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1.  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
2.  Parkinson’s Disease and Osteoporosis 
Parkinson’s disease (PD) and osteoporosis are two conditions that affect a considerable proportion of the elderly population and have a significant socio-economic impact, which is linked partly to increases in hospital admissions following fractures and partly to increased consumption of drugs.
Reduced walking speed, difficulty walking in tandem, reduced visual acuity and reduced thigh circumference are independent risk factors for fall-related hip fractures. Falls are a major fracture risk factor in elderly people and are the leading cause of emergency department admissions in parkinsonian patients. Falls are a much more frequent occurrence in PD patients than in their healthy peers and the factors that contribute most to this increased risk are older age, longer disease duration, more severe disease (as measured using the Hoehn & Yahr scale), bradykinesia, rigidity, gait disorders, postural instability, the presence of dementia and the presence of atypical parkinsonism. Fractures, obviously correlated with the frequency of falls, are also more common in individuals with PD compared with the age-matched healthy population, and the femur is the most frequent fracture site. A reduced bone mass density (BMD) appears to be a factor correlated with increased fracture risk in parkinsonian subjects. Individuals with PD have lower BMD values than healthy, age-matched controls and this reduction seems to be related to their bodyweight (a low body mass index, BMI), reduced physical activity, disease duration, disease severity (Hoehn and Yahr stage), calcium intake and exposure to sunlight. From a pathophysiological point of view, various factors are implicated in osteoporosis in PD: - immobilisation: this is known to be a factor in bone loss, even though, at present, the precise pathophysiological mechanism by which it might induce osteopenia remains unclear; one hypothesis suggests an increase in osteoclast activity and a suppression of osteoblast activity.- endocrine factors: in addition to reduced levels of GH, ACTH and cortisol in PD patients versus age-matched controls, there also seems to be a vitamin D deficiency. Vitamin D acts not only on bone metabolism but also on various other tissues, including the nervous system.- nutritional factors: weight loss is a factor often present in patients with PD, even early in the disease; however, it is much more marked in the advanced stages of PD, when the cognitive problems, dysphagia and delayed gastric emptying appear. BMD is even lower in PD patients with low bodyweight compared with the overall population of PD patients who, per se, already have a low BMD compared with that of the general population. Low bodyweight and low physical activity are risk factors for low BMD in PD. Fracture risk may be reduced by dietary supplementation of calcium and vitamin D.- iatrogenic factors: a recent study showed that high daily doses of levodopa are associated with an increased fracture risk and this is probably linked to the fact that levodopa increases hyperhomocysteinaemia in subjects with PD.
Given the mortality and morbidity of fractures in the elderly population, and particularly in subjects with PD, it is reasonable to suggest that these patients should be submitted to measurement of vitamin levels (vitamins D, B12 and folate), BMD measurement and assessment of fall risk, and also that preventive measures should be implemented in order to reduce their fracture risk. In the absence of specific guidelines and recommendations on the treatment and prevention of osteoporosis in PD, it currently seems reasonable to follow the existing indications for post-menopausal treatment of osteoporosis, given that the fracture risk profile in PD subjects may differ from that of the general population on account of their increased fall risk, low level of physical activity, reduced vitamin D intake and swallowing difficulties.
PMCID: PMC3213812
3.  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
4.  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
5.  Vitamin D deficiency and its relation to bone mineral density and liver fibrosis in HIV–HCV coinfection 
Antiviral therapy  2012;18(2):237-242.
Background
Fractures and cirrhosis are major causes of morbidity and mortality among HIV–HCV-coinfected individuals. It is not known whether vitamin D deficiency is associated with these outcomes.
Methods
Between 2005 and 2007, 116 HIV–HCV- coinfected individuals underwent dual-energy X-ray absorptiometry within 1 year of a liver biopsy. 25-Hydroxy-vitamin D (25OHD) and parathyroid hormone were measured from archived samples. Low bone mineral density (BMD) was defined as BMD≥2 standard deviations lower than age-, sex- and race-matched controls (Z-score ≤−2.0) at the total hip, femoral neck or lumbar spine. Histological fibrosis staging was assessed according to the METAVIR system (0 [no fibrosis] to 4 [cirrhosis]).
Results
The cohort was 87% African-American and 63% male. The median age (IQR) was 49.9 years (46.5–53.3). A total of 89% had a CD4+ T-cell count >200 cells/mm3 and 64% were receiving HAART. The median 25OHD was 19 ng/ ml (IQR 11.0–26.0). Hypovitaminosis D (25OHD≤15 ng/ml) was present in 41% and secondary hyperparathyroidism, defined by parathyroid hormone >65 pg/ml, was present in 24%. In total, 27% had low BMD (Z-score ≤−2) at the spine, femoral neck or total hip, and 39% had significant hepatic fibrosis (METAVIR≥2). In multivariate analysis, vitamin D deficiency was not associated with significant fibrosis or with BMD at any site.
Conclusions
Vitamin D deficiency was highly prevalent in this mostly African-American HIV–HCV-coinfected population, but was not related to BMD or liver disease severity. These data suggest that efforts to increase vitamin D levels in this population may not improve bone or liver outcomes.
doi:10.3851/IMP2264
PMCID: PMC3790468  PMID: 22910231
6.  Vitamin D Status and Bone Mineral Density in African American Children with Crohn’s Disease 
Journal of pediatric gastroenterology and nutrition  2013;57(5):10.1097/MPG.0b013e31829e0b89.
Background
Vitamin D deficiency and low bone mineral density (BMD) are complications of inflammatory bowel disease. Vitamin D deficiency is more prevalent among individuals of color compared to Caucasians. There is little data comparing differences in serum 25-hydroxyvitamin D (25OHD) concentrations and BMD between African American and Caucasian children with Crohn’s Disease (CD).
Methods
We compared serum 25OHD concentrations of African American children with CD (n=52) to Caucasian children with CD (n=64) and healthy African American controls (n=40). We also analyzed BMD using dual energy x-ray absorptiometry (DXA) results from our pediatric CD population.
Results
African American children with CD had lower serum 25OHD concentrations [16.1 (14.5-17.9, 95%CI) ng/mL] than Caucasians with CD [22.3 (20.2-24.6, 95%CI) ng/mL; p<0.001]. African Americans with CD and controls exhibited similar serum 25OHD concentration [16.1 (14.5-17.9, 95%CI) vs 16.3 (14.4-18.4, 95%CI) ng/mL; NS]. African Americans with CD exhibited no difference in serum 25OHD concentration when controlling for seasonality, disease severity and surgical history, though serum 25OHD concentration was significantly decreased in overweight children (BMI≥85%, p =0.003). Multiple regression analysis demonstrated that obese African American females with CD had the lowest serum 25OHD concentrations [9.6 (6.8-13.5, 95%CI) ng/mL]. BMD was comparable between African American and Caucasian children with CD (Z score −0.4 ± 0.9 vs −0.7 ± 1.2; NS).
Conclusions
African American children with CD are more likely to have vitamin D deficiency compared to Caucasian with CD, but have similar BMD. CD disease severity and history of surgery do not affect serum 25OHD concentrations among African American children with CD. African American children have low serum 25OHD concentrations, independent of CD, compared to Caucasian children. Future should research should focus on how race affects vitamin D status and BMD in children with CD.
doi:10.1097/MPG.0b013e31829e0b89
PMCID: PMC3845217  PMID: 23760229
Vitamin D; Epidemiology; Crohn’s disease; IBD; children
7.  Disease-specific definitions of vitamin D deficiency need to be established in autoimmune and non-autoimmune chronic diseases: a retrospective comparison of three chronic diseases 
Arthritis Research & Therapy  2010;12(5):R191.
Introduction
We compared the odds of vitamin D deficiency in three chronic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 2 diabetes (T2DM), adjusting for medications, demographics, and laboratory parameters, common to all three diseases. We also designed multivariate models to determine whether different factors are associated with vitamin D deficiency in different racial/ethnic groups.
Methods
We identified all patients with non-overlapping diagnoses of SLE, RA, and T2DM, with 25-hydroxyvitamin D (25OHD) levels measured between 2000 and 2009. Vitamin D deficiency was defined as 25OHD levels <20 ng/ml, based on previously established definitions. Race/ethnicity was analyzed as African-American non-Hispanic (African-American), Hispanic non-African-American (Hispanic), and Other based on self report.
Results
We included 3,914 patients in the final analysis: 123 SLE, 100 RA, and 3,691 T2DM. Among African-Americans the frequency of vitamin D deficiency was 59% in SLE, 47% in RA, and 67% in T2DM. Among Hispanics the frequency of vitamin D deficiency was 67% in SLE, 50% in RA, and 59% in T2DM. Compared with the SLE group, the adjusted odds ratio of vitamin D deficiency was 1.1, 95% CI (0.62, 2.1) in the RA group, and 2.0, 95% CI (1.3, 3.1) in the T2DM group. In the multivariate analysis, older age, higher serum calcium and bisphosphonate therapy were associated with a lower odds of vitamin D deficiency in all three racial/ethnic groups: 1,330 African-American, 1,257 Hispanic, and 1,100 Other. T2DM, serum creatinine, and vitamin D supplementation were associated with vitamin D deficiency in some, but not all, racial/ethnic groups.
Conclusions
Vitamin D deficiency is highly prevalent in our patients with SLE, RA, and T2DM. While the odds of vitamin D deficiency are similar in RA and SLE patients in a multivariate analysis, T2DM patients have much higher odds of being vitamin D deficient. Different demographic and laboratory factors may be associated with vitamin D deficiency within different racial/ethnic groups. Therefore, disease-specific and race/ethnicity-specific definitions of vitamin D deficiency need to be established in future studies in order to define goals of vitamin D replacement in patients with autoimmune and non-autoimmune chronic diseases.
doi:10.1186/ar3161
PMCID: PMC2991026  PMID: 20946654
8.  Vitamin D supplementation in older people (VDOP): Study protocol for a randomised controlled intervention trial with monthly oral dosing with 12,000 IU, 24,000 IU or 48,000 IU of vitamin D3 
Trials  2013;14:299.
The randomised, double blind intervention trial ‘Optimising Vitamin D Status in Older People’ (VDOP) will test the effect of three oral dosages of vitamin D given for one year on bone mineral density (BMD) and biochemical markers of vitamin D metabolism, bone turnover and safety in older people. VDOP is funded by Arthritis Research UK, supported through Newcastle University and MRC Human Nutrition Research and sponsored by the Newcastle upon Tyne Hospitals NHS Foundation Trust.a
Background
Vitamin D insufficiency is common in older people and may lead to secondary hyperparathyroidism, bone loss, impairment of muscle function and increased risk of falls and fractures. Vitamin D supplementation trials have yielded conflicting results with regard to decreasing rates of bone loss, falls and fractures and the optimal plasma concentration of 25 hydroxy vitamin D (25OHD) for skeletal health remains unclear.
Method/design
Older (≥70 years) community dwelling men and women are recruited through General Practices in Northern England and 375 participants are randomised to take 12,000 international units (IU), 24,000 IU or 48,000 IU of vitamin D3 orally each month for one year starting in the winter or early spring. Hip BMD and anthropometry are measured at baseline and 12 months. Fasting blood samples are collected at baseline and three-month intervals for the measurement of plasma 25OHD, parathyroid hormone (PTH), biochemical markers of bone turnover and biochemistry to assess the dose–response and safety of supplementation. Questionnaire data include falls, fractures, quality of life, adverse events and outcomes, compliance, dietary calcium intake and sunshine exposure.
Discussion
This is the first integrated vitamin D supplementation trial in older men and women using a range of doses given at monthly intervals to assess BMD, plasma 25OHD, PTH and biochemical markers of bone turnover and safety, quality of life and physical performance. We aim to investigate the vitamin D supplementation and plasma 25OHD concentration required to maintain bone health and to develop a set of biochemical markers that reflects the effect of vitamin D on bone. This will aid future studies investigating the effect of vitamin D supplementation on fracture risk.
#ISRCTN 35648481 (assigned 16 August 2012), EudraCT 2011-004890-10.
doi:10.1186/1745-6215-14-299
PMCID: PMC3848647  PMID: 24041337
Vitamin D supplementation trial; Bone mineral density; 25 hydroxy vitamin D; Parathyroid hormone; Bone markers; Older people
9.  Bone Mineral Density as a Predictor of Atherosclerosis and Arterial Wall Stiffness in Obese African-American Women 
Cardiorenal Medicine  2012;2(4):328-334.
Bone demineralization is associated with higher cardiovascular event rates, possibly due to vascular calcification and accelerated atherosclerosis. African-Americans have less bone loss and less calcium content within atherosclerotic plaques. However, whether loss of bone mass is related to atherosclerosis has not been examined in African-Americans. The objective of this study was to evaluate possible associations between bone mineral density (BMD), carotid intimal-medial thickness (CIMT), and arterial stiffness. We studied 100 obese African-American women (BMI: 26.6 ± 6.2; age: 63 ± 14 years) referred for BMD estimation by dual-energy X-ray absorptiometry scan. BMD (g/cm2) was obtained at the lumbar spine (L1–L4), femoral neck, and total hip. Arterial stiffness was evaluated by the heart rate-corrected augmentation index (AI@75) and pulse wave velocity (PWV) using applanation tonometry. CIMT was measured by vascular ultrasound. Mean CIMT, AI@75, and PWV were 0.72 ± 0.14 mm, 28.8 ± 9.0%, and 8.9 ± 1.6 m/s, respectively. Mean BMD values at the lumbar spine, femoral neck, and hip were 0.96 ± 0.19, 0.80 ± 0.16, and 0.91 ± 0.17 g/cm2. Older subjects had higher CIMT (r = 0.61, p < 0.001) and AI@75 (r = 0.42, p < 0.001). There was a significant correlation between AI@75 and CIMT (r = 0.45, p < 0.001). BMD was negatively correlated with AI@75 (lumbar: r = −0.22, p = 0.03; femoral neck: r = −0.24, p = 0.01; hip: r = −0.21, p = 0.03). BMD was unrelated to CIMT (lumbar: r = −0.09, p = 0.42; femoral neck: r = −0.15, p = 0.17; hip: r = −0.13, p = 0.23). On multivariate analysis, age (p < 0.001), hypertension (p = 0.02), and lumbar BMD (p = 0.01, R2 = 0.30) were independent predictors of increased AI@75 after adjusting for age, height, and cardiovascular risk factors. These findings were unchanged upon substitution of femoral neck BMD (p = 0.05, R2 = 0.28) into the model. There was a trend with hip BMD (p = 0.06, R2 = 0.28) in the regression model. Age-matched comparison between normal BMD (n = 25) and osteoporotic patients (n = 34) demonstrated a significant difference in AI@75 (26.6 ± 8.9 vs. 31.6 ± 9.1%, p = 0.04). In summary, women with lower BMD had increased arterial stiffness. There was no relationship between BMD and atherosclerosis. In conclusion, age, hypertension, and BMD are independent predictors of higher arterial stiffness. Vascular changes are related to bone mineral loss, suggesting lower BMD may increase cardiovascular risk in African-Americans.
doi:10.1159/000345461
PMCID: PMC3551407  PMID: 23381741
Bone mineral density; Osteoporosis; Atherosclerosis; Wave reflection; Aortic stiffness
10.  Utilization of DXA Bone Mineral Densitometry in Ontario 
Executive Summary
Issue
Systematic reviews and analyses of administrative data were performed to determine the appropriate use of bone mineral density (BMD) assessments using dual energy x-ray absorptiometry (DXA), and the associated trends in wrist and hip fractures in Ontario.
Background
Dual Energy X-ray Absorptiometry Bone Mineral Density Assessment
Dual energy x-ray absorptiometry bone densitometers measure bone density based on differential absorption of 2 x-ray beams by bone and soft tissues. It is the gold standard for detecting and diagnosing osteoporosis, a systemic disease characterized by low bone density and altered bone structure, resulting in low bone strength and increased risk of fractures. The test is fast (approximately 10 minutes) and accurate (exceeds 90% at the hip), with low radiation (1/3 to 1/5 of that from a chest x-ray). DXA densitometers are licensed as Class 3 medical devices in Canada. The World Health Organization has established criteria for osteoporosis and osteopenia based on DXA BMD measurements: osteoporosis is defined as a BMD that is >2.5 standard deviations below the mean BMD for normal young adults (i.e. T-score <–2.5), while osteopenia is defined as BMD that is more than 1 standard deviation but less than 2.5 standard deviation below the mean for normal young adults (i.e. T-score< –1 & ≥–2.5). DXA densitometry is presently an insured health service in Ontario.
Clinical Need
 
Burden of Disease
The Canadian Multicenter Osteoporosis Study (CaMos) found that 16% of Canadian women and 6.6% of Canadian men have osteoporosis based on the WHO criteria, with prevalence increasing with age. Osteopenia was found in 49.6% of Canadian women and 39% of Canadian men. In Ontario, it is estimated that nearly 530,000 Ontarians have some degrees of osteoporosis. Osteoporosis-related fragility fractures occur most often in the wrist, femur and pelvis. These fractures, particularly those in the hip, are associated with increased mortality, and decreased functional capacity and quality of life. A Canadian study showed that at 1 year after a hip fracture, the mortality rate was 20%. Another 20% required institutional care, 40% were unable to walk independently, and there was lower health-related quality of life due to attributes such as pain, decreased mobility and decreased ability to self-care. The cost of osteoporosis and osteoporotic fractures in Canada was estimated to be $1.3 billion in 1993.
Guidelines for Bone Mineral Density Testing
With 2 exceptions, almost all guidelines address only women. None of the guidelines recommend blanket population-based BMD testing. Instead, all guidelines recommend BMD testing in people at risk of osteoporosis, predominantly women aged 65 years or older. For women under 65 years of age, BMD testing is recommended only if one major or two minor risk factors for osteoporosis exist. Osteoporosis Canada did not restrict its recommendations to women, and thus their guidelines apply to both sexes. Major risk factors are age greater than or equal to 65 years, a history of previous fractures, family history (especially parental history) of fracture, and medication or disease conditions that affect bone metabolism (such as long-term glucocorticoid therapy). Minor risk factors include low body mass index, low calcium intake, alcohol consumption, and smoking.
Current Funding for Bone Mineral Density Testing
The Ontario Health Insurance Program (OHIP) Schedule presently reimburses DXA BMD at the hip and spine. Measurements at both sites are required if feasible. Patients at low risk of accelerated bone loss are limited to one BMD test within any 24-month period, but there are no restrictions on people at high risk. The total fee including the professional and technical components for a test involving 2 or more sites is $106.00 (Cdn).
Method of Review
This review consisted of 2 parts. The first part was an analysis of Ontario administrative data relating to DXA BMD, wrist and hip fractures, and use of antiresorptive drugs in people aged 65 years and older. The Institute for Clinical Evaluative Sciences extracted data from the OHIP claims database, the Canadian Institute for Health Information hospital discharge abstract database, the National Ambulatory Care Reporting System, and the Ontario Drug Benefit database using OHIP and ICD-10 codes. The data was analyzed to examine the trends in DXA BMD use from 1992 to 2005, and to identify areas requiring improvement.
The second part included systematic reviews and analyses of evidence relating to issues identified in the analyses of utilization data. Altogether, 8 reviews and qualitative syntheses were performed, consisting of 28 published systematic reviews and/or meta-analyses, 34 randomized controlled trials, and 63 observational studies.
Findings of Utilization Analysis
Analysis of administrative data showed a 10-fold increase in the number of BMD tests in Ontario between 1993 and 2005.
OHIP claims for BMD tests are presently increasing at a rate of 6 to 7% per year. Approximately 500,000 tests were performed in 2005/06 with an age-adjusted rate of 8,600 tests per 100,000 population.
Women accounted for 90 % of all BMD tests performed in the province.
In 2005/06, there was a 2-fold variation in the rate of DXA BMD tests across local integrated health networks, but a 10-fold variation between the county with the highest rate (Toronto) and that with the lowest rate (Kenora). The analysis also showed that:
With the increased use of BMD, there was a concomitant increase in the use of antiresorptive drugs (as shown in people 65 years and older) and a decrease in the rate of hip fractures in people age 50 years and older.
Repeat BMD made up approximately 41% of all tests. Most of the people (>90%) who had annual BMD tests in a 2-year or 3-year period were coded as being at high risk for osteoporosis.
18% (20,865) of the people who had a repeat BMD within a 24-month period and 34% (98,058) of the people who had one BMD test in a 3-year period were under 65 years, had no fracture in the year, and coded as low-risk.
Only 19% of people age greater than 65 years underwent BMD testing and 41% received osteoporosis treatment during the year following a fracture.
Men accounted for 24% of all hip fractures and 21 % of all wrist fractures, but only 10% of BMD tests. The rates of BMD tests and treatment in men after a fracture were only half of those in women.
In both men and women, the rate of hip and wrist fractures mainly increased after age 65 with the sharpest increase occurring after age 80 years.
Findings of Systematic Review and Analysis
Serial Bone Mineral Density Testing for People Not Receiving Osteoporosis Treatment
A systematic review showed that the mean rate of bone loss in people not receiving osteoporosis treatment (including postmenopausal women) is generally less than 1% per year. Higher rates of bone loss were reported for people with disease conditions or on medications that affect bone metabolism. In order to be considered a genuine biological change, the change in BMD between serial measurements must exceed the least significant change (variability) of the testing, ranging from 2.77% to 8% for precisions ranging from 1% to 3% respectively. Progression in BMD was analyzed, using different rates of baseline BMD values, rates of bone loss, precision, and BMD value for initiating treatment. The analyses showed that serial BMD measurements every 24 months (as per OHIP policy for low-risk individuals) is not necessary for people with no major risk factors for osteoporosis, provided that the baseline BMD is normal (T-score ≥ –1), and the rate of bone loss is less than or equal to 1% per year. The analyses showed that for someone with a normal baseline BMD and a rate of bone loss of less than 1% per year, the change in BMD is not likely to exceed least significant change (even for a 1% precision) in less than 3 years after the baseline test, and is not likely to drop to a BMD level that requires initiation of treatment in less than 16 years after the baseline test.
Serial Bone Mineral Density Testing in People Receiving Osteoporosis Therapy
Seven published meta-analysis of randomized controlled trials (RCTs) and 2 recent RCTs on BMD monitoring during osteoporosis therapy showed that although higher increases in BMD were generally associated with reduced risk of fracture, the change in BMD only explained a small percentage of the fracture risk reduction.
Studies showed that some people with small or no increase in BMD during treatment experienced significant fracture risk reduction, indicating that other factors such as improved bone microarchitecture might have contributed to fracture risk reduction.
There is conflicting evidence relating to the role of BMD testing in improving patient compliance with osteoporosis therapy.
Even though BMD may not be a perfect surrogate for reduction in fracture risk when monitoring responses to osteoporosis therapy, experts advised that it is still the only reliable test available for this purpose.
A systematic review conducted by the Medical Advisory Secretariat showed that the magnitude of increases in BMD during osteoporosis drug therapy varied among medications. Although most of the studies yielded mean percentage increases in BMD from baseline that did not exceed the least significant change for a 2% precision after 1 year of treatment, there were some exceptions.
Bone Mineral Density Testing and Treatment After a Fragility Fracture
A review of 3 published pooled analyses of observational studies and 12 prospective population-based observational studies showed that the presence of any prevalent fracture increases the relative risk for future fractures by approximately 2-fold or more. A review of 10 systematic reviews of RCTs and 3 additional RCTs showed that therapy with antiresorptive drugs significantly reduced the risk of vertebral fractures by 40 to 50% in postmenopausal osteoporotic women and osteoporotic men, and 2 antiresorptive drugs also reduced the risk of nonvertebral fractures by 30 to 50%. Evidence from observational studies in Canada and other jurisdictions suggests that patients who had undergone BMD measurements, particularly if a diagnosis of osteoporosis is made, were more likely to be given pharmacologic bone-sparing therapy. Despite these findings, the rate of BMD investigation and osteoporosis treatment after a fracture remained low (<20%) in Ontario as well as in other jurisdictions.
Bone Mineral Density Testing in Men
There are presently no specific Canadian guidelines for BMD screening in men. A review of the literature suggests that risk factors for fracture and the rate of vertebral deformity are similar for men and women, but the mortality rate after a hip fracture is higher in men compared with women. Two bisphosphonates had been shown to reduce the risk of vertebral and hip fractures in men. However, BMD testing and osteoporosis treatment were proportionately low in Ontario men in general, and particularly after a fracture, even though men accounted for 25% of the hip and wrist fractures. The Ontario data also showed that the rates of wrist fracture and hip fracture in men rose sharply in the 75- to 80-year age group.
Ontario-Based Economic Analysis
The economic analysis focused on analyzing the economic impact of decreasing future hip fractures by increasing the rate of BMD testing in men and women age greater than or equal to 65 years following a hip or wrist fracture. A decision analysis showed the above strategy, especially when enhanced by improved reporting of BMD tests, to be cost-effective, resulting in a cost-effectiveness ratio ranging from $2,285 (Cdn) per fracture avoided (worst-case scenario) to $1,981 (Cdn) per fracture avoided (best-case scenario). A budget impact analysis estimated that shifting utilization of BMD testing from the low risk population to high risk populations within Ontario would result in a saving of $0.85 million to $1.5 million (Cdn) to the health system. The potential net saving was estimated at $1.2 million to $5 million (Cdn) when the downstream cost-avoidance due to prevention of future hip fractures was factored into the analysis.
Other Factors for Consideration
There is a lack of standardization for BMD testing in Ontario. Two different standards are presently being used and experts suggest that variability in results from different facilities may lead to unnecessary testing. There is also no requirement for standardized equipment, procedure or reporting format. The current reimbursement policy for BMD testing encourages serial testing in people at low risk of accelerated bone loss. This review showed that biannual testing is not necessary for all cases. The lack of a database to collect clinical data on BMD testing makes it difficult to evaluate the clinical profiles of patients tested and outcomes of the BMD tests. There are ministry initiatives in progress under the Osteoporosis Program to address the development of a mandatory standardized requisition form for BMD tests to facilitate data collection and clinical decision-making. Work is also underway for developing guidelines for BMD testing in men and in perimenopausal women.
Conclusion
Increased use of BMD in Ontario since 1996 appears to be associated with increased use of antiresorptive medication and a decrease in hip and wrist fractures.
Data suggest that as many as 20% (98,000) of the DXA BMD tests in Ontario in 2005/06 were performed in people aged less than 65 years, with no fracture in the current year, and coded as being at low risk for accelerated bone loss; this is not consistent with current guidelines. Even though some of these people might have been incorrectly coded as low-risk, the number of tests in people truly at low risk could still be substantial.
Approximately 4% (21,000) of the DXA BMD tests in 2005/06 were repeat BMDs in low-risk individuals within a 24-month period. Even though this is in compliance with current OHIP reimbursement policies, evidence showed that biannual serial BMD testing is not necessary in individuals without major risk factors for fractures, provided that the baseline BMD is normal (T-score < –1). In this population, BMD measurements may be repeated in 3 to 5 years after the baseline test to establish the rate of bone loss, and further serial BMD tests may not be necessary for another 7 to 10 years if the rate of bone loss is no more than 1% per year. Precision of the test needs to be considered when interpreting serial BMD results.
Although changes in BMD may not be the perfect surrogate for reduction in fracture risk as a measure of response to osteoporosis treatment, experts advised that it is presently the only reliable test for monitoring response to treatment and to help motivate patients to continue treatment. Patients should not discontinue treatment if there is no increase in BMD after the first year of treatment. Lack of response or bone loss during treatment should prompt the physician to examine whether the patient is taking the medication appropriately.
Men and women who have had a fragility fracture at the hip, spine, wrist or shoulder are at increased risk of having a future fracture, but this population is presently under investigated and under treated. Additional efforts have to be made to communicate to physicians (particularly orthopaedic surgeons and family physicians) and the public about the need for a BMD test after fracture, and for initiating treatment if low BMD is found.
Men had a disproportionately low rate of BMD tests and osteoporosis treatment, especially after a fracture. Evidence and fracture data showed that the risk of hip and wrist fractures in men rises sharply at age 70 years.
Some counties had BMD utilization rates that were only 10% of that of the county with the highest utilization. The reasons for low utilization need to be explored and addressed.
Initiatives such as aligning reimbursement policy with current guidelines, developing specific guidelines for BMD testing in men and perimenopausal women, improving BMD reports to assist in clinical decision making, developing a registry to track BMD tests, improving access to BMD tests in remote/rural counties, establishing mechanisms to alert family physicians of fractures, and educating physicians and the public, will improve the appropriate utilization of BMD tests, and further decrease the rate of fractures in Ontario. Some of these initiatives such as developing guidelines for perimenopausal women and men, and developing a standardized requisition form for BMD testing, are currently in progress under the Ontario Osteoporosis Strategy.
PMCID: PMC3379167  PMID: 23074491
11.  Ethnic variability in bone geometry as assessed by hip structure analysis: Findings from the Hip Strength Across the Menopausal Transition study 
Racial/ethnic origin plays an important role in fracture risk. Racial/ethnic differences in fracture rates cannot be fully explained by bone mineral density (BMD). Studies examining the influence of bone geometry and strength on fracture risk have focused primarily on older adults and have not included people from diverse racial/ethnic backgrounds. Our goal was to explore racial/ethnic differences in hip geometry and strength in a large sample of midlife women. We performed Hip Structure Analysis (HSA) on hip DXA scans from 1942 pre- and early peri-menopausal women. The sample included Caucasian (50%), African American (27%), Chinese (11%) and Japanese (12%) women, age 42–52 years. HSA was performed using software developed at John’s Hopkins University. African American women had higher conventional (8.4–9.7%) and HSA BMD (5.4–19.8%) than other groups with the exception being Japanese women who had the highest HSA BMD (9.7–31.4%). HSA indices associated with more favorable geometry and greater strength and resistance to fracture were more prevalent in African American and Japanese women. Femurs of African American women had a smaller outer diameter, a larger cross-sectional area and section modulus, and a lower buckling ratio. Japanese women presented a different pattern with a higher section modulus and lower buckling ratio, similar to African American women, but a wider outer diameter; this was offset by a greater cross-sectional area and a more centrally located centroid. Chinese women had similar conventional BMD as Caucasian women but a smaller neck region area and HSA BMD at both regions. They also had a smaller cross-sectional area and section modulus, a more medially located centroid, and a higher buckling ratio than Caucasian women. The observed biomechanical differences may help explain racial/ethnic variability in fracture rates. Future research should explore the contribution of hip geometry to fracture risk across all race/ethnicities.
doi:10.1002/jbmr.1781
PMCID: PMC3586935  PMID: 23044816
Hip Structure Analysis; Bone Geometry; Bone Mineral Density; Ethnicity; Women
12.  High Vitamin C Intake Is Associated with Lower 4-Year Bone Loss in Elderly Men1,2 
The Journal of nutrition  2008;138(10):1931-1938.
Vitamin C is essential for collagen formation and normal bone development. We evaluated associations of total, supplemental, and dietary vitamin C intake with bone mineral density (BMD) at the hip [femoral neck, trochanter], spine, and radial shaft and 4-y BMD change in elderly participants from the Framingham Osteoporosis Study. Energy-adjusted vitamin C intakes were estimated from the Willett FFQ in 1988–89. Mean BMD and 4-y BMD change was estimated, for men and women, by tertile/category of vitamin C intake, adjusting for covariates. We tested for interaction with smoking, calcium, and vitamin E intake. Among 334 men and 540 women, the mean age was 75 y and mean vitamin D intake was 8.25 µg/d (women) and 8.05 µg/d (men). We observed negative associations between total and supplemental vitamin C intake and trochanter-BMD among current male smokers (P-trend = 0.01). Among male nonsmokers, total vitamin C intake was positively associated with femoral neck BMD (P-trend = 0.04). Higher total vitamin C intake was associated with less femoral neck and trochanter-BMD loss in men with low calcium (all P-trend ≤ 0.03) or vitamin E intakes (all P-trend = 0.03). Higher dietary vitamin C intake tended to be associated with lower femoral neck-BMD loss (P-trend = 0.09). These associations were attenuated but retained borderline significance (P-trend < 0.1) after adjusting for potassium intake (a marker of fruit and vegetable intake), suggesting that vitamin C effects may not be separated from other protective factors in fruit and vegetables. Null associations were observed among women. These results suggest a possible protective role of vitamin C for bone health in older men.
PMCID: PMC2752366  PMID: 18806103
13.  Vitamin D and Cognitive Impairment in the Elderly U.S. Population 
Background.
Recent European studies suggest that vitamin D deficiency may be associated with increased odds of cognitive impairment in older persons, although findings from the United States are equivocal. Our objective was to investigate the association between vitamin D deficiency and cognitive impairment in the elderly U.S. population.
Methods.
Three thousand and three hundred twenty-five adults aged 65 years or more completed cognitive assessments, medical examinations, and physical performance measures and provided blood samples in the Third National Health and Nutrition Examination Survey, a nationally representative cross-sectional study of the U.S. noninstitutionalized population. We determined whether low levels of serum 25-hydroxyvitamin D (25(OH)D) were associated with increased odds of cognitive impairment using logistic regression models. Cognitive impairment was assessed using measures of immediate and delayed verbal memory, orientation, and attention (impairment was defined as the worst 10% of the distribution of combined scores).
Results.
The multivariate adjusted odds ratios (95% confidence interval) of cognitive impairment in participants who were 25(OH)D insufficient (≥50 < 75 nmol/L), deficient (≥25 < 50 nmol/L), and severely deficient (<25 nmol/L) in comparison with those sufficient (≥75 nmol/L) were 0.9 (0.6–1.3), 1.4 (1.0–2.1), and 3.9 (1.5–10.4), respectively (p for linear trend = .02). Log-transformed levels of 25(OH)D were also significantly associated with the odds of cognitive impairment (p = .02).
Conclusions.
These findings suggest that vitamin D deficiency is associated with increased odds of cognitive impairment in the elderly U.S. population. Further exploration of a possible causal relationship between vitamin D deficiency and cognitive impairment is warranted.
doi:10.1093/gerona/glq185
PMCID: PMC3011960  PMID: 21041201
Cognitive impairment; Cognition; Dementia; Vitamin D; Serum 25-hydroxyvitamin D
14.  Bone mass and mineral metabolism in HIV+ postmenopausal women 
The objective of this cross-sectional study was to estimate the prevalence of and risk factors for osteoporosis in HIV+ postmenopausal women. Bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) and biochemical indices of mineral metabolism were measured in 31 Hispanic and African American HIV+ postmenopausal women. BMD was compared with 186 historical controls, matched for age, ethnicity and postmenopausal status. Mean BMD was significantly lower at the lumbar spine and total hip in the HIV+ group, as compared with controls. Prevalence of osteoporosis was higher in the HIV+ group than controls at the lumbar spine (42% vs 23%, p=0.03) and total hip (10% vs 1%, p=0.003). Among HIV+ women, time since menopause and weight were significant predictors of BMD, while duration or class of antiretroviral therapy (ART), AIDS diagnosis, nadir CD4, steroid use, and vitamin D deficiency were not. Prevalence of osteoporosis is substantially higher in HIV+ Hispanic and African-American postmenopausal women than in controls. Established osteoporosis risk factors were more important in predicting BMD than factors associated with HIV infection and ART. Long-term management of the growing female HIV population should include the evaluation for and management of osteoporosis.
doi:10.1007/s00198-005-1845-0
PMCID: PMC3108020  PMID: 15754081
Bone metabolism; HIV; Osteoporosis; Postmenopausal women
15.  The Oldest Old: Red blood cell and plasma folate in African American and White Octogenarians and Centenarians in Georgia 
Objective
To determine the overall folate status of a population-based multi-ethnic sample of octogenarians and centenarians and the specific dietary, demographic and physiological factors associated with observed abnormalities.
Design
Population-based multiethnic sample of adults aged 80 to 89 and 98 and above. Setting: Northern Georgia, USA
Setting
Northern Georgia, USA
Participants
Men and women aged 80 to 89 (octogenarians, n = 77) and 98 and older (centenarians, n = 198)
Analyses
Wilcoxon rank sum tests, and Chi square and logistic regression analyses were used to examine associations of low and high folate status with hematological indicators and other variables of interest.
Results
The prevalence of low red blood cell (RBC) folate was low overall, but tended to be higher in centenarians than in octogenarians (6.5% vs. 1.3%, p = 0.058; defined as RBC folate < 317 nmol/L). The risk of having lower RBC folate (< 25th vs. ≥25th percentile for RBC folate for 60yr+ in NHANES 1999–2000) was greater in association with vitamin B12 deficiency (OR = 5.36; 95%CI: 2.87–10.01), African American race (OR = 4.29; 95%CI: 2.08–8.83), and residence in a skilled nursing facility (OR = 3.25; 95%CI: 1.56–6.78) but was not influenced by age, gender, B-vitamin supplement use, high/low food score or presence of atrophic gastritis. Combined high plasma folate and low vitamin B12 status was present in some individuals (n=11), but was not associated with increased prevalence of anemia or cognitive impairment in this study.
Conclusions
Low RBC folate status (< 317 nmol/L) was rare in this post folic acid fortification sample of octogenarians and centenarians. RBC folate status (< 25th percentile) was strongly associated with 1) vitamin B12 deficiency, which has strong implications for vitamin treatment, and 2) with being African American, suggesting racial disparities exist even in the oldest old.
PMCID: PMC3233985  PMID: 22089222
16.  Vitamin D Status and Anthropometric Indices of an Omani Study Population 
Objectives:
Serum 25-hydroxyvitamin D [25(OH)D] concentrations reflect vitamin D status, with deficiency implicated as causative of many diseases. This study assessed vitamin D status and anthropometric indices in a sample of healthy Omanis.
Methods:
Serum 25(OH)D concentrations were measured by high performance liquid chromatography in 206 healthy Omanis, aged 18–55 years (mean age: men 31.1, women 26.8) in Muscat, Oman. Of this number, 95% indicated that they had never taken vitamin D supplements. Findings were compared with published values for populations domiciled in more northerly latitudes. Classical procedures were used to determine global obesity (body mass index [BMI]), and central obesity determined by waist circumference, waist-to-hip ratio (WHR), and waist-to-height ratio.
Results:
Women, as compared to men, had markedly lower concentrations of 25(OH)D. Applying the cut-off point of serum 25(OH)D levels at 50 nmol/L, the prevalence of vitamin D deficiency in the study population was 87.5%; this was higher than the rates reported for the British, and European-, Hispanic-, and African-Americans. At a BMI cut-point of ≥30 kg/m2, the prevalence of obesity was 14.6%; this was lower than the rates reported for European-, Hispanic-, and African-Americans. Levels of 25(OH) D increased relative to age and obesity. WHR was the main predictor of 25(OH)D levels.
Conclusion:
The striking vitamin D deficiency seen in the study population, relative to more northerly populations, may be linked to sun avoidance, inadequate dietary vitamin D, and virtual non-intake of supplemental vitamin D. Age and male-gender determined the status of vitamin D and of obesity.
PMCID: PMC3706111  PMID: 23862027
Vitamin D; 25-hydroxyvitamin D; High-performance liquid chromatography; Anthropometric indices; Oman
17.  Vitamin D deficiency is associated with development of subclinical coronary artery disease in HIV-infected African American cocaine users with low Framingham-defined cardiovascular risk 
Chronic cocaine use may lead to premature atherosclerosis, but the prevalence of and risk factors for coronary artery disease (CAD) in asymptomatic cocaine users have not been reported. The objective of this study was to examine whether vitamin D deficiency is associated with the development of CAD in human immunodeficiency virus (HIV)-infected African American cocaine users with low CAD risk.
Methods
In this prospective follow-up study, we investigated 169 HIV-infected African American cocaine users with low Framingham risk at baseline. The main outcome measures were incidence of subclinical CAD and development of subclinical CAD.
Results
Fifty of the 169 African Americans had evidence of subclinical disease on the initial cardiac computed tomography. A second cardiac computed tomography was performed on the 119 African Americans without disease on the first scan. The total sum of person-years of follow-up was 289.6. Subclinical CAD was detected in 11 of these, yielding an overall incidence of 3.80/100 person-years (95% confidence interval 1.90–6.80). Among the factors investigated, only vitamin D deficiency was independently associated with development of subclinical CAD. The study did not find significant associations between CD4 count, HIV viral load, or antiretroviral treatment use and the incidence of subclinical CAD. This study appears to suggest that there is a threshold level of vitamin D (10 ng/mL) above which the effect of vitamin D on subclinical CAD is diminished.
Conclusion
The incidence of subclinical CAD in HIV-infected African American cocaine users with low CAD risk is high, especially in those with vitamin D deficiency. Well designed randomized clinical trials are warranted to confirm the role of vitamin D deficiency in the development of CAD in HIV-infected African American cocaine users with low CAD risk.
doi:10.2147/VHRM.S50537
PMCID: PMC3833705  PMID: 24265555
vitamin D deficiency; subclinical coronary artery disease; cocaine use; prospective follow-up study; African Americans
18.  Vitamin D deficiency and psychotic features in mentally ill adolescents: A cross-sectional study 
BMC Psychiatry  2012;12:38.
Background
Vitamin D deficiency is a re-emerging epidemic, especially in minority populations. Vitamin D is crucial not only for bone health but for proper brain development and functioning. Low levels of vitamin D are associated with depression, seasonal affective disorder, and schizophrenia in adults, but little is known about vitamin D and mental health in the pediatric population.
Methods
One hundred four adolescents presenting for acute mental health treatment over a 16-month period were assessed for vitamin D status and the relationship of 25-OH vitamin D levels to severity of illness, defined by presence of psychotic features.
Results
Vitamin D deficiency (25-OH D levels <20 ng/ml) was present in 34%; vitamin D insufficiency (25-OH D levels 20–30 ng/ml) was present in 38%, with a remaining 28% in the normal range. Adolescents with psychotic features had lower vitamin D levels (20.4 ng/ml vs. 24.7 ng/ml; p = 0.04, 1 df). The association for vitamin D deficiency and psychotic features was substantial (OR 3.5; 95% CI 1.4-8.9; p <0.009). Race was independently associated with vitamin D deficiency and independently associated with psychosis for those who were Asian or biracial vs. white (OR = 3.8; 95% CI 1.1‒13.4; p < 0.04). Race was no longer associated with psychosis when the results were adjusted for vitamin D level.
Conclusions
Vitamin D deficiency and insufficiency are both highly prevalent in adolescents with severe mental illness. The preliminary associations between vitamin D deficiency and presence of psychotic features warrant further investigation as to whether vitamin D deficiency is a mediator of illness severity, result of illness severity, or both. Higher prevalence of vitamin D deficiency but no greater risk of psychosis in African Americans, if confirmed, may have special implications for health disparity and treatment outcome research.
doi:10.1186/1471-244X-12-38
PMCID: PMC3441857  PMID: 22571731
Vitamin D; Adolescents; Deficiency; Psychosis
19.  Prevalence of Vitamin D Insufficiency in African American Children with Forearm Fractures: A Preliminary Study 
Journal of pediatric orthopedics  2010;30(2):106-109.
Objectives
Forearm fractures account for a significant proportion of childhood injuries and appear to be increasing in incidence. Poor vitamin D status increases overall fracture risk in infants with rickets and adults with osteoporosis. Children with vitamin D insufficiency (serum 25-hydroxy vitamin D level < 20 ng/mL) have decreased bone mineral density (BMD) compared to children with normal vitamin D status. The relationship between vitamin D status and childhood forearm fracture has not been investigated.
Methods
This prospective study is enrolling African American children, ages 5–9 years, with a forearm fracture. Bone health evaluation includes measurement of serum 25-hydroxy vitamin D level and BMD by dual energy xray absorptiometry (DXA) scan. Univariable analyses are used to test the associations between fracture status and the independent variables serum vitamin D level and BMD.
Results
Vitamin D levels are available for seventeen cases. The mean (± SD) 25-hydroxy vitamin D level is 20.1 (± 7.3) ng/mL with a range of 10–38 ng/mL. The mean of this group is at the cutpoint for vitamin D insufficiency. Ten cases (59%) were vitamin D insufficient. DXA scan results for these patients are consistent with normal bony mineralization for age.
Conclusions
A significant proportion of African American children with fractures in our study are vitamin D insufficient. Analysis of serum 25-hydroxy vitamin D levels and BMD in additional cases and controls will determine the significance of these findings.
Clinical Relevance
Vitamin D insufficiency may play a previously unrecognized role in childhood fractures. Strong consideration should be given to routine vitamin D testing in African American children with forearm fractures.
doi:10.1097/BPO.0b013e3181d076a3
PMCID: PMC2847369  PMID: 20179554
Bone Health; Fractures; Vitamin D
20.  Vitamin-D nutrition and bone mass in adolescent black girls. 
OBJECTIVE: To examine the relationship between bone mass and serum levels of 25-hydroxyvitamin D and parathyroid hormone in African-American adolescent girls. STUDY DESIGN: A cross-sectional sample at a suburban research center. METHODS: Twenty-one adolescent black girls 12-14 years of age, were studied during winter with biochemical measurements of serum 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH). Bone mass assessment was done with dual energy x-ray absorbsiometry (DXA) and peripheral quantitative computed tomography of the radius (p-QCT). Anthropometric, physical activity and nutritional data were collected. RESULTS: All participants were vitamin-D deficient (serum 25-OHD level <50 nmol/L), of whom nine (43%) were severely vitamin-D deficient (serum 25-OHD level <20 nmol/L). Mean daily intake of dietary calcium was 540 mg/d and vitamin D was 195 IU/d. There was a positive correlation, although statistically not significant, between serum 25-OHD and various bone mass measurements. Serum PTH was inversely correlated to total body BMD (r = -0.51, p = 0.02) and other bone mineral density at the lumbar spine, total femur and mid-radius. CONCLUSION: Vitamin-D insufficiency is a widely prevalent problem among adolescent African-American girls. Our data implies that enhancing vitamin-D nutrition resulting in lower serum PTH levels could potentially influence their peak bone mass.
PMCID: PMC2574367  PMID: 17595934
21.  Worsening severity of vitamin D deficiency is associated with increased length of stay, surgical intensive care unit cost, and mortality rate in surgical intensive care unit patients 
American journal of surgery  2012;204(1):37-43.
BACKGROUND
Vitamin D deficiency is the most common nutritional deficiency in the United States. It is seldom measured or recognized, and rarely is treated, particularly in critically ill patients. The purpose of this study was to investigate the prevalence and impact of vitamin D deficiency in surgical intensive care unit patients. We hypothesized that severe vitamin D deficiency increases the length of stay, mortality rate, and cost in critically ill patients admitted to surgical intensive care units.
METHODS
We performed a prospective observational study of vitamin D status on 258 consecutive patients admitted to the Surgical Intensive Care Unit at Grady Memorial Hospital between August 2009 and January 2010. Vitamin D levels (25 [OH]2 vitamin-D3) were measured by high-pressure liquid chromatography and tandem mass spectrometry. Vitamin D deficiency was defined as follows: severe deficiency was categorized as less than 13 ng/mL; moderate deficiency was categorized as 14 to 26 ng/mL; mild deficiency was categorized as 27 to 39 ng/mL; and normal levels were categorized as greater than 40 ng/mL.
RESULTS
Of the 258 patients evaluated, 70.2% (181) were men, and 29.8% (77) were women; 57.6% (148) were African American and 32.4% (109) were Caucasian. A total of 138 (53.5%) patients had severe vitamin D deficiency, 96 (37.2%) had moderate deficiency, 18 (7.0%) had mild deficiency, and 3 (1.2%) of the patients had normal vitamin D levels. The mean length of stay in the Surgical Intensive Care Unit for the severe vitamin D–deficient group was 13.33 ± 19.5 days versus 7.29 ± 15.3 days and 5.17 ± 6.5 days for the moderate and mild vitamin D-deficient groups, respectively, which was clinically significant (P = .002). The mean treatment cost during the patient stay in the surgical intensive care unit was $51,413.33 ± $75,123.00 for the severe vitamin D–deficient group, $28,123.65 ± $59,752.00 for the moderate group, and $20,414.11 ± $25,714.30 for the mild vitamin D–deficient group, which also was clinically significant (P = .027). More importantly, the mortality rate for the severe vitamin D–deficient group was 17 (12.3%) versus 11 (11.5%) in the moderate group (P = .125). Because no deaths occurred in the mildly or normal vitamin D–deficient groups, we compared the mortality rate between severe/moderate and mild/normal vitamin D groups (P = .047).
CONCLUSIONS
In univariate analysis, severe and moderate vitamin D deficiency was related inversely to the length of stay in the surgical intensive care unit (r = .194; P = .001), related inversely to surgical intensive care unit treatment cost (r = .194; P = .001) and mortality (r = .125; P = .023), compared with the mild vitamin D–deficient group, after adjusting for age, sex, race, and comorbidities (myocardial infarctions, acute renal failure, and pneumonia); the length of stay, surgical intensive care unit cost, and mortality remained significantly associated with vitamin D deficiency.
doi:10.1016/j.amjsurg.2011.07.021
PMCID: PMC3992708  PMID: 22325335
Vitamin D; Deficiency; Surgical intensive care unit; Severe
22.  Serum vitamin E concentrations among highly functioning hip fracture patients are higher than in nonfracture controls 
Malnutrition after hip fracture is common and associated with poor outcomes and protracted recovery. Low concentrations of vitamin E have been associated with incident decline in physical function among older adults and may, therefore, be particularly important to functionally compromised patients hip fracture patients. Serum concentrations of α-tocopherol and γ-tocopherol, the 2 major forms of vitamin E, were assessed in 148 female hip fracture patients 65 years or older from the Baltimore Hip Studies cohort 4 around the time of fracture (baseline) and at 2, 6, and 12 month postfracture follow-up visits (recovery). It was hypothesized that mean concentrations of both forms of vitamin E among these hip fracture patients would be lowest at the baseline visit and increase at each study visit during the year after fracture. Linear regression and generalized estimating equations were used to assess changes in vitamin E concentrations after adjustment for covariates and to determine predictors of vitamin E concentrations at baseline and throughout recovery. It was also hypothesized that vitamin E concentrations shortly after hip fracture would be lower than those in nonfracture controls after adjustment for covariates. To evaluate this hypothesis, linear regression was used to perform adjusted comparisons of baseline vitamin E concentrations among Baltimore Hip Studies cohort 4 participants to 1076 older women without history of hip fracture from the Women’s Health and Aging Study I, Invecchiare in Chianti Study, and the National Health and Nutrition Examination Surveys. Mean α-tocopherol was lowest at baseline, and time from fracture to blood draw was positively associated with baseline α-tocopherol (P = .005). Mean γ-tocopherol did not change appreciably throughout the year after fracture, although it fluctuated widely within individuals. Serum concentrations of α-tocopherol and γ-tocopherol were highest among the hip fracture population after adjustment (P < .0001). In general, highly cognitively and physically functioning hip fracture patients demonstrated higher vitamin E concentrations. Thus, the relatively high degree of function among this cohort of hip fracture patients may explain their higher-than-expected vitamin E concentrations.
doi:10.1016/j.nutres.2011.03.005
PMCID: PMC4153436  PMID: 21481714
Vitamin E; Tocopherols; Antioxidants; Micronutrients; Hip fracture; Older women
23.  Association Between Vitamin D Status and Physical Performance: The InCHIANTI Study 
Background
Vitamin D status has been hypothesized to play a role in musculoskeletal function. Using data from the InCHIANTI study, we examined the association between vitamin D status and physical performance.
Methods
A representative sample of 976 persons aged 65 years or older at study baseline were included. Physical performance was assessed using a short physical performance battery (SPPB) and handgrip strength. Multiple linear regression was used to examine the association between vitamin D (serum 25OHD), parathyroid hormone (PTH), and physical performance adjusting for sociodemographic variables, behavioral characteristics, body mass index, season, cognition, health conditions, creatinine, hemoglobin, and albumin.
Results
Approximately 28.8% of women and 13.6% of men had vitamin D levels indicative of deficiency (serum 25OHD < 25.0 nmol/L) and 74.9% of women and 51.0% of men had vitamin D levels indicative of vitamin D insufficiency (serum 25OHD < 50.0 nmol/L). Vitamin D levels were significantly associated with SPPB score in men (β coefficient [standard error (SE)]: 0.38 [0.18], p = .04) and handgrip strength in men (2.44 [0.84], p = .004) and women (1.33 [0.53], p =.01). Men and women with serum 25OHD < 25.0 nmol/L had significantly lower SPPB scores whereas those with serum 25OHD < 50 nmol/L had significantly lower handgrip strength than those with serum 25OHD ≥25 and ≥50 nmol/L, respectively (p < .05). PTH was significantly associated with handgrip strength only (p = .01).
Conclusions
Vitamin D status was inversely associated with poor physical performance. Given the high prevalence of vitamin D deficiency in older populations, additional studies examining the association between vitamin D status and physical function are needed.
PMCID: PMC2645652  PMID: 17452740
24.  Associations of Bone Mineral Density and Lead Levels in Blood, Tibia, and Patella in Urban-Dwelling Women 
Environmental Health Perspectives  2008;116(6):784-790.
Objective
The objective of this study was to evaluate the relations between bone mineral density (BMD) and lead in blood, tibia, and patella and to investigate how BMD modifies these lead biomarkers in older women.
Design
In this study, we used cross-sectional analysis.
Participants
We studied 112 women, 50–70 years of age, including both whites and African Americans, residing in Baltimore, Maryland.
Measurements
We measured lumbar spine BMD, blood and bone lead by dual energy X-ray absorptiometry, anodic stripping voltammetry, and 109Cd-induced K-shell X-ray fluorescence, respectively. We measured vitamin D receptor and apolipoprotein E (APOE) genotypes using standard methods.
Results
Mean (± SD) BMD and lead levels in blood, tibia, and patella were 1.02 ± 0.16 g/cm2, 3.3 ± 2.2 μg/dL, 19.7 ± 13.2 μg/g, and 5.7 ± 15.3 μg/g, respectively. In adjusted analysis, higher BMD was associated with higher tibia lead levels (p = 0.03). BMD was not associated with lead levels in blood or patella. There was evidence of significant effect modification by BMD on relations of physical activity with blood lead levels and by APOE genotype on relations of BMD with tibia lead levels. There was no evidence that BMD modified relations between tibia lead or patella lead and blood lead levels.
Conclusions
We believe that BMD represents the capacity of bone that can store lead, by substitution for calcium, and thus the findings may have relevance for effect-size estimates in persons with higher BMD.
Relevance to clinical practice
The results have implications for changes in lead kinetics with aging, and thus the related risk of health effects associated with substantial early- and midlife lead exposure in older persons.
doi:10.1289/ehp.10977
PMCID: PMC2430235  PMID: 18560535
biomarkers; bone mineral density; dual energy X-ray absorptiometry; epidemiology; lead; X-ray fluorescence; women
25.  Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin 
Diabetes Care  2013;36(10):2981-2987.
OBJECTIVE
To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes.
RESEARCH DESIGN AND METHODS
Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n = 480) or mild cognitive impairment (n = 187) and those who were cognitively intact (n = 687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n = 104) or impaired glucose tolerance (n = 22).
RESULTS
Participants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]).
CONCLUSIONS
Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.
doi:10.2337/dc13-0229
PMCID: PMC3781568  PMID: 24009301

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