conducted on 50 Egyptian hepatitis C virus (HCV) genotype number IV-infected patients and 25 age- and gender-matched healthy subjects. Venous blood samples were obtained. Samples were allowed to clot and sera were separated by centrifugation and stored at -20 °C. A 25 hydroxy vitamin D assay was carried out using solid phase RIA. A 1,25 dihydroxy vitamin D assay was carried out using a commercial kit purchased from Incstar Corporation. IL-17 and -23 and MCP-1 were assayed by an enzyme immunoassay. Quantitative and qualitative polymerase chain reaction for HCV virus were done by TaqMan technology. Only HCV genotype IV-infected subjects were included in the study. The mean ± SD were determined, a t-test for comparison of means of different parameters was used. Correlation analysis was done using Pearson’s correlation. Differences among different groups were determined using the Kruskal-Wallis test.
RESULTS: The mean vitamin D level in HCV patients (group I) was 15 ± 5.2 ng/mL while in control (group II) was 39.7 ± 10.8. For active vitamin D in group I as 16.6 ± 4.8 ng/mL while in group II was 41.9 ± 7.9. IL-23 was 154 ± 97.8 in group I and 6.7 ± 2.17 in group II. IL-17 was 70.7 ± 72.5 in cases and 1.2 ± 0.4 in control. MCP-1 was 1582 ± 794.4 in group I and 216.1 ± 5.38 in group II. Vitamin D deficiency affected 72% of HCV-infected patients and 0% of the control group. Vitamin D insufficiency existed in 28% of HCV-infected patients and 12% of the control group. One hundred percent of the cirrhotic patients and 40% of non cirrhotic HCV-infected patients had vitamin D deficiency. IL-23, IL-17, and MCP-1 were markedly increased in HCV-infected patients in comparison to controls.A significant negative correlation between vitamin D and IL-17 and -23 and MCP-1 was detected. HCV-infected males and females showed no differences with respect to viral load, vitamin D levels, IL-17, IL-23 and MCP-1. The viral load was negatively correlated with vitamin D and active vitamin D (P = 0.0001 and P = 0.001, respectively), while positively correlated with IL-23, IL-17, and MCP-1. We classified the patients according to sonar findings into four groups. Group Ia with bright hepatomegaly and included 14 patients. Group Ib with perihepatic fibrosis and included 11 patients. Group Ic with liver cirrhosis and included 11 patients. Group Id with hepatocellular carcinoma (HCC) and included 14 patients. Vitamin D and active vitamin D were shown to be lower in cirrhotic patients and much lower in patients with HCC, and this difference was highly significant (P = 0.0001). IL-17 and -23 and MCP-1 were higher in advanced liver disease) and the differences were highly significant (P = 0.0001).
CONCLUSION: Whether the deficiency of vitamin D is related to HCV-induced chronic liver disease or predisposing factor for higher viral load is a matter of debate.
doi:10.4254/wjh.v4.i8.242
PMCID: PMC3443706  PMID: 22993666
Vitamin D; Macrophage chemoattractant protin-1; Liver cirrhosis; Interleukin-23; Interleukin-17; Liver cirrhosis
21.  Disturbances of parathyroid hormone–vitamin D axis in non-cholestatic chronic liver disease: a cross-sectional study 
Hepatology International  2010;4(3):634-640.
Purpose
Liver has an important role in metabolism of vitamin D. This study aimed to evaluate the patterns of vitamin D–parathyroid hormone (PTH) disturbance and correlate it in patients with non-cholestatic chronic liver disease (CLD).
Methods
A total of 40 healthy controls and 90 consecutive patients with evidence of non-cholestatic CLD due to hepatitis C (n = 28), hepatitis B (n = 26), autoimmune hepatitis (n = 19), and cryptogenic causes (n = 17) were enrolled. Cirrhosis was evident in 51 patients. Serum concentrations of 25-hydroxy vitamin D, PTH, calcium, phosphate, and liver enzymes were measured. Child–Pugh classification was determined in cirrhotic patients.
Results
Vitamin D deficiency (<50 nmol/l) was found in 46 (51.1%) patients and vitamin D insufficiency (50–80 nmol/l) in 15 (16.7%) patients. Secondary hyperparathyroidism (serum PTH > 6.8 pmol/l) was present in 6 (6.7%) patients. The prevalence of vitamin D deficiency was significantly higher in cirrhotic versus noncirrhotic patients (76.5 vs. 17.9%; P < 0.001), whereas there was no significant difference in serum calcium, phosphate, and PTH levels. Child–Pugh class B and C patients had significantly lower vitamin D level compared with class A patients (P < 0.001), whereas there was no significant difference in serum calcium, phosphate, and PTH levels. No significant correlation was seen between vitamin D and PTH, calcium or phosphate levels. Lower serum level of vitamin D was associated with coagulopathy, hyperbilirubinemia, hypoalbuminemia, anemia, and thrombocytopenia.
Conclusions
Vitamin D inadequacy and the severity of liver dysfunction move in parallel in patients with non-cholestatic CLD. Vitamin D assessment and replacement should be considered in the management of patients with non-cholestatic CLD.
doi:10.1007/s12072-010-9194-2
PMCID: PMC2940008  PMID: 21063488
Vitamin D; Liver; Cirrhosis; Parathyroid hormone; Child–Pugh score; MELD
22.  Association of Vitamin D Deficiency with Functional Disability and Chronic Diseases Among Veterans Entering a Nursing Home 
Background
Nursing home residents are at high risk of vitamin D deficiency. There has been only one previous study about vitamin D status on admission to the nursing home, and limited data are available about associations with functional disability and chronic diseases.
Methods
Data were collected by retrospective chart review of electronic medical records and Minimum Data Set (MDS) for all veterans admitted to a VA nursing home in Honolulu, Hawai‘i, between January 2011 and June 2012. All veterans had a comprehensive geriatric assessment and measurement of serum 25-hydroxyvitamin D level within 7 days of admission. Females, hospice patients, vitamin D supplement users, and those transferred from other nursing homes were excluded, leaving a final analytic sample of 104 patients. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D level <20 ng/mL. Baseline data collected included age, ethnicity, BMI, functional disability (mobility, bathing, dressing, toileting, continence, and feeding) and prevalent chronic diseases to study cross-sectional associations of vitamin D deficiency using logistic regression.
Results
Prevalence of vitamin D deficiency on admission to the nursing home was 49.0% (51/104) among male veterans not taking supplements. The mean age was 70.6 years (range 35–95), with ethnicity as follows: 51 (49.0%) White, 34 (32.7%) Asian, and 6 (5.8%) Black. In multiple logistic regression models adjusted for age, ethnicity and BMI, vitamin D deficiency was significantly associated with number of ADL disabilities (OR = 1.36 for each increase in ADL disability, 95%CI = 1.03–1.78, P = .03) and prevalent diabetes (OR = 2.99, 95%CI = 1.12–7.99, P = .03). When all six ADL disabilities were entered separately into the multivariate logistic regression model instead of total number of ADL disabilities, only the disability in feeding (OR = 4.74, 95%CI = 0.97–23.23, P = .05) and prevalent diabetes (OR = 2.92, 95%CI = 1.03–8.24, P = .04) remained significant. There were no significant associations between vitamin D deficiency and prevalent hypertension, hypercholesterolemia, coronary artery disease, stroke, cancer, depression or dementia.
Conclusions
Almost half the male patients entering a nursing home in Hawai‘i had vitamin D deficiency. A high number of ADL disabilities, disability in feeding, and prevalent diabetes were independently associated with vitamin D deficiency. Future studies should focus on targeting these patients for screening and intervention with supplementation to possibly prevent adverse health outcomes of vitamin D deficiency.
PMCID: PMC3764550
23.  Effect of physical activity and sun exposure on vitamin D status of Saudi children and adolescents 
BMC Pediatrics  2012;12:92.
Background
Accumulating evidence suggests an increased prevalence of vitamin D deficiency in the Middle East. In this context, we aimed to determine whether the prevalence of vitamin D deficiency is related to degree of physical activity and sun exposure among apparently healthy Saudi children and adolescents, a little studied population.
Methods
A total of 331 Saudi children aged 6–17 years (153 boys and 178 girls) were included in this cross sectional study. Levels of physical activity and sun exposure were determined using a standard questionnaire. Anthropometry, serum calcium and 25-(OH) vitamin D were analyzed.
Results
All subjects were vitamin D deficient, the majority being moderately deficient (71.6%). Age was the single most significant predictor affecting 25 (OH) Vitamin D levels, explaining 21% of the variance perceived (p = 1.68 x 10-14). Age-matched comparisons revealed that for groups having the same amount of sun exposure, those with moderate or are physically active will have higher levels of vitamin D status, though levels in across groups remained deficient.
Conclusion
Vitamin D deficiency is common among Saudi children and adolescents, and is influenced by both sun exposure and physical activity. Promotion of an active outdoor lifestyle among Saudi children in both homes and schools may counteract the vitamin D deficiency epidemic in this vulnerable population. Vitamin D supplementation is suggested in all groups, including those with the highest sun exposure and physical activity.
doi:10.1186/1471-2431-12-92
PMCID: PMC3407533  PMID: 22759399
Vitamin D; Saudi children
24.  Prevalence of Vitamin D Deficiency in Uninsured Women 
Journal of General Internal Medicine  2007;22(8):1180-1183.
Background
Vitamin D deficiency, an important risk factor for osteoporosis and other chronic medical conditions, is epidemic in the United States. Uninsured women may be at an even higher risk for vitamin D deficiency than others owing to low intake of dietary and supplemental vitamin D and limited sun exposure.
Objective
Our goal was to determine the prevalence of vitamin D deficiency in this vulnerable population.
Setting and Participants
We enrolled 145 uninsured women at a County Free Medical Clinic in urban Michigan. Questionnaires were used to obtain information about demographics, medical history, vitamin supplementation, sunlight exposure, and dietary vitamin D intake.
Results
The 96 women who were tested for vitamin D status ranged in age from 21 to 65 years (mean 48 ± 11), and 67% were vitamin D deficient as indicated by a 25-hydroxyvitamin D [25(OH)D)] level <50 nmol/L (20 ng/mL). Non-Caucasians were 3 times more likely than Caucasians to be vitamin D deficient (P = .049). Mean dietary vitamin D intake was low (125 ± 109 IU/d) and only 24% of the participants used any supplemental vitamin D. Participants with total vitamin D intake <400 IU/day from diet and supplements were 10 times more likely to be vitamin D deficient than others (P < .001).
Conclusions
These results demonstrate a high prevalence of vitamin D deficiency in an uninsured, medically underserved female population. Uninsured women should be strongly encouraged to increase their vitamin D intake.
doi:10.1007/s11606-007-0245-x
PMCID: PMC2305742  PMID: 17546478
vitamin D deficiency; uninsured; women; prevalence
25.  Vitamin D levels in healthy men in eastern Saudi Arabia 
Annals of Saudi Medicine  2009;29(5):378-382.
BACKGROUND
Studies in 1980s and 1990s indicated that vitamin D levels in the ethnic Saudi Arabian population were low but no studies since that time have evaluated vitamin D levels among healthy young or middle-aged Saudi men. Thus, we assessed the serum level of 25-hydroxyvitamin D (25OHD) among healthy Saudi Arabian men living in the Eastern Province.
SUBJECTS AND METHODS:
One hundred males aged 25-35 years (the age range of peak bone mass) and 100 males aged 50 years or older were randomly selected and evaluated clinically, including measurement of serum calcium, parathyroid hormone (PTH) and serum 25OHD levels. Vitamin D deficiency was defined as a serum level of 25OHD of ≤20 ng/mL and insufficiency as a serum level between >20 ng/mL and <30 ng/mL and normal ≥30 ng/mL.
RESULTS:
The mean (SD) age of subjects in the younger age group was 28.2 (4.5) years. Twenty-eight (28%) had low 25OHD levels; 10 (10%) subjects were vitamin D deficient with a mean level of 16.6 (3.4) ng/mL and 18 (18%) were vitamin D insufficient with a mean level of 25.4 (2.7) ng/mL. In the older age group, the mean age was 59.4 (15.6) years and 37 (37%) had low 25OHD; 12 (12%) subjects were deficient with a mean 25OHD level of 16.7 (3.4) ng/mL and 25 (25%) were insufficient with a mean 25OHD level of 25.3 (3.3) ng/mL.
CONCLUSION:
The prevalence of vitamin D deficiency among healthy Saudi men is between 28% to 37%. Vitamin D deficiency among young and middle age Saudi Arabian males could lead to serious health consequences if the issue is not urgently addressed.
doi:10.4103/0256-4947.55168
PMCID: PMC3290044  PMID: 19700896

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