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1.  Bariatric surgery in an obese patient with Albright hereditary osteodystrophy: a case report 
Introduction
We report for the first time the case of a patient with Albright hereditary osteodystrophy and pseudopseudohypoparathyroidism who underwent a Roux-en-Y gastric bypass.
Case presentation
A 26-year-old obese Caucasian woman with Albright hereditary osteodystrophy with pseudopseudohypoparathyroidism (heterozygous mutation (L272F) in GNAS1 exon 10 on molecular analysis) was treated with gastric bypass. She had the classical features of Albright hereditary osteodystrophy: short stature (138cm), obesity (body mass index 49.5kg/m2), bilateral shortening of the fourth and fifth metacarpals, short neck, round and wide face with bombed front and small eyes. Before the gastric bypass was performed, biochemical determination revealed a slightly low serum calcium level (2.09mmol/L; normal range 2.1 to 2.5mmol/l), and an elevated parathyroid hormone level (87ng/L; normal range 10 to 70ng/L) associated with low vitamin D level (19μg/L; normal range 30 to 50μg/L). Vitamin D supplementation was prescribed before surgery. After the Roux-en-Y gastric bypass, she achieved a progressive substantial weight loss, from 94kg (body mass index 49.5kg/m2) to 49kg (body mass index 25.9kg/m2) in one year. Her weight then stabilized at 50kg (body mass index 26kg/m2) during our three years of follow-up. Before the operation and every three months after it, she was screened for nutritional deficiencies, and serum markers of bone turnover and renal function were monitored. Considering the deficiencies in zinc, magnesium, calcium, vitamin D and vitamin B12, appropriate supplementation was prescribed. Before and two years after the Roux-en-Y gastric bypass, a dual-energy X-ray absorptiometry assessment of bone density was performed that showed no changes on her lumbar column (0.882g/cm2 and both T-score and Z-score of −1.5 standard deviation). In addition, bone microarchitecture with a measurement of her trabecular bone score was found to be normal.
Conclusion
This is the first case of Roux-en-Y gastric bypass described in a patient with pseudopseudohypoparathyroidism showing that such a procedure seems to be safe in obese patients with Albright hereditary osteodystrophy and pseudopseudohypoparathyroidism if appropriately followed up. As obesity is a prominent feature of Albright hereditary osteodystrophy, such patients might seek bariatric surgery. After a Roux-en-Y gastric bypass, patients with Albright hereditary osteodystrophy associated with pseudopseudohypoparathyroidism need long-term follow-up on nutritional and metabolic issues.
doi:10.1186/1752-1947-7-111
PMCID: PMC3651286  PMID: 23617958
Roux-en-Y gastric bypass; Pseusopseudohypoparathyroidism; Albright hereditary osteodystrophy; Bone; Calcium
2.  Pharmacokinetics and safety issues of an accidental overdose of 2,000,000 IU of vitamin D3 in two nursing home patients: a case report 
Background
Administration of intermittent high doses of vitamin D3 is increasingly used as a strategy for rapid normalization of low 25-hydroxyvitamin D (25(OH)D) blood concentrations in patients with vitamin D deficiency. Here, we describe the pharmacokinetics of an accidental single oral overdose of 2,000,000 IU of vitamin D3 in two elderly nursing home patients and discuss safety issues.
Case presentation
Two patients, a Caucasian 90-year old man and a 95-year old woman, were monitored from 1 h up to 3 months after intake for clinical as well as biochemical signs of vitamin D intoxication. Blood vitamin D3 concentrations showed a prompt increase with the highest peak area already hours after the dose, followed by a rapid decrease to undetectable levels after day 14. Peak blood 25(OH)D3 concentrations were observed 8 days after intake (527 and 422 nmol/L, respectively (ref: 50–200 nmol/L)). Remarkably, plasma calcium levels increased only slightly up to 2.68 and 2.73 mmol/L, respectively (ref: 2.20–2.65 mmol/L) between 1 and 14 days after intake, whereas phosphate and creatinine levels remained within the reference range. No adverse clinical symptoms were noted.
Conclusion
A single massive oral dose of 2,000,000 IU of vitamin D3 does not cause clinically apparent toxicity requiring hospitalization, with only slightly elevated plasma calcium levels in the first 2 weeks. Toxicity in the long term cannot be excluded as annual doses of 500,000 IU of vitamin D3 for several years have shown an increase in the risk of fractures. This means that plasma calcium levels may not be a sensitive measure of vitamin D toxicity in the long term in the case of a single high overdose. To prevent a similar error in the future, the use of multiple-dose bottles need to be replaced by smaller single-unit dose formulations.
doi:10.1186/2050-6511-15-57
PMCID: PMC4185191  PMID: 25269374
Vitamin D; Intoxication; Single high dose
3.  Refractory immune thrombocytopenia successfully treated with high-dose vitamin D supplementation and hydroxychloroquine: two case reports 
Introduction
Immune thrombocytopenic purpura is thought to be characterized by an immune response against the host’s own platelets. If the thrombocytopenia is severe, patients are initially treated with high-dose steroids. Other more toxic second line treatments are considered if steroids fail. Here, we report the case of two patients in whom conventional treatment was unsuccessful but who responded to hydroxychloroquine and high-dose vitamin D replacement therapy. To the best of our knowledge, this is the first description of successful treatment for immune thrombocytopenia with high-dose vitamin D and hydroxychloroquine.
Case presentation
Case 1: We report the case of a 79-year-old Caucasian man who presented with high titer antinuclear antibodies, positive anti-SSA/Ro autoantibodies and clinically was felt to have an overlap of systemic lupus erythematosus and/or Sjögren’s syndrome with profound life-threatening thrombocytopenia. There was no evidence of underlying malignancy. The patient’s platelet count significantly increased with vitamin D and hydroxychloroquine treatment, but upon vitamin D discontinuation his platelet levels plummeted. Hydroxychloroquine therapy was maintained throughout treatment. With reinstitution of high-dose vitamin D therapy, platelet counts were restored to normal levels.
Case 2: We also report the case of an 87-year-old Caucasian woman who presented with high titer antinuclear antibodies, positive anti-SSA/Ro autoantibodies and was felt to have an overlap of systemic lupus erythematosus and/or Sjögren’s syndrome with immune thrombocytopenia; she also had severely low levels of 25-hydroxy vitamin D (17ng/mL). There was no evidence of underlying malignancy. She responded to high-dose vitamin D replacement and hydroxychloroquine treatment, thereby alleviating the need for high-dose steroid treatment. She remains in remission while taking vitamin D, hydroxychloroquine and very low-dose prednisone. No untoward side effects were observed in either patient.
Conclusions
In our two case reports, we found an association between vitamin D deficiency and immune thrombocytopenia where platelet levels responded to vitamin D treatment and hydroxychloroquine but not to prednisone. We believe there may be synergism between vitamin D supplementation and hydroxychloroquine. The mechanism by which high-dose vitamin D results in increased platelet counts in immune thrombocytopenia patients is unknown. However, vitamin D has long been thought to play an immunomodulatory role, which may include a dampened immune response in patients with immune thrombocytopenia or other autoimmune diseases.
doi:10.1186/1752-1947-7-91
PMCID: PMC3623781  PMID: 23556539
Immune thrombocytopenia; Plaquenil®; Platelets; Prednisone; T regulatory cells; Vitamin D
4.  Juvenile Paget’s Disease In An Iranian Kindred With Vitamin D Deficiency And Novel Homozygous TNFRSF11B Mutation 
Juvenile Paget’s disease (JPD) is a rare heritable osteopathy characterized biochemically by markedly increased serum alkaline phosphatase (ALP) activity emanating from generalized acceleration of skeletal turnover. Affected infants and children typically suffer bone pain and fractures and deformities, become deaf, and have macrocranium. Some who survive to young adult life develop blindness from retinopathy engendered by vascular microcalcification. Most cases of JPD are caused by osteoprotegerin (OPG) deficiency due to homozygous loss-of-function mutations within the TNFRSF11B gene that encodes OPG. We report a 3-year-old Iranian girl with JPD and craniosynostosis who had vitamin D deficiency in infancy. She presented with fractures during the first year-of-life followed by bone deformities, delayed development, failure-to-thrive, and pneumonias. At 1 year-of-age, biochemical studies of serum revealed marked hyperphosphatasemia together with low-normal calcium and low inorganic phosphate and 25-hydroxyvitamin D levels. Several family members in previous generations of this consanguineous kindred may also have had JPD and vitamin D deficiency. Mutation analysis showed homozygosity for a unique missense change (c.130T>C, p.Cys44Arg) in TNFRSF11B that would compromise the cysteine-rich domain of OPG that binds receptor activator of NF-κB ligand (RANKL). Both parents were heterozygous for this mutation. The patient’s serum OPG level was extremely low and RANKL level markedly elevated. She responded well to rapid oral vitamin D repletion followed by pamidronate treatment given intravenously. Our patient is the first Iranian reported with JPD. Her novel mutation in TNFRSF11B plus vitamin D deficiency in infancy was associated with severe JPD uniquely complicated by craniosynostosis. Pamidronate treatment with vitamin D sufficiency can be effective treatment for the skeletal disease caused by the OPG deficiency form of JPD.
doi:10.1002/jbmr.1868
PMCID: PMC3663917  PMID: 23322328
alkaline phosphatase; bone remodeling; craniosynostosis; deafness; hyperphosphatasemia; hyperphosphatasia; osteoclast; osteolysis; osteoprotegerin; pamidronate; retinopathy; rickets; tumor necrosis factor; vascular calcification; vitamin D deficiency
5.  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
6.  The effect of a combined oral calcium and vitamin D supplement for treating mild to moderate vitamin D deficiency in postmenopausal women 
Clinical Interventions in Aging  2008;3(1):183-186.
Objective
To evaluate the efficacy of a combined calcium and vitamin D (Ca-D3) supplement for vitamin D deficiency in a small group of postmenopausal women.
Methods
A prospective open label 3 month-study.
Participants
23 postmenopausal women (mean age 61.2 yrs) with vitamin D deficiency were given a combined oral Ca-D3 supplement called “Osteoblast”. The supplement comprises 500 mg elemental calcium and 500 IU of cholecalciferol. The dosing regimen comprised a loading dose of 1000 IU of cholecalciferol per day for one month (two tablets) and thereafter a maintenance dose of 500 IU of cholecalciferol per day for 2 months (one tablet).
Outcome measure
Serum was collected for calcium, 25 hydroxyvitamin D3 (25OHD3), and PTH measurements, as well as early morning 2-hour urine calcium/creatinine excretion index (Uca/creat). Specimens were collected at baseline and after 3 months of therapy. Data are reported as mean ± 1 standard error and 95% confidence intervals.
Results
Data was available for the 21 subjects who completed the study. Two subjects (9%) withdrew because of gastrointestinal intolerance. There were 3 subjects with moderate (12.5–24 nmol/L) and 18 with mild (25–49 nmol/L) vitamin D deficiency. Ten subjects (48%) had secondary hyperparathyroidism. Following the oral Ca-D3 combination, serum 25OHD3 levels normalised in all subjects with 18 (86%) subjects achieving values of greater than 70 nmol/L. Serum 25OHD3 levels increased from 36 (31–41) to 91 (79–102) nmol/L (p = 0.0001), increasing by an average of 152% over the 3-month period. There was a corresponding 38% decrease in serum PTH concentrations at 3 months (5.1 + 0.6 pmol/L), compared with baseline (8.0 + 1 pmol/L) (p = 0.001). No subject developed hypercalcemia, but an elevated Uca/creat excretion index occurred in one subjects.
Conclusions
A combined oral Ca-D3 product (Osteoblast) is effective for treating vitamin D deficiency and is adequately tolerated.
PMCID: PMC2544364  PMID: 18488888
7.  Bone pain and extremely low bone mineral density due to severe vitamin D deficiency in celiac disease 
Archives of Osteoporosis  2011;6(1-2):209-213.
Case report
A 29-year-old wheelchair-bound woman was presented to us by the gastroenterologist with suspected osteomalacia. She had lived in the Netherlands all her life and was born of Moroccan parents. Her medical history revealed iron deficiency, growth retardation, and celiac disease, for which she was put on a gluten-free diet. She had progressive bone pain since 2 years, difficulty with walking, and about 15 kg weight loss. She had a short stature, scoliosis, and pronounced kyphosis of the spine and poor condition of her teeth. Laboratory results showed hypocalcemia, an immeasurable serum 25-hydroxyvitamin D level, and elevated parathyroid hormone and alkaline phosphatase levels. Spinal radiographs showed unsharp, low contrast vertebrae. Bone mineral density measurement at the lumbar spine and hip showed a T-score of −6.0 and −6.5, respectively. A bone scintigraphy showed multiple hotspots in ribs, sternum, mandible, and long bones. A duodenal biopsy revealed villous atrophy (Marsh 3C) and positive antibodies against endomysium, transglutaminase, and gliadin, compatible with active celiac disease. A bone biopsy showed severe osteomalacia but normal bone volume. She was treated with calcium intravenously and later orally. Furthermore, she was treated with high oral doses of vitamin D and a gluten-free diet. After a few weeks of treatment, her bone pain decreased, and her muscle strength improved.
Discussion
In this article, the pathophysiology and occurrence of osteomalacia as a complication of celiac disease are discussed. Low bone mineral density can point to osteomalacia as well as osteoporosis.
doi:10.1007/s11657-011-0059-7
PMCID: PMC3235277  PMID: 22207878
Celiac disease; Osteomalacia; Vitamin D; Bone mineral density; Histomorphometry
8.  Hypoparathyroidism after Roux-en-Y gastric bypass - a challenge for clinical management: a case report 
Introduction
In this report, we describe challenges we encountered in the clinical management of a patient with hypoparathyroidism who had previously undergone a bariatric procedure.
Case presentation
We report the case of a 38-year-old Caucasian woman who had undergone a Roux-en-Y gastric bypass procedure for treatment of obesity. She also had a past history of right lobectomy to treat a benign thyroid nodule. Another thyroid nodule was diagnosed after her bariatric surgery, so a new thyroid surgery was performed. Permanent hypoparathyroidism occurred after the second thyroid surgery. A Roux-en-Y gastric bypass resulted in important weight loss, but the preferential site of calcium absorption was bypassed. The lack of endogenous parathyroid hormone secretion due to post-surgical hypoparathyroidism abolished the physiological mechanism that compensates the reduced calcium absorption, which was a challenge for us to overcome. In this report, we describe our clinical therapeutic choices to maintain normocalcemia and normophosphatemia in this patient. Higher doses of exogenous calcium citrate, calcitriol and cholecalciferol were used, but hypocalcemia was still present. To improve vitamin D absorption with resultant improvement of calcium homeostasis, we speculated that adding pancrelipase to meals would increase lipid absorption and possibly fat-soluble vitamins, including vitamin D. Only after the addition of pancrelipase did the patient improve without weight regain according to clinical and laboratory assessments.
Conclusion
The use of exogenous pancreatic enzymes improved calcium homeostasis in this bariatric patient. The role of these enzymes on vitamin D absorption and subsequent rise in calcium levels in hypoparathyroid patients who undergo bariatric procedures need further investigation.
doi:10.1186/1752-1947-8-357
PMCID: PMC4232227  PMID: 25348653
Bariatric surgery; Hypocalcemia; Hyperparathyroidism
9.  An initial loading-dose vitamin D versus placebo after hip fracture surgery: baseline characteristics of a randomized controlled trial (REVITAHIP) 
BMC Geriatrics  2014;14:101.
Background
Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture. There are currently no agreed strategies for vitamin D replenishment after hip fracture surgery. The REVITAHIP Study is a multisite, double-blinded randomized-controlled trial investigating the effects of an oral vitamin D loading dose on gait velocity after hip fracture surgery. We describe the baseline characteristics of participants, aiming to document hypovitaminosis D and its associations after hip fracture.
Methods
Participants, over 65, recruited within 7 days following hip fracture surgery from 3 Australia hospitals, were randomly allocated to receive a loading dose of vitamin D3 (250,000IU) or placebo, followed by oral maintenance vitamin D3/calcium (800 IU/500 mg) and the usual hip fracture rehabilitation pathway. Demographic and clinical data were collected, including surgical procedure, pre-fracture functional status, Mini Mental State Examination (MMSE) score, serum 25-hydroxyvitamin D (25-OHD), Verbal Rating Scale (VRS) for pain, grip strength and gait velocity. The associations of baseline 25-OHD levels with demographic and clinical data were assessed using Pearson’s correlation, ANOVA and regression analyses.
Results
Two-hundred-and-eighteen people with hip fracture participated in the study. Mean age was 83.9+/-7.2 years, 77% were women and 82% lived in private homes. Fifty-six percent had a subcapital fracture. Mean comorbidity count was 3.13+/-2.0. Mean MMSE was 26.1+/-3.9. Forty-seven percent of participants had hypovitaminosis D (<50 nmol/L). Multivariate regression models demonstrated higher baseline vitamin D levels were significantly associated with higher premorbid Barthel index scores, lower post-operative VRS pain levels and use of vitamin D.
Conclusion
This study cohort shared similar demographic characteristics and comorbidities with other cohorts of people with hip fracture, with the probable exception of less cognitive impairment. Hypovitaminosis D was not as prevalent as previously documented. Patients taking vitamin D supplements and with higher premorbid Barthel index, reflecting greater independence and activity, tended to have higher 25-OHD levels at baseline. Further, lower VRS pain ratings following surgery were associated with higher vitamin D levels. Such associations will need further investigation to determine causation. (ANZCTR number, ACTRN12610000392066).
Trial registration
The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry ANZCTRN ACTRN12610000392066.
doi:10.1186/1471-2318-14-101
PMCID: PMC4164764  PMID: 25200552
Fragility fractures; Hip fracture; Vitamin D; Aged care; Metabolic bone disorders; Osteoporosis; Rehabilitation; Trauma surgery
10.  Treatment of osteomalacia associated with primary biliary cirrhosis with parenteral vitamin D2 or oral 25-hydroxyvitamin D3. 
Gut  1979;20(2):133-136.
The histological and biochemical response of osteomalacia has been studied in four patients with primary biliary cirrhosis, who were treated with oral 25-hydroxyvitamin D3, 50 microgram daily, or intramuscular vitamin D2, 150,000 units once weekly, for five to 12 months. All patients showed complete histological healing of osteomalacia, despite rapidly deteriorating liver function in three. Plasma 25-hydroxyvitamin D concentrations were low in all patients before treatment, but became normal during either vitamin therapy. Serum calcium and phosphate levels, and urinary calcium excretion were not always reliable in predicting the histological response to treatment. Serum alkaline phosphatase activity decreased in all patients during vitamin D therapy. We conclude that both high-dose parenteral vitamin D2 and oral 25-hydroxyvitamin D3 may be effective in healing osteomalacia associated with primary biliary cirrhosis. Measurement of plasma 25-hydroxyvitamin D levels during vitamin D therapy provides useful information about 25-hydroxylation of the parent vitamin and intestinal absorption of orally administered 25-hydroxyvitamin D3.
PMCID: PMC1419456  PMID: 311747
11.  Dose response to vitamin D supplementation among postmenopausal African American women123 
Background
Reports on the dose response to vitamin D are conflicting, and most data were derived from white men and women.
Objective
The objective was to determine the response of serum 25-hydroxyvitamin D [25(OH)D] to oral vitamin D3 supplementation in an African American population.
Design
Healthy black postmenopausal women (n = 208) participated in a vitamin D3 supplementation trial for a period of 3 y. Analyses were done in the vitamin D supplementation arm (n = 104) to quantify the response in serum 25-hydroxyvitamin D concentrations at a steady state vitamin D input. The participants received 20 μg/d (800 IU) oral vitamin D3 for the initial 2 y and 50 μg/d (2000 IU) for the third year.
Results
Supplementation with 20 μg/d (800 IU/d) vitamin D3 raised the mean serum 25(OH)D concentration from a baseline of 46.9 ± 20.6 nmol/L to 71.4 ± 21.5 nmol/L at 3 mo. The mean (± SD) concentration of serum 25(OH)D was 87.3 ± 27.0 nmol/L 3 mo after supplementation increased to 50 μg/d (2000 IU/d). All participants achieved a serum 25(OH)D concentration >35 nmol/L, 95% achieved a concentration >50 nmol/L, but only 60% achieved a concentration >75 nmol/L. All patients had concentrations <153 nmol/L. On the basis of our findings, an algorithm for prescribing vitamin D so that patients reach optimal serum concentrations was developed. The algorithm suggests a dose of 70 μg (2800 IU/d) for those with a concentration >45 nmol/L and a dose of 100 μg (4000 IU/d) for those with a concentration <45 nmol/L.
Conclusions
Supplementation with 50 μg/d (2000 IU/d) oral vitamin D3 is sufficient to raise serum 25-hydroxyvitamin D concentrations to >50 nmol/L in almost all postmenopausal African American women. However, higher doses were needed to achieve concentrations >75 nmol/L in many women in this population.
PMCID: PMC2581841  PMID: 18065583
Ethnicity; vitamin D; 25-hydroxyvitamin D; osteoporosis; vitamin D deficiency; African Americans
12.  Vitamin D: a critical and essential micronutrient for human health 
Vitamin D is a micronutrient that is needed for optimal health throughout the whole life. Vitamin D3 (cholecalciferol) can be either synthesized in the human skin upon exposure to the UV light of the sun, or it is obtained from the diet. If the photoconversion in the skin due to reduced sun exposure (e.g., in wintertime) is insufficient, intake of adequate vitamin D from the diet is essential to health. Severe vitamin D deficiency can lead to a multitude of avoidable illnesses; among them are well-known bone diseases like osteoporosis, a number of autoimmune diseases, many different cancers, and some cardiovascular diseases like hypertension are being discussed. Vitamin D is found naturally in only very few foods. Foods containing vitamin D include some fatty fish, fish liver oils, and eggs from hens that have been fed vitamin D and some fortified foods in countries with respective regulations. Based on geographic location or food availability adequate vitamin D intake might not be sufficient on a global scale. The International Osteoporosis Foundation (IOF) has collected the 25-hydroxy-vitamin D plasma levels in populations of different countries using published data and developed a global vitamin D map. This map illustrates the parts of the world, where vitamin D did not reach adequate 25-hydroxyvitamin D plasma levels: 6.7% of the papers report 25-hydroxyvitamin D plasma levels below 25 nmol/L, which indicates vitamin D deficiency, 37.3% are below 50 nmol/Land only 11.9% found 25-hydroxyvitamin D plasma levels above 75 nmol/L target as suggested by vitamin D experts. The vitamin D map is adding further evidence to the vitamin D insufficiency pandemic debate, which is also an issue in the developed world. Besides malnutrition, a condition where the diet does not match to provide the adequate levels of nutrients including micronutrients for growth and maintenance, we obviously have a situation where enough nutrients were consumed, but lacked to reach sufficient vitamin D micronutrient levels. The latter situation is known as hidden hunger. The inadequate vitamin D status impacts on health care costs, which in turn could result in significant savings, if corrected. Since little is known about the effects on the molecular level that accompany the pandemic like epigenetic imprinting, the insufficiency-triggered gene regulations or the genetic background influence on the body to maintain metabolic resilience, future research will be needed. The nutrition community is highly interested in the molecular mechanism that underlies the vitamin D insufficiency caused effect. In recent years, novel large scale technologies have become available that allow the simultaneous acquisition of transcriptome, epigenome, proteome, or metabolome data in cells of organs. These important methods are now used for nutritional approaches summarized in emerging scientific fields of nutrigenomics, nutrigenetics, or nutriepigenetics. It is believed that with the help of these novel concepts further understanding can be generated to develop future sustainable nutrition solutions to safeguard nutrition security.
doi:10.3389/fphys.2014.00248
PMCID: PMC4092358  PMID: 25071593
vitamin D; 25-hydroxyvitamin D; nutrition; micronutrients; hidden hunger; nutrition security; nutritional pathways; nutrigenomics
13.  Treatment of severe neutropenia with high-dose pyridoxine in a patient with chronic graft versus host disease and squamous cell carcinoma: a case report 
Introduction
The differential diagnosis of neutropenia includes medications, infections, autoimmune diseases, and deficiencies of Vitamin B12 and folate. The association of Vitamin B6 deficiency with severe neutropenia is a rare finding.
Case presentation
A 51-year-old Caucasian woman presented with fever and profound neutropenia (48 neutrophils/uL). Her clinical history included non-Hodgkin lymphoma, in remission following treatment with allogeneic bone marrow transplantation, quiescent chronic graft-versus-host disease, and squamous cell carcinoma of the skin metastatic to cervical lymph nodes. Medications included atenolol, topical clobetasol, Ditropan (oxybutynin), prophylactic voriconazole, prophylactic valganciclovir, Soriatane (acitretin), and Carac (fluorouracil) cream. The bone marrow was hypocellular without metastatic cancer or myelodysplasia. Neutropenia did not respond to stopping medications that have been associated with neutropenia (valganciclovir, voriconazole and Soriatane) or treatment with antibiotics or granulocyte colony stimulating factor. Blood tests revealed absence of antineutrophil antibodies, normal folate and B12 levels, moderate zinc deficiency and severe Vitamin B6 deficiency. Replacement therapy with oral Vitamin B6 restored blood vitamin levels to the normal range and corrected the neutropenia. Her cervical adenopathy regressed clinically and became negative on scintography following Vitamin B6 therapy and normalization of the blood neutrophil count.
Conclusion
Severe pyridoxine deficiency can lead to neutropenia. Screening for Vitamin B6 deficiency, along with folate and Vitamin B12 levels, is recommended in patients with refractory neutropenia, especially those with possible malabsorption syndromes, or a history of chronic-graft-versus host disease. Severe neutropenia may facilitate progression of squamous cell carcinoma.
doi:10.1186/1752-1947-5-372
PMCID: PMC3169495  PMID: 21838907
14.  Vitamin B12 Deficiency Presenting as Pancytopenia in Pregnancy: A Case Report 
Vitamin B12 deficiency is a well-known cause of megaloblastic anaemia and pancytopenia. However, the incidence in pregnancy is rarely reported. We present a case of a 32-year old multigravid woman who was diagnosed with megaloblastic anaemia since 22 weeks gestation and progressed to develop severe pancytopenia at 30 weeks gestation. She was also diagnosed with vitamin B12 deficiency related to dietary and sociocultural habits. Folate and iron levels were normal throughout pregnancy. Treatment with parenteral cyano-cobalamin resulted in sustained improvement of haematological parameters. The pregnancy was carried to term and the baby was born weighing 2,050gm but otherwise well at birth and had normal developmental milestones thereafter. This case illustrates the clinical presentation of maternal vitamin B12 deficiency and demonstrates the importance of detecting and treating maternal vitamin B12 deficiency during pregnancy in at-risk patients. Failure to diagnose and institute treatment carries significant risks to both mother and child. Oral vitamin B12 supplementation should be considered for patients who are strict vegetarians or consume very little animal products.
PMCID: PMC4170433  PMID: 25606257
Vitamin B12 deficiency; pancytopaenia; pregnancy
15.  Vitamin B12 Intramuscular Injections Versus Oral Supplements 
Background
Vitamin B12 deficiency can lead to adverse health effects such as anemia and, in some cases, permanent neurologic damage. In Canada, patients with vitamin B12 deficiency are typically given intramuscular injections, which incur considerable cost and inconvenience. The clinical evidence-based analysis has found that oral supplementation is as effective as intramuscular injections.
Objectives
This economic analysis aimed to estimate the cost savings of switching from intramuscular injections to high-dose oral supplements for patients aged 18 years and older with confirmed vitamin B12 deficiency.
Data Sources
Population-based administrative databases for Ontario were used to identify patients receiving vitamin B12 intramuscular injections in any fiscal year between 2006 and 2011. The Ontario Drug Benefit (ODB) database was used to identify patients who were prescribed vitamin B12 injections, and the Ontario Health Insurance Plan database was used to identify all physician claims for intramuscular injections as well as laboratory tests assessing vitamin B12 levels. The Registered Physicians Database was used to identify the type of physician; the analysis was restricted to family physicians and internists.
Review Methods
Two cohorts of patients were identified. For cohort 1, the ODB database was used to identify patients who were prescribed vitamin B12 injections. Those covered under the ODB are 65 years of age or older and are economically deprived. A second cohort was created to capture those 18 to 64 years of age receiving injections. Cohort 2 consisted of patients (not in cohort 1) who received 6 or more intramuscular injections within 1 year and had a laboratory test 2 months before the intramuscular injection claim. Physician experts were consulted to estimate the resources and costs of converting patients to oral supplements. The Ministry of Health and Long-Term Care perspective was taken, and all costs are expressed in 2013 Canadian dollars.
Results
The budget impact analysis demonstrated costs of $2.8 million to the Ministry of Health and Long-Term Care in the first year of conversion; however, in subsequent years there are savings of $4.2 million per year. The cumulative 5-year budget impact demonstrates savings of $14.2 million to the health care system.
Limitations
This analysis represents the cost of conversion for those currently receiving intramuscular injections. There are no conversion costs for those who are prescribed oral supplements as an initial therapy, and so the savings could be even greater than reported. As well, an underlying assumption of this analysis is that patients will comply with oral supplementation.
Conclusions
Over 5 years, there are savings of $14.2 million to the health care system from switching to vitamin B12 oral supplements.
Plain Language Summary
Vitamin B12 deficiency has long been thought to be associated with dementia and other neurocognitive disorders. In a separate report, Health Quality Ontario (HQO) reviewed the published research on this issue and found only weak evidence that vitamin B12 deficiency is associated with the onset of dementia. That review also found moderate evidence that treatment with vitamin B12 does not improve dementia and that oral supplements are as effective as injections of vitamin B12.
In 2010, more than 2.9 million serum vitamin B12 tests were performed in Ontario at a cost of $40 million. Each year, approximately 110,000 residents receive vitamin B12 injections to boost their levels of vitamin B12. HQO commissioned an economic analysis to estimate the cost savings of switching from vitamin B12 injections to high-dose oral supplements for patients aged 18 years and older with confirmed B12 deficiency. This study concluded that the Ontario health care system could save $14.5 million in 5 years by switching to oral supplements, assuming that patients took the oral supplements as required.
PMCID: PMC3874775  PMID: 24379898
16.  25-Hydroxyvitamin D Status of Healthy, Low-Income, Minority Children in Atlanta, Georgia 
Pediatrics  2010;125(4):633-639.
OBJECTIVES
The goals were to determine the prevalence of vitamin D deficiency among minority children in a southern US city, to examine differences in serum 25-hydroxyvitamin D levels between non-Hispanic black and Hispanic children, and to determine dietary sources of vitamin D.
METHODS
Low-income, minority children (N = 290; mean age: 2.5 ± 1.2 years) were recruited during well-child clinic visits. Serum 25-hydroxyvitamin D and calcium levels were measured and dietary information was assessed.
RESULTS
The mean 25-hydroxyvitamin D3 level was 26.2 ± 7.6 ng/mL, whereas 25-hydroxyvitamin D2 was not detected. Overall, 22.3% of children had deficient serum 25-hydroxyvitamin D3 levels (≤20 ng/mL), 73.6% had less-than-optimal serum 25-hydroxyvitamin D levels (≤30 ng/mL), and 1.4% had low serum calcium levels (≤9 mg/dL). A significantly larger proportion of non-Hispanic black children, compared with Hispanic children, had vitamin D deficiency (26% vs 18%; P<.05). Age and season of recruitment were significantly associated with vitamin D deficiency and low serum calcium levels. Older children (≥3 years) were less likely to have vitamin D deficiency (odds ratio [OR]: 0.89 [95% confidence interval [CI]: 0.81– 0.96]; P < .001). Study enrollment during spring and summer reduced the likelihood of vitamin D deficiency by ~20% (spring, OR: 0.85 [95% CI: 0.73– 0.98]; P = .03; summer, OR: 0.82 [95% CI: 0.73– 0.92]; P < .01). Fortified milk provided most dietary vitamin D (62%), with Hispanic children reporting greater intake.
CONCLUSIONS
Suboptimal vitamin D status was common among apparently healthy, low-income, minority children. Age and season were significant predictors of vitamin D deficiency.
doi:10.1542/peds.2009-1928
PMCID: PMC2857317  PMID: 20351012
vitamin D; 25-hydroxvitamin D; low-income; minority; preschool; children
17.  Effect of Vitamin D3 on Untreated Graves’ Disease with Vitamin D Deficiency 
OBJECTIVE
Besides its classical role in calcium and bone homeostasis, vitamin D is considered a potent immunomodulator that can affect the pathogenesis of several autoimmune diseases. Our aim is to evaluate the effect of vitamin D correction to a patient with new onset Graves’ disease (GD) with an underlying vitamin D deficiency.
METHOD
We describe the effect of vitamin D3 on untreated Graves’ disease with vitamin D deficiency.
RESULTS
A healthy Saudi woman in her 40s sought consultation with a three-month history of palpitation. She denied any history of heat intolerance, weight loss, menstrual irregularity or sweating. She has a history of chronic muscle aches and pains. Physical examination revealed a mild diffusely enlarged and non-tender thyroid gland with no bruit. She had no signs of Graves’ ophthalmopathy. In laboratory examinations, the initial thyroid function test, which was done in an outside hospital, revealed a TSH, 0.01 mIU/L; FT4, 22.5 pmol/L and FT3, 6.5 pmol/L. Vitamin D 25-OH level was done in our hospital and showed a result of 26.0 nmol/L with a TSH, 0.013 mIU/L; FT4, 16.7 pmol/L; and FT3, 3.8 pmol/L. TSH receptor antibody was positive. TC-99 m thyroid scintigraphy demonstrated an enlarged thyroid gland with increased radiotracer trapping and heterogeneous distribution. The patient was given only oral cholecalciferol 4000 IU per day since November 2012 (prescribed by an outside hospital) then from May 2013 onwards she was given 50,000 IU per month. Follow-up laboratory exams revealed improved vitamin D levels as well as TSH and FT4. She eventually improved both clinically and biochemically with a satisfactory outcome.
CONCLUSION
Vitamin D deficiency may exacerbate the onset and/or development of GD and correction of the deficiency may be able to reverse it. However, further prospective clinical studies will be needed to define the role of vitamin D treatment in GD.
doi:10.4137/CCRep.S13157
PMCID: PMC4133032  PMID: 25187748
Autoimmune diseases; Graves’ disease; vitamin D deficiency; Vitamin D3
18.  Improving Mobility and Reducing Disability in Older People Through Early High-Dose Vitamin D Replacement Following Hip Fracture: A Protocol for a Randomized Controlled Trial and Economic Evaluation 
Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture and has been linked with poorer lower extremity functioning, falls, and fractures. There is evidence that disability severity and fall rates may be reduced by adequate vitamin D replacement. However, the ideal regimen for vitamin D administration to have these benefits in older people who have been in the hospital has not been established. This randomized controlled trial will investigate the effects of an oral vitamin D loading dose with maintenance oral vitamin D and calcium on lower extremity function (gait velocity), correction of hypovitaminosis D, falls, and fractures among older people after hip fracture surgery. The cost-effectiveness of the REVITAHIP program from the health and community service provider’s perspective will also be established, as will predictors of adherence with the treatment. A total of 450 older people who have recently had a hip fracture requiring surgical intervention will be screened to achieve 250 participants for the study. Participants will have no medical contraindications to vitamin D replacement. The primary outcome measure will be mobility-related disability as measured with the 2.4-m gait velocity test. Secondary measures will be 25-hydroxyvitamin D (25-OHD) levels at 2, 4, and 26 weeks, number of falls and fractures, and additional measures of mobility, disability, quality of life, health system and community–service contact, adherence to the intervention, and adverse events. After surgical fixation and being deemed medically stable, participants will be randomly allocated to an intervention or placebo-control group. Participants of the intervention group will receive initial oral 250 000 IU (5 × 50 000 IU) vitamin D3 tablets. Both groups will receive oral maintenance vitamin D3 and calcium and will follow the usual hip fracture rehabilitation pathway. The study will determine the impact of a vitamin D loading dose on mobility-related disability in older people following hip fracture and will discuss the efficacy and cost-effectiveness of a loading dose vitamin D replacement more generally. The results will have direct implications for future use of vitamin D therapy for this high-risk group.
doi:10.1177/2151458511406723
PMCID: PMC3597307  PMID: 23569677
fragility fractures; geriatric medicine; hospitalist; metabolic bone disorders; osteoporosis; physical medicine and rehabilitation; trauma surgery
19.  Correction of vitamin D deficiency in critically ill patients - VITdAL@ICU study protocol of a double-blind, placebo-controlled randomized clinical trial 
Background
Vitamin D deficiency is associated with multiple adverse health outcomes including increased morbidity and mortality in the general population and in critically ill patients. However, no randomized controlled trial has evaluated so far whether treatment with sufficiently large doses of vitamin D can improve clinical outcome of patients in an intensive care setting.
Methods/design
The VITdAL@ICU trial is an investigator-initiated, non-commercial, double-blind, placebo-controlled randomized clinical trial. This study compares high-dose oral cholecalciferol (vitamin D3) versus placebo treatment in a mixed population of 480 critically ill patients with low 25-hydroxyvitamin-D levels at study enrollment (≤ 20ng/ml). Following an initial loading dose of 540,000 IU of vitamin D3, patients receive 90,000 IU of vitamin D3 on a monthly basis for 5 months. The study is designed to compare clinical outcome in the two study arms with the primary endpoint being length of hospital stay. Secondary endpoints include among others length of ICU stay, the percentage of patients with 25(OH)D levels > 30 ng/ml at day 7, ICU and hospital mortality and duration of mechanical ventilation. We describe here the VITdAL@ICU study protocol for the primary report.
Discussion
This trial is designed to evaluate whether high-dose vitamin D3 is able to improve morbidity and mortality in a mixed population of adult critically ill patients and correct vitamin D deficiency safely.
Trial registration
ClinicalTrials: NCT01130181
doi:10.1186/1472-6823-12-27
PMCID: PMC3534412  PMID: 23134762
Critical Illness; Vitamin D deficiency; Cholecalciferol; Vitamin D; Critical care; Intensive care; Vitamin D3
20.  Significant 25-Hydroxyvitamin D Deficiency in Child and Adolescent Survivors of Acute Lymphoblastic Leukemia: Treatment with Chemotherapy Compared with Allogeneic Stem Cell Transplant 
Pediatric blood & cancer  2010;56(7):1114-1119.
Background
25-hydroxyvitamin D insufficiency is common in healthy children and adolescents. There have been limited studies of the 25-hydroxyvitamin D status of survivors of pediatric and adolescent acute lymphoblastic leukemia (ALL).
Procedure
In a cohort of 78 ALL survivors (52 chemotherapy-treated and 26 HCT-treated), we determined the prevalence of, and host, treatment and environmental risk factors for 25-hydroxyvitamin D insufficiency and deficiency.
Results
There were no differences in serum 25-hydroxyvitamin D levels between ALL survivors treated with conventional chemotherapy and those treated with HCT (median 26.0 vs 25.5 ng/ ml). Fifty-three percent of pediatric ALL survivors were 25-hydroxyvitamin D insufficient (15-29 ng/ dl), and 12% were deficient (<15 ng/ dl). Younger age, higher reported dietary vitamin D intake, use of vitamin D supplementation, and increased ambient ultraviolet light were associated with higher serum 25-hydroxyvitamin D levels. There was not enough evidence to suggest treatment type, gender, race, years since diagnosis or BMI were associated with serum 25-hydroxyvitamin D levels. Only 27% of conventional chemotherapy-treated ALL survivors and 8% of HCT-treated ALL survivors met RDA for dietary vitamin D intake.
Conclusions
The prevalence of vitamin D deficiency and insufficiency in ALL survivors is similar to that of the general pediatric population in the United States, and there is no difference in serum 25-hydroxyvitamin D status between chemotherapy-treated and HCT-treated ALL survivors. ALL survivors rarely meet the RDA requirements for vitamin D. Further studies are needed to determine whether dietary and behavioral interventions can improve the vitamin D status of ALL survivors.
doi:10.1002/pbc.22949
PMCID: PMC3135735  PMID: 21488156
vitamin D deficiency; acute lymphoblastic leukemia; cancer survivorship; late effects; vitamin D insufficiency
21.  P36 - Severe Osteoporosis in Cushing’s Syndrome 
Cushing’s syndrome is characterised by a series of clinical manifestations due to hypersecretion of cortisol. These include: arterial hypertension, diabetes mellitus (DM), asthenia, amenorrhea, osteoporosis and pathological fractures. We describe the case of a 70-year-old woman with Cushing’s syndrome with right adrenal adenoma, vertebral compression fractures (VCFs) and severe secondary osteoporosis. This patient had been diagnosed with Cushing’s syndrome in May 2008, three years after the onset of arterial hypertension and type II DM, treated with insulin; in July 2008, she underwent right adrenalectomy and replacement therapy with cortisone acetate, 37.5 mg/day, in association with a multiple drug regimen for hypertension and DM; she also had an at least 10-year history of dorso-lumbar pain with multiple disc protrusions. As part of a series of investigations for Cushing’s syndrome the patient underwent femoral bone mineral densitometry, recording a T-score <−3, radiographic examination of the dorso-lumbar spine, which revealed collapse of the superior endplate of D7 and a wedge fracture of D8. At the endocrinology centre of reference for Cushing’s syndrome, she began treatment with alendronate 70 mg/day without undergoing blood chemistry tests of bone metabolism and without calcium and vitamin D supplementation. At the end of August 2009, she experienced worsening spinal pain due to a new severe fracture of D9, which was confirmed on MRI as a recent fracture. At the end of December 2009 she received kyphoplasty of D9, antiresorptive therapy and a CAMP-C35 brace.
In January 2010 she was admitted to the specialist rehabilitation unit for functional recovery, in view of her comorbidities, and bone disease investigation, with collection of history relating to osteoporosis risk factors. First- and second-level blood chemistry analyses revealed the presence of iron-deficiency anaemia, mild chronic renal insufficiency, and secondary hyerparathyroidism (PTH 101ng/ml); spinal radiography revealed severe VCFs of D7, D8 and D9, treated with kyphoplasty; the patient was also assessed using the VAS for pain, the FIM to evaluate independence in activities of daily living, and the SF-36 to investigate quality of life. The alendronate treatment was suspended and the patient was given cholecalciferol 300,000 IU, administered as an oral bolus, followed by a maintenance dose of 800 IU/day. When PTH values had returned to normal, she began treatment with teriparatide 20 mcg/day s.c. (therapeutic plan in compliance with Note 79 issued by the AIFA - Italian Drug Agency).
In conclusion, this case underlines the importance of a correct diagnostic and therapeutic approach in patients with severe osteoporosis. Over time, we will evaluate the efficacy of the treatment in preventing new fractures and the whether the use of a bone anabolic agent might be the correct choice also in order to control pain and improve quality of life. There are no reports in the literature of patients with Cushing’s syndrome treated with teriparatide.
PMCID: PMC3213844
22.  Antioxidative vitamines for prevention of cardiovascular disease for patients after renal transplantation and patients with chronic renal failure  
Introduction
The mortality from cardiovascular disease in patients with chronic renal failure is much higher than in the general population. In particular, patients with chronic renal failure with replacement therapies (dialysis patients and patients with renal transplantation) show both increased traditional risk factors and risk factors due to the dysfunction of the renal system. In combination with necessary medication for renal insufficiency oxidative stress is elevated. Progression of atherosclerosis is promoted due to increased oxidation of lipids and endothelium damage. This link between lipid oxidation and artherogenesis provides the rationale for the supposed beneficial effect of supplementation with antioxidative vitamins (vitamin A, C and E). Such an effect could not be demonstrated for patients with a history of cardiovascular disease and without kidney diseases. However, in high risk patients with chronic renal failure and renal replacement therapies this could be different.
Objectives
The objective of this systematic literature review was to assess the clinical effectiveness and cost-effectiveness of supplementation with antioxidative vitamins A, C or E to reduce cardiovascular events in patients with chronic kidney diseases, dialysis-requiring patients and patients after a renal transplantation with or without cardiovascular diseases.
Methods
A systematic literature review was conducted with documented search and selection of the literature, using a priori defined inclusion and exclusion criteria as well as a documented extraction and assessment of the literature according to the methods of evidence-based medicine.
Results
21 publications met the inclusion criteria for the evaluation of clinical effectiveness. No study could be identified for the economic evaluation. Two studies (four publications) analysed the effect of oral supplementation on the secondary prevention of clinical cardiovascular endpoints. Studies analysing the effect on patients without a history of cardiovascular disease could not be identified. 17 studies analysed the effect of oral supplementation or infusion with antioxidative vitamins or the supplementation with dialysis membranes coated with vitamin E on intermediate outcomes like oxidative stress or vessel parameters.
The two randomized clinical trials analysing the effect of orally supplemented vitamin E on clinical endpoints in patients with mild-to-moderate renal insufficiency and for haemodialysis patients respectively reported different results. After 4.5 years supplementation with a daily dose of 400 IU vitamin E renal insufficiency patients showed neither a beneficial nor a harmful effect on a combined event rate of myocardial infarction, stroke or death by cardiovascular causes. The second study reported a 50% risk reduction (RR=0.46, 95%-KI: 0.27-0.78, p=0.014) on the combined event rate of fatal myocardial infarction, nonfatal myocardial infarction, stroke, peripheral vascular disease or unstable angina pectoris in the study arm with vitamin E-Supplementation of 800 IU daily.
In 16 of 17 studies with intermediate endpoints the supplementation with vitamins was associated with a change of one or several of the examined endpoints in the expected direction. This means that the concentrations of the markers for oxidative stress decreased in the Vitamin E-group, the progression of aortic calcification (only one study) was reduced, the intima media thickness decreased and the lipid profile improved. No studies regarding costs or cost-effectiveness were identified.
Discussion
A possible explanation for the different results in the two studies with clinical endpoints may be due to the different study populations with different risk profiles, to different dosage during the intervention or to variation by chance. Due to the absence of clinically meaningful endpoints, the relevance of studies analysing the effect of antioxidative vitamins on intermediate endpoints like oxidative stress markers is basically limited to show single intermediate steps of the postulated biological effect mechanisms by which a potentially preventive effect could possibly be mediated. The mainly unsatisfactory planning and reporting quality of the 17 identified studies and a possible "publication bias" are further limitations.
Conclusion
The available evidence is not sufficient to support or to reject an effect of antioxidative vitamins on secondary prevention for cardiovascular disease for patients with chronic renal insufficiency or renal replacement therapy. There is a lack of randomized, placebo-controlled studies with a sufficient number of cases and clinical endpoints of cardiovascular disease, on the effect of antioxidative vitamins either orally applied or given by vitamin E-modified dialysers.
No data are available about supplementation with antioxidative vitamins for primary prevention of cardiovascular disease. Therefore the current evidence does not allow to draw conclusions concerning this subject either. As opposed to patients with a history of cardiovascular disease without kidney diseases where there is enough evidence to exclude a beneficial effect on secondary prevention of cardiovascular disease for patients with chronic renal insufficiency and renal replacement therapy this question remains unanswered. Conclusions about costs and cost-effectiveness also cannot be drawn.
PMCID: PMC3011345  PMID: 21289965
23.  First Trimester Vitamin D, Vitamin D Binding Protein, and Subsequent Preeclampsia 
Hypertension  2010;56(4):758-763.
Prior studies report an association between vitamin D deficiency and hypertension, including the pregnancy-specific disorder, preeclampsia. Circulating vitamin D is almost entirely bound to vitamin D binding protein, which increases 2-fold during pregnancy, but previous studies have not examined vitamin D binding protein or free vitamin D levels. We performed a nested case-control study within the Massachusetts General Hospital Obstetrical Maternal Study (MOMS), measuring first trimester total 25-hydroxyvitamin D and vitamin D binding protein, and calculating free 25-hydroxyvitamin D levels. We compared these levels from pregnancies complicated by subsequent preeclampsia (cases, n=39) with those from normotensive pregnancies (controls, n=131). First trimester total 25-hydroxyvitamin D levels were similar in cases and controls (27.4 ±1.9 ng/ml vs. 28.8±0.80 ng/ml, p=0.435). Despite an association between higher first trimester blood pressures and subsequent preeclampsia, first trimester total 25-hydroxyvitamin D was not associated with first trimester systolic (r=0.11, p=0.16) or diastolic blood pressures (r=0.03, p=0.72). Although there was a trend toward increased risk of preeclampsia with 25-hydroxyvitamin D levels less than 15 ng/ml (OR 2.5, 95% CI 0.89-6.9), this was attenuated after adjustment for body mass index and other covariates (OR 1.35 95% CI 0.40-4.5). First trimester vitamin D binding protein and free 25-hydroxyvitamin D levels were similar in cases and controls and were not associated with first trimester blood pressures. These data suggest that first trimester total and free 25-hydroxyvitamin D levels are not independently associated with first trimester blood pressure or subsequent preeclampsia.
doi:10.1161/HYPERTENSIONAHA.110.158238
PMCID: PMC3775612  PMID: 20733087
vitamin D; vitamin D Binding Protein; preeclampsia; pregnancy
24.  Is There an Epidemic Vitamin D Deficiency in German Orthopaedic Patients? 
Background
Vitamin D plays an essential role in bone health and muscle function. Some studies have shown a widespread rate of vitamin D deficiency in the general population, but few have reported on the vitamin D status of orthopaedic patients.
Questions/purposes
We investigated (1) the extent of hypovitaminosis D in orthopaedic patients, (2) seasonal variations in vitamin D levels, and (3) possible risk factors for insufficient vitamin D levels.
Methods
Vitamin D levels in 1119 patients consecutively admitted to an orthopaedic surgery department in 2011 were measured. To investigate the correlation between climate factors and vitamin D levels, the sunshine hours for each month in 2011 were collected by Deutscher Wetterdienst (the German weather service) in the region where most tested patients lived. The prevalence of normal (> 30 ng/mL), insufficient (20–30 ng/mL), and deficient (< 20 ng/mL) 25-hydroxyvitamin D levels was determined. Univariate and multivariate analyses were used to assess risk factors for insufficient vitamin D levels.
Results
Overall, 84% of patients had insufficient levels of vitamin D and 60% were vitamin D deficient. Only 15% were in the target range of 30 to 60 ng/mL. The prevalence of low vitamin D levels was greater during winter and months with fewer sunshine hours. Vitamin D levels did not vary according to age, sex, and disease. Individuals with obesity, hypertension, and osteoporosis were more likely to have low vitamin D levels compared with their healthy counterparts.
Conclusions
There is an alarmingly high rate of hypovitaminosis D and vitamin D deficiency among orthopaedic patients in this region of Germany, whose latitude (50° N) is approximately the same as those of Vancouver (49°, 15’ N) and Paris (48°, 51’ N). Given the well-known effects on bone metabolism and muscle health, low vitamin D levels may negatively affect patients. Screening and treating hypovitaminosis D appears to be important in this patient population.
Level of Evidence
Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-013-2996-5
PMCID: PMC3734399  PMID: 23609810
25.  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

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