Effect of high-dose vitamin D supplementation on peripheral arterial calcification: secondary analysis of a randomized controlled trial


Effect of high-dose vitamin D supplementation on peripheral arterial calcification: secondary analysis of a randomized controlled trial

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Although high-dose vitamin D supplementation is common, effects on arterial calcification remain unexplored. Tibial artery calcification was identified and quantified over 3 years in participants randomized to 400, 4000, or 10,000 IU vitamin D3 daily. High-dose vitamin D supplementation did not affect the development or progression of arterial calcification.IntroductionTo determine whether vitamin D supplementation has a dose-dependent effect on development and progression of arterial calcification.Methods This was a secondary analysis of the Calgary Vitamin D Study, a 3-year, double-blind, randomized controlled trial conducted at a single-center in Calgary, Canada. Participants were community-dwelling adults aged 55–70 years with serum 25-hydroxyvitamin D 30–125 nmol/L. Participants were randomized 1:1:1 to receive vitamin D3 400, 4000, or 10,000 IU/day for 3 years. Tibial artery calcification was identified and quantified (in milligrams of hydroxyapatite, mgHA) using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6, 12, 24, and 36 months. Changes in calcification over time and treatment group interaction were evaluated using a constrained linear mixed effects model.ResultsOf 311 randomized participants, 302 (400: 105, 4000: 96, 10,000: 101) were eligible for analysis of arterial calcification (54% male, mean (SD) age 62 (4) years, mean (SD) 25-hydroxyvitamin D 78.9 (19.9) nmol/L). At baseline, 85 (28%) had tibial artery calcification, and mean (95% CI) calcification quantity was 2.8 mgHA (95% CI 1.7–3.9). In these 85 participants, calcification quantity increased linearly by 0.020 mgHA/month (95% CI 0.012–0.029) throughout the study, with no evidence of a treatment-group effect (p = 0.645 for interaction). No participants developed new arterial calcifications during the study.Conclusions In this population of community-dwelling adults who were vitamin D replete at baseline, supplementation with vitamin D 400, 4000, or 10,000 IU/day did not have differential effects on the development or progression of arterial calcification over 3 years.Trial (NCT01900860)

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... Thirty-four articles published results investigating a possible association between calcium and arterial calcification (Alagoz et al., 2014;Arad et al., 1998;Billington et al., 2020;Chen et al., 2006;Criqui et al., 2010;Foley et al., 2009;Grønhøj et al., 2016;Kim et al., 2013;Kwak et al., 2014;Liang et al., 2021;Nam et al., 2017;Nielsen et al., 2021;Park et al., 2011;Park et al., 2016;Shin et al., 2012;Tuersun et al., 2020; Tuttle and Short, 2009;Wei et al., 2020;Wu et al., 2016b;Zagura et al., 2011;Barbarash et al., 2016;Cancela et al., 2012;Chai et al., 2017;Davaine et al., 2016;Diederichsen et al., 2017;Donate-Correa et al., 2019;Golovkin et al., 2016;Liu et al., 2019;Masai et al., 2013;Pirro et al., 2013;Schlieper et al., 2010;Torii et al., 2016;Awan et al., 2010;Razavi et al., 2021). Of these studies, nine reported positive associations (Grønhøj et al., 2016;Kwak et al., 2014;Nielsen et al., 2021;Shin et al., 2012;Tuttle and Short, 2009;Zagura et al., 2011;Diederichsen et al., 2017;Golovkin et al., 2016;Awan et al., 2010) and 25 reported no significant association (Alagoz et al., 2014;Arad et al., 1998;Billington et al., 2020;Chen et al., 2006;Criqui et al., 2010;Foley et al., 2009;Kim et al., 2013;Liang et al., 2021;Nam et al., 2017;Park et al., 2011;Park et al., 2016;Tuersun et al., 2020;Wei et al., 2020;Wu et al., 2016b;Barbarash et al., 2016;Cancela et al., 2012;Chai et al., 2017;Davaine et al., 2016;Donate-Correa et al., 2019;Liu et al., 2019;Masai et al., 2013;Pirro et al., 2013;Schlieper et al., 2010;Torii et al., 2016;Razavi et al., 2021). ...
... Thirty-four articles published results investigating a possible association between calcium and arterial calcification (Alagoz et al., 2014;Arad et al., 1998;Billington et al., 2020;Chen et al., 2006;Criqui et al., 2010;Foley et al., 2009;Grønhøj et al., 2016;Kim et al., 2013;Kwak et al., 2014;Liang et al., 2021;Nam et al., 2017;Nielsen et al., 2021;Park et al., 2011;Park et al., 2016;Shin et al., 2012;Tuersun et al., 2020; Tuttle and Short, 2009;Wei et al., 2020;Wu et al., 2016b;Zagura et al., 2011;Barbarash et al., 2016;Cancela et al., 2012;Chai et al., 2017;Davaine et al., 2016;Diederichsen et al., 2017;Donate-Correa et al., 2019;Golovkin et al., 2016;Liu et al., 2019;Masai et al., 2013;Pirro et al., 2013;Schlieper et al., 2010;Torii et al., 2016;Awan et al., 2010;Razavi et al., 2021). Of these studies, nine reported positive associations (Grønhøj et al., 2016;Kwak et al., 2014;Nielsen et al., 2021;Shin et al., 2012;Tuttle and Short, 2009;Zagura et al., 2011;Diederichsen et al., 2017;Golovkin et al., 2016;Awan et al., 2010) and 25 reported no significant association (Alagoz et al., 2014;Arad et al., 1998;Billington et al., 2020;Chen et al., 2006;Criqui et al., 2010;Foley et al., 2009;Kim et al., 2013;Liang et al., 2021;Nam et al., 2017;Park et al., 2011;Park et al., 2016;Tuersun et al., 2020;Wei et al., 2020;Wu et al., 2016b;Barbarash et al., 2016;Cancela et al., 2012;Chai et al., 2017;Davaine et al., 2016;Donate-Correa et al., 2019;Liu et al., 2019;Masai et al., 2013;Pirro et al., 2013;Schlieper et al., 2010;Torii et al., 2016;Razavi et al., 2021). Five studies were longitudinal, of which one showed a positive association (Arad et al., 1998;Foley et al., 2009;Tuttle and Short, 2009;Diederichsen et al., 2017;Liu et al., 2019). ...
... Thirty-five studies investigated a possible association between phosphate and arterial calcification (Alagoz et al., 2014;Billington et al., 2020;Chen et al., 2006;Criqui et al., 2010;Foley et al., 2009;Grønhøj et al., 2016;Kim et al., 2013;Kwak et al., 2014;Liang et al., 2021;Nam et al., 2017;Nielsen et al., 2021;Park et al., 2011;Park et al., 2016;Shin et al., 2012;Tuersun et al., 2020;Tuttle and Short, 2009;Wei et al., 2020;Wu et al., 2016b;Barbarash et al., 2016;Cancela et al., 2012;Chai et al., 2017;Diederichsen et al., 2017;Donate-Correa et al., 2019;Golovkin et al., 2016;Liu et al., 2019;Masai et al., 2013;Pirro et al., 2013;Schlieper et al., 2010;Torii et al., 2016;Awan et al., 2010;Razavi et al., 2021;Martín-Reys et al., 2016;Barbarash et al., 2019;McPherson et al., 2012;Park et al., 2020). Of these studies, fourteen reported a significant positive association (Foley et al., 2009;Kim et al., 2013;Kwak et al., 2014;Park et al., 2011;Park et al., 2016;Shin et al., 2012;Tuersun et al., 2020;Tuttle and Short, 2009;Cancela et al., 2012;Diederichsen et al., 2017;Barbarash et al., 2019;McPherson et al., 2012;Park et al., 2020), three a negative association (Chen et al., 2006;Kim et al., 2013;Razavi et al., 2021) and twenty no significant association (Alagoz et al., 2014;Billington et al., 2020;Criqui et al., 2010;Grønhøj et al., 2016;Liang et al., 2021;Nam et al., 2017;Nielsen et al., 2021;Wei et al., 2020;Wu et al., 2016b;Barbarash et al., 2016;Chai et al., 2017;Donate-Correa et al., 2019;Golovkin et al., 2016;Liu et al., 2019;Masai et al., 2013;Pirro et al., 2013;Schlieper et al., 2010;Torii et al., 2016;Awan et al., 2010;Martín-Reys et al., 2016). ...
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Aim To clarify the role of mediators of ectopic mineralization as biomarkers for arterial calcifications. Methods MEDLINE and Embase were searched for relevant literature, until January 4th 2022. The investigated biomarkers were: calcium, phosphate, parathyroid hormone, vitamin D, pyrophosphate, osteoprotegerin, receptor activator of nuclear factor-kappa B ligand (RANKL), fibroblast growth factor-23 (FGF-23), Klotho, osteopontin, osteocalcin, Matrix Gla protein (MGP) and its inactive forms and vitamin K. Studies solely performed in patients with kidney insufficiency or diabetes mellitus were excluded. Results After screening of 8985 articles, a total of 129 articles were included in this systematic review. For all biomarkers included in this review, the results were variable and more than half of the studies for each specific biomarker had a non-significant result. Also, the overall quality of the included studies was low, partly as a result of the mostly cross-sectional study designs. The largest body of evidence is available for phosphate, osteopontin and FGF-23, as a little over half of the studies showed a significant, positive association. Firm statements for these biomarkers cannot be drawn, as the number of studies was limited and hampered by residual confounding or had non-significant results. The associations of the other mediators of ectopic mineralization with arterial calcifications were not clear. Conclusion Associations between biomarkers of ectopic mineralization and arterial calcification are variable in the published literature. Future longitudinal studies differentiating medial and intimal calcification could add to the knowledge of biomarkers and mechanisms of arterial calcifications.
Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration <30 nmol/l) should be corrected, whereas most guidelines recommend serum 25OHD concentrations of >50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected.
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Importance Few studies have assessed the effects of daily vitamin D doses at or above the tolerable upper intake level for 12 months or greater, yet 3% of US adults report vitamin D intakes of at least 4000 IU per day. Objective To assess the dose-dependent effect of vitamin D supplementation on volumetric bone mineral density (BMD) and strength. Design, Setting, and Participants Three-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017, including 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L. Interventions Daily doses of vitamin D3 for 3 years at 400 IU (n = 109), 4000 IU (n = 100), or 10 000 IU (n = 102). Calcium supplementation was provided to participants with dietary intake of less than 1200 mg per day. Main Outcomes and Measures Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis. Results Of 311 participants who were randomized (53% men; mean [SD] age, 62.2 [4.2] years), 287 (92%) completed the study. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10 000-IU group. There were significant group × time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (−3.9 mg HA/cm³ [95% CI, −6.5 to −1.3]) and 10 000 IU group (−7.5 mg HA/cm³ [95% CI, −10.1 to −5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of −1.2% (400 IU group), −2.4% (4000 IU group), and −3.5% (10 000 IU group). Tibial volumetric BMD differences from the 400 IU group were −1.8 mg HA/cm³ (95% CI, −3.7 to 0.1) in the 4000 IU group and −4.1 mg HA/cm³ in the 10 000 IU group (95% CI, −6.0 to −2.2), with mean percent change values of −0.4% (400 IU), −1.0% (4000 IU), and −1.7% (10 000 IU). There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12). Conclusions and Relevance Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful. Trial Registration Identifier: NCT01900860
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Since 2000, there has been an increase in research on possible health benefits of vitamin D. However, a 2011 Institute of Medicine (IOM; now the National Academy of Medicine) report concluded that vitamin D was beneficial for bone health but evidence was insufficient for extraskeletal health.¹ Several large-scale trials are ongoing to evaluate the effect of vitamin D supplementation on extraskeletal outcomes.² The IOM report noted possible harm (eg, hypercalcemia, soft tissue or vascular calcification) for intakes above the tolerable upper limit, which is the highest level of intake likely to pose no risk of adverse effects for most adults.
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Background: Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods: We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings: Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation: At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Funding: Bill & Melinda Gates Foundation.
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Introduction: Here, we report the relationships of bone geometry, volumetric bone mineral density (BMD) and bone microarchitecture with lower leg arterial calcification (LLAC) as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods: We utilized the Hertfordshire Cohort Study (HCS), where we were able to study associations between measures obtained from HR-pQCT of the distal radius and distal tibia in 341 participants with or without LLAC. Statistical analyses were performed separately for women and men. We used linear regression models to investigate the cross-sectional relationships between LLAC and bone parameters. Results: The mean (SD) age of participants was 76.4 (2.6) and 76.1 (2.5) years in women and men, respectively. One hundred and eleven of 341 participants (32.6 %) had LLAC that were visible and quantifiable by HR-pQCT. The prevalence of LLAC was higher in men than in women (46.4 % (n = 83) vs. 17.3 % (n = 28), p < 0.001). After adjustment for confounding factors, we found that women with LLAC had substantially lower Ct.area (β = -0.33, p = 0.016), lower Tb.N (β = -0.54, p = 0.013) and higher Tb.Sp (β = 0.54, p = 0.012) at the distal tibia and lower Tb.Th (β = -0.49, p = 0.027) at the distal radius compared with participants without LLAC. Distal radial or tibial bone parameter analyses in men according to their LLAC status revealed no significant differences with the exception of Tb.N (β = 0.27, p = 0.035) at the distal tibia. Conclusion: In the HCS, the presence of LLAC assessed by HR-pQCT was associated with relevant bone microstructure abnormalities in women. These findings need to be replicated and further research should study possible pathophysiological links between vascular calcification and osteoporosis.
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The transdifferentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells has been implicated in the context of vascular calcification. We investigated the roles of vitamin D receptor (Vdr) and runt-related transcription factor 2 (Runx2) in the osteoblastic differentiation of VSMCs in response to vitamin D3 using in vitro VSMCs cultures and in vivo in Vdr knockout (Vdr (-/-) ) and Runx2 carboxy-terminus truncated heterozygous (Runx2 (+/ΔC) ) mice. Treatment of VSMCs with active vitamin D3 promoted matrix mineral deposition, and increased the expressions of Vdr, Runx2, and of osteoblastic genes but decreased the expression of smooth muscle myosin heavy chain in primary VSMCs cultures. Immunoprecipitation experiments suggested an interaction between Vdr and Runx2. Furthermore, silencing Vdr or Runx2 attenuated the procalcific effects of vitamin D3. Functional cooperation between Vdr and Runx2 in vascular calcification was also confirmed in in vivo mouse models. Vascular calcification induced by high-dose vitamin D3 was completely inhibited in Vdr (-/-) or Runx2 (+/ΔC) mice, despite elevated levels of serum calcium or alkaline phosphatase. Collectively, these findings suggest that functional cooperation between Vdr and Runx2 is necessary for vascular calcification in response to vitamin D3.
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Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium.Kidney International advance online publication, 29 August 2012; doi:10.1038/ki.2012.322.
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The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation more accurately estimates glomerular filtration rate (GFR) than the Modification of Diet in Renal Disease (MDRD) Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking. To evaluate risk implications of estimated GFR using the CKD-EPI equation compared with the MDRD Study equation in populations with a broad range of demographic and clinical characteristics. A meta-analysis of data from 1.1 million adults (aged ≥ 18 years) from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts. Data transfer and analyses were conducted between March 2011 and March 2012. All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years). Estimated GFR was classified into 6 categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m(2)) by both equations. Compared with the MDRD Study equation, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR <60 mL/min/1.73 m(2)) was reduced from 8.7% to 6.3%. In estimated GFR of 45 to 59 mL/min/1.73 m(2) by the MDRD Study equation, 34.7% of participants were reclassified to estimated GFR of 60 to 89 mL/min/1.73 m(2) by the CKD-EPI equation and had lower incidence rates (per 1000 person-years) for the outcomes of interest (9.9 vs 34.5 for all-cause mortality, 2.7 vs 13.0 for cardiovascular mortality, and 0.5 vs 0.8 for ESRD) compared with those not reclassified. The corresponding adjusted hazard ratios were 0.80 (95% CI, 0.74-0.86) for all-cause mortality, 0.73 (95% CI, 0.65-0.82) for cardiovascular mortality, and 0.49 (95% CI, 0.27-0.88) for ESRD. Similar findings were observed in other estimated GFR categories by the MDRD Study equation. Net reclassification improvement based on estimated GFR categories was significantly positive for all outcomes (range, 0.06-0.13; all P < .001). Net reclassification improvement was similarly positive in most subgroups defined by age (<65 years and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in the high-risk and CKD cohorts were largely consistent with the general population cohorts. The CKD-EPI equation classified fewer individuals as having CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.
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Low levels of 25-hydroxy vitamin D (25(OH)D) are associated with cardiovascular diseases. Herein, we tested the hypothesis that vitamin D deficiency could be a causal factor in atherosclerotic vascular changes and vascular calcification. Aortic root sections of vitamin D receptor knockout (VDR(-/-)) mice that were stained for vascular calcification and immunostained for osteoblastic differentiation factors showed more calcified areas and a higher expression of the osteogenic key factors Msx2, Bmp2, and Runx2 than the wild-type mice (P<0.01). Data from LDL receptor knockout (LDLR(-/-)) mice that were fed western diet with either low (50 IU/kg), recommended (1,000 IU/kg), or high (10,000 IU/kg) amounts of vitamin D(3) over 16 weeks revealed increasing plasma concentrations of 25(OH)D (P<0.001) with increasing intake of vitamin D, whereas levels of calcium and phosphorus in plasma and femur were not influenced by the dietary treatment. Mice treated with the low vitamin D diet had more calcified lesions and a higher expression of Msx2, Bmp2, and Runx2 in aortic roots than mice fed recommended or high amounts of vitamin D (P<0.001). Taken together, these findings indicate vitamin D deficiency as a risk factor for aortic valve and aortic vessel calcification and a stimulator of osteogenic key factor expression in these vascular areas.
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Vascular calcification is a highly regulated process. Tumor necrosis factor-α (TNF-α) has been shown to accelerate the highly regulated osteogenic process in vascular smooth muscle cells (VSMCs). Vitamin D receptor activators (VDRAs) have been associated with beneficial cardiovascular outcomes in patients with chronic kidney disease. We examined whether maxacalcitol, a vitamin D(3) analog, exhibits a suppressive effect on VSMC mineralization induced by phosphate and TNF-α. Human VSMCs were treated with either vehicle, maxacalcitol (10(-9) to 10(-7) M), or calcitriol (10(-9) to 10(-7) M) in 2.5 mM of phosphate media with TNF-α (1 ng/mL) for 9 days. VSMC mineralization was determined and expression of genes associated with the osteogenic process was examined by real-time reverse transcription-polymerase chain reaction. Expression of matrix metalloproteinase-2 (MMP-2) messenger RNA (mRNA) in VSMCs and MMP-2 protein in media was also analyzed. Vehicle-treated VSMCs exhibited massive mineralization, which was inhibited by maxacalcitol in a concentration-dependent manner. Calcitriol also inhibited the mineralization. While vehicle-treated VSMCs exhibited increased mRNA expression of genes associated with the osteogenic process (Cbfa1/Runx2 and osteocalcin) compared with VSMCs grown in normal media without TNF-α (control), maxacalcitol and calcitriol suppressed the increase in mRNA species. Furthermore, vehicle-treated VSMCs exhibited increased MMP-2 mRNA and protein in the media that were suppressed notably by maxacalcitol. Both the VDRAs abrogated the acceleration of the osteogenic process induced by phosphate and TNF-α in VSMCs, which was linked to inhibition of mineralization in VSMCs. MMP-2 blockade by VDRAs may contribute to an inhibitory effect on vascular calcification.
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In this observational study, we found a positive relationship between low calcidiol levels and the risk of aortic calcification progression. A 10-ng/mL increase of calcidiol was associated with a decrease in the risk of progression by 44%. This figure was higher than that observed if we increased age by 10 years. The aim of this study was to investigate the relationship between serum calcidiol levels and the onset and progression of aortic calcifications in a community-based sample of ambulatory subjects. Three hundred two men and women aged 50 and over underwent two lateral X-rays and were followed up for 4 years. Abdominal aortic calcifications were classified as absent, mild-moderate, and severe. The biochemical measurements of serum calcium, phosphorus, parathyroid hormone, total alkaline phosphatase, tartrate-resistant acid phosphatase, creatinine, calcidiol, calcitriol, and osteocalcin were determined. Subjects who had received anti-osteoporotic treatments were excluded from the analysis. Subjects with progression of aortic calcifications had significantly lower serum calcidiol levels than those without progression. In the multivariate analysis, using the agreed upon serum levels for calcidiol (>30 ng/mL) as the reference, those subjects with calcidiol levels between 10 and 20 ng/mL showed a higher risk of progression of aortic calcification (odds ratio (OR) = 3.95; 95% confidence interval (CI) = 1.16 to 13.40). An even higher OR was observed in subjects with calcidiol values <10 ng/mL (OR = 4.10; 95% CI = 1.12 to 14.99). In addition, an increase by 1 ng/mL in osteocalcin levels was associated with a 17% reduction of the risk of aortic calcification progression. An increase by 10 ng/mL of calcidiol was associated with a decrease in the risk of aortic calcifications progression by 44%. This figure was even higher than that observed if we increased age by 10 years. Levels of calcidiol higher than 30 ng/mL seem to be desirable to reduce the progression of aortic calcification and to maintain bone turnover.
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Our objective in this study was to estimate calcium intakes from food, water, dietary supplements, and antacids for U.S. citizens aged >or=1 y using NHANES 2003-2006 data and the Dietary Reference Intake panel age groupings. Similar estimates were calculated for vitamin D intake from food and dietary supplements using NHANES 2005-2006. Diet was assessed with 2 24-h recalls; dietary supplement and antacid use were determined by questionnaire. The National Cancer Institute method was used to estimate usual nutrient intake from dietary sources. The mean daily nutrient intake from supplemental sources was added to the adjusted dietary intake estimates to produce total usual nutrient intakes for calcium and vitamin D. A total of 53% of the U.S. population reported using any dietary supplement (2003-2006), 43% used calcium (2003-2006), and 37% used vitamin D (2005-2006). For users, dietary supplements provided the adequate intake (AI) recommendation for calcium intake for approximately 12% of those >or=71 y. Males and females aged 1-3 y had the highest prevalence of meeting the AI from dietary and total calcium intakes. For total vitamin D intake, males and females >or=71, and females 14-18 y had the lowest prevalence of meeting the AI. Dietary supplement use is associated with higher prevalence of groups meeting the AI for calcium and vitamin D. Monitoring usual total nutrient intake is necessary to adequately characterize and evaluate the population's nutritional status and adherence to recommendations for nutrient intake.
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Several imaging techniques may reveal calcification of the arterial wall or cardiac valves. Many studies indicate that the risk for cardiovascular disease is increased when calcification is present. Recent meta-analyses on coronary calcification and cardiovascular risk may be confounded by indication. Therefore, this meta-analysis was performed with extensive subgroup analysis to assess the overall cardiovascular risk of finding calcification in any arterial wall or cardiac valve when using different imaging techniques. A meta-analysis of prospective studies reporting calcifications and cardiovascular end-points was performed. Thirty articles were selected. The overall odds ratios (95% confidence interval [CI]) for calcifications versus no calcifications in 218,080 subjects after a mean follow-up of 10.1 years amounted to 4.62 (CI 2.24 to 9.53) for all cause mortality, 3.94 (CI 2.39 to 6.50) for cardiovascular mortality, 3.74 (CI 2.56 to 5.45) for coronary events, 2.21 (CI 1.81 to 2.69) for stroke, and 3.41 (CI 2.71 to 4.30) for any cardiovascular event. Heterogeneity was largely explained by length of follow up and sort of imaging technique. Subgroup analysis of patients with end stage renal disease revealed a much higher odds ratio for any event of 6.22 (CI 2.73 to 14.14). The presence of calcification in any arterial wall is associated with a 3-4-fold higher risk for mortality and cardiovascular events. Interpretation of the pooled estimates has to be done with caution because of heterogeneity across studies.
Context Over 3% of adults report vitamin D intakes ≥4000 IU/day, but the safety of this practice is unknown. Objective To establish whether vitamin D doses up to 10000 IU/day are safe and well-tolerated. Design The Calgary Vitamin D Study was a three-year double-blind RCT. Setting Single-centre study at the University of Calgary, Canada. Participants Healthy adults (n=373) aged 55-70 with serum 25-hydroxyvitamin D 30-125 nmol/L. Interventions Participants were randomized 1:1:1 to vitamin D3 400, 40000 or 10000 IU/day. Calcium supplementation was initiated if dietary calcium intake was <1200mg/day. Main Outcome Measures In these pre-specified secondary analyses, changes in serum 25-hydroxyvitamin D, calcium, creatinine, 24-hour urine calcium excretion, and incidence of adverse events were assessed. Between-group differences in adverse events were examined using incident rate differences and logistic regression. Results Of 373 participants (400:124, 4000:125, 10000:124), 49% were male, mean (SD) age was 64 (4) years, and 25-hydroxyvitamin D 78.0 (19.5) nmol/L. Serum calcium, creatinine, and 24-hour urine calcium excretion did not differ between treatments. Mild hypercalcemia (2.56-2.64 mmol/L) occurred in 15 (4%) participants (400:0%, 4000:3%, 10000:9%, p=0.002); all cases resolved on repeat testing. Hypercalciuria occurred in 87 (23%) participants (400:17%, 4000:22%, 10000:31%, p=0.011). Clinical adverse events were experienced by 365 (97.9%) participants and were balanced across treatment arms. Conclusions The safety profile of vitamin D supplementation is similar for doses of 400, 4000 and 10000 IU/day. Hypercalciuria was common and occurred more frequently with higher doses. Hypercalcemia occurred more frequently with higher doses but was rare, mild, and transient.
Importance Observational studies have reported an association between low serum vitamin D levels and elevated risk of cardiovascular disease (CVD) events, but such studies cannot prove causation because of possible unmeasured confounding. Objective We conducted a meta-analysis of randomized clinical trials that tested the association of vitamin D supplementation with reduced CVD events and all-cause mortality. Data Sources Literature search through PubMed, the Cochrane Library, and Embase was completed by 2 reviewers from each database’s inception to December 15, 2018. Study Selection Inclusion criteria were randomized clinical trials that reported the effect of long-term (≥1 year) vitamin D supplementation on CVD events and all-cause mortality. Studies that did not include cardiovascular outcomes were excluded. Data Extraction and Synthesis Data were abstracted independently by 2 authors. Random-effects models were used to report the risk ratios (RRs) and 95% CIs. Main Outcomes and Measures Major adverse cardiovascular events was the primary outcome, and rates of myocardial infarction, stroke or cerebrovascular accident, CVD mortality, and all-cause mortality were the secondary end points. Results Twenty-one randomized clinical trials were included (including 83 291 patients, of whom 41 669 received vitamin D and 41 622 received placebos). The mean (SD) age of trial participants was 65.8 (8.4) years; 61 943 (74.4%) were female. Only 4 trials had prespecified CVD as a primary end point. Vitamin D supplementation compared with placebo was not associated with reduced major adverse cardiovascular events (RR, 1.00 [95% CI, 0.95-1.06]; P = .85) nor the secondary end points of myocardial infarction (RR, 1.00 [95% CI, 0.93-1.08]; P = .92), stroke (RR, 1.06 [95% CI, 0.98-1.15]; P = .16), CVD mortality (RR, 0.98 [95% CI, 0.90-1.07]; P = .68), or all-cause mortality (RR, 0.97 [95% CI, 0.93-1.02]; P = .23). Results were generally consistent by sex, baseline 25-hydroxyvitamin D level, vitamin D dosage, formulation (daily vs bolus dosing), and presence or absence of concurrent calcium administration. Conclusions and Relevance In this updated meta-analysis, vitamin D supplementation was not associated with reduced major adverse cardiovascular events, individual CVD end points (myocardial infarction, stroke, CVD mortality), or all-cause mortality. The findings suggest that vitamin D supplementation does not confer cardiovascular protection and is not indicated for this purpose.
Background: Although areal bone mineral density (aBMD) assessed by dual-energy x-ray absorptiometry (DXA) is the clinical standard for determining fracture risk, most older adults who sustain a fracture have T scores greater than -2·5 and thus do not meet the clinical criteria for osteoporosis. Importantly, bone fragility is due to low BMD and deterioration in bone structure. We assessed whether indices of high-resolution peripheral quantitative CT (HR-pQCT) were associated with fracture risk independently of femoral neck aBMD and the Fracture Risk Assessment Tool (FRAX) score. Methods: We assessed participants in eight cohorts from the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazard ratios (HRs) to estimate the association between HR-pQCT bone indices (per 1 SD of deficit) and incident fracture, adjusting for age, sex, height, weight, and cohort, and then additionally for femoral neck DXA aBMD or FRAX. Findings: 7254 individuals (66% women and 34% men) were assessed. Mean baseline age was 69 years (SD 9, range 40-96). Over a mean follow-up of 4·63 years (SD 2·41) years, 765 (11%) participants had incident fractures, of whom 633 (86%) had femoral neck T scores greater than -2·5. After adjustment for age, sex, cohort, height, and weight, peripheral skeleton failure load had the greatest association with risk of fracture: tibia HR 2·40 (95% CI 1·98-2·91) and radius 2·13 (1·77-2·56) per 1 SD decrease. HRs for other bone indices ranged from 1·12 (95% CI 1·03-1·23) per 1 SD increase in tibia cortical porosity to 1·58 (1·45-1·72) per 1 SD decrease in radius trabecular volumetric bone density. After further adjustment for femoral neck aBMD or FRAX score, the associations were reduced but remained significant for most bone parameters. A model including cortical volumetric bone density, trabecular number, and trabecular thickness at the distal radius and a model including these indices plus cortical area at the tibia were the best predictors of fracture. Interpretation: HR-pQCT indices and failure load improved prediction of fracture beyond femoral neck aBMD or FRAX scores alone. Our findings from a large international cohort of men and women support previous reports that deficits in trabecular and cortical bone density and structure independently contribute to fracture risk. These measurements and morphological assessment of the peripheral skeleton might improve identification of people at the highest risk of fracture. Funding: National Institutes of Health National Institute of Arthritis Musculoskeletal and Skin Diseases.
Background It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited. Methods We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n−3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo. Results A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified. Conclusions Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL number, NCT01169259.)
The optimum dose of vitamin D and corresponding serum 25-hydroxyvitamin D (25OHD) concentration for bone health is still debated and some health practitioners are recommending doses well above the Canada/USA recommended Dietary Reference Intake (DRI). We designed a three-year randomized double-blind clinical trial investigating whether there are dose-dependent effects of vitamin D supplementation above the Dietary Reference Intake (DRI) on bone health. The primary aims of this study are to assess, whether supplementation of vitamin D3increases 1) volumetric bone mineral density measured by high-resolution peripheral quantitative computed tomography (HR-pQCT); 2) bone strength assessed by finite element analysis, and 3) areal bone mineral density by dual X-ray absorptiometry (DXA). Secondary aims are to understand whether vitamin D3supplementation improves parameters of bone microarchitecture, balance, physical function and quality of life. Participants are men and women aged 55-70 years, with women at least 5-years post-menopause. The intervention is daily vitamin D3supplementation doses of 400, 4000 or 10,000 IU. Participants not achieving adequate dietary calcium intake are provided with calcium supplementation, up to a maximum supplemental dose of 600 mg elemental calcium per day. Results from this three-year study will provide evidence whether daily vitamin D3supplementation with adequate calcium intake can affect bone density, bone microarchitecture and bone strength in men and women. Furthermore, the safety of high dose daily vitamin D3supplementation will be explored.
Importance: Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D. Objective: To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population. Design, setting, and participants: The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis. Interventions: Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years). Main outcomes and measures: The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis. Results: Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes. Conclusions and relevance: Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study. Trial registration: Identifier: ACTRN12611000402943.
Vitamin D has an important role in bone metabolism and may be involved in the process of vascular calcification. The objective of this study was to evaluate the effect of vitamin D status on the presence of abdominal aortic calcification (AAC). We enrolled, in a cross-sectional study, 429 postmenopausal women [mean age, weight, and BMI of 59.5???8.3 (50-83) years, 75.8???13.3 (35-165) kg, and 29.9???5.2 (14.6-50.8) kg/m(2), respectively]. Lateral vertebral fracture assessment (VFA) images and scans of the lumbar spine and proximal femur were obtained using a Lunar Prodigy densitometer. Vertebral fractures (VFs) were defined using the Genant semiquantitative (SQ) approach. We used the Kauppila score to assess AAC extension. Clinical risk factors of osteoporosis were collected, and 25-hydroxy vitamin D was measured using electrochemiluminescence (Roche). Prevalence of osteoporosis and hypovitaminosis D (<20?ng/ml) was 21.0% and 78.1%, respectively. VFs grade 2/3 were identified in 76 patients (17.7%). Two thirds of the evaluable participants did not have any detectable AAC. The prevalence of significant atherosclerotic burden, defined as a radiographic 24-point AAC score of 5 or higher, was 7.9%. The group of women with extended AAC were older and had a statistically significant higher menopause duration and more prevalent grade 2/3 VFs. Compared to women with normal values of vitamin D, women with vitamin D insufficiency (<20?ng/ml) and deficiency (<10?ng/ml) had a lower BMD and more prevalent VFs. No difference was noted with regard to AAC among the three groups. Multiple stepwise conditional logistic regression analysis showed that the presence of AAC was associated significantly with age and the presence of VFs. Extended aortic calcifications are independently associated with prevalent VFA-identified VFs but not with serum vitamin D levels in postmenopausal women. VFA imaging using DXA may detect at the same time prevalent VFs and AAC, an important cardiovascular disease risk factor.
An increasing evidence base suggests that low bone mineral density (BMD) and fractures are associated with cardiovascular disease (CVD). We conducted a systematic review and meta-analysis summarizing the evidence of low BMD and fractures as risk factors for future CVD. Two independent authors searched major databases from inception to 1st August 2016 for longitudinal studies reporting data on CVD incidence (overall and specific CVD) and BMD status and fractures. The association between low BMD, fractures and CVD across longitudinal studies was explored by calculating pooled adjusted hazard ratios (HRs) ± 95% confidence intervals (CIs) with a random-effects meta-analysis. Twenty-eight studies (18 regarding BMD and 10 fractures) followed-up a total of 1,107,885 participants for a median of 5 years. Taking those with higher BMD as the reference, people with low BMD were at increased risk of developing CVD during follow-up (11 studies; HR = 1.33; 95%CI: 1.27-1.38; I2 = 53%), after adjusting for a median of 8 confounders. This finding was confirmed using a decrease in one standard deviation of baseline BMD (9 studies; HR = 1.16; 95%CI: 1.09-1.24; I2 = 69%). The presence of fractures at baseline was associated with an increased risk of developing CVD (HR = 1.20; 95%CI: 1.06-1.37; I2 = 91%). Regarding specific CVD, low BMD was associated with an increased risk of developing coronary artery disease, cerebrovascular conditions, and CVD associated death. Fractures at baseline was associated with an increased risk of cerebrovascular conditions and death due to CVD. In conclusion, low BMD and fractures are associated with a small, but significant increased risk of CVD risk and possibly death.
Objective: Although a significant positive association of vitamin D deficiency with coronary heart disease has been demonstrated in cross-sectional as well as prospective studies, only a few studies have examined the association of vitamin D deficiency with subclinical atherosclerosis. We examined whether vitamin D deficiency is associated with subclinical atherosclerosis, as measured by coronary artery calcification (CAC) in asymptomatic adults. Methods: In a population-based cross-sectional study, 195 men aged 40 to 49 years without cardiovascular disease were randomly selected (98 Caucasian and 97 Japanese American men). Liquid chromatography-tandem mass spectrometry was utilized to measure serum vitamin D. CAC was examined by electron beam computed tomography using standardized protocols and read centrally at the University of Pittsburgh using Agatston's methods. To investigate an association between vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL) and CAC (defined as Agatston score ≥ 10), we utilized multivariable logistic regression models. Results: Prevalence of CAC and vitamin D deficiency was 27.2% and 10.3%, respectively. Participants with CAC were significantly older, had significantly higher body mass index (BMI), and had higher rates of smoking. Those with CAC were 3.31 times likely to be vitamin D deficient, after adjusting for traditional cardiovascular risk factors (odds ratio [OR] = 3.31, 95% confidence interval [CI], 1.12-9.77). Conclusions: In this population-based study of healthy middle-aged men, vitamin D deficiency had a significant positive association with the presence of CAC.
In men and women, there is a significant association between the risk of cardiovascular event (myocardial infarction, stroke) and risk of major fragility fracture (hip, vertebra). Abdominal aortic calcification (AAC) can be assessed using semiquantitative scores on spine radiographs and spine scans obtained by DXA. Severe AAC is associated with higher risk of major cardiovascular event. Not only does severe AAC reflect poor cardiovascular health status, but also directly disturbs blood flow in the vascular system. Severe (but not mild or moderate) AAC is associated with lower bone mineral density (BMD), faster bone loss and higher risk of major fragility fracture. The fracture risk remains increased after adjustment for BMD and other potential risk factors. The association between severe AAC and fracture risk was found in both sexes, mainly in the follow-ups of less than 10 years. Many factors contribute to initiation and progression of AAC: lifestyle, co-morbidities, inorganic ions, dyslipidemia, hormones, cytokines (e.g. inflammatory cytokines, RANKL), matrix vesicles, microRNAs, structural proteins (e.g. elastin), vitamin K-dependent proteins, medications (e.g. vitamin K antagonists). Osteogenic transdifferentiation of vascular smooth muscle cells (VSMC) and circulating osteoprogenitors penetrating into vascular wall plays a major role in the AAC initiation and progression. Vitamin K-dependent proteins protect vascular tunica media against formation of calcified deposits (matrix GLA protein, GLA-rich protein) and against VSMC apoptosis (Gas6). Further studies are needed to investigate clinical utility of AAC for the assessment of fracture and cardiovascular risk at the individual level and develop new medications permitting to prevent AAC progression.
It is unclear whether low vitamin D is a significant risk factor for the presence of either calcific atherosclerosis or obstructive coronary artery stenoses. In this study, we measured the 25-OH vitamin D levels of 1131 consecutive individuals who underwent coronary artery calcium (CAC) scoring and coronary computed tomographic angiography at our institution. We looked for any association of 25-OH vitamin D levels with CAC scores. We also studied the relation of 25-OH vitamin D levels with the presence of 70% or more obstructive coronary artery stenoses, found initially by coronary computed tomographic angiography and confirmed subsequently by invasive angiography. There were 132 (11.7%) 25-OH vitamin D deficient (<20 ng/ml) and 295 (26.1%) 25-OH vitamin D insufficient (21-29 ng/ml) individuals in this study. There was no detectable association between 25-OH vitamin D levels and CAC scores. The median (interquartile range) CAC score of 25-OH vitamin D deficient, insufficient, and adequate patients was 451 (80-1083), 338 (52-830), and 450 (100-1062), respectively. Also, no relation was noted between 25-OH vitamin D levels and the presence of severely obstructive coronary artery disease. The frequency of severe coronary artery disease in 25-OH vitamin D deficient, insufficient, and adequate patients was 3.8, 2.0, and 4.0%, respectively. Low 25-OH vitamin D levels were not associated with CAC or severely obstructive stenoses.
The cardiovascular risk factors that contribute to coronary calcification have been extensively studied while those related to tibial artery calcium are less well defined. We sought to determine the associations between cardiovascular risk factors and tibial artery calcification in a cohort of patients with and without significant peripheral atherosclerosis. A total of 222 patients without end-stage renal disease were identified in a prospectively maintained database containing tibial artery calcification (TAC) scores, and demographic, cardiovascular, and biochemical risk factor information. Patients with prevalent tibial artery calcification were more likely to be older, male, and have a history positive for hypertension, hyperlipidemia, diabetes, and tobacco use. Patients with an abnormal ankle-brachial index (ABI) or symptoms of peripheral artery disease (PAD) were also more likely to have higher calcium values. In analyses using multivariable logistic regression, age, gender, diabetes, and tobacco use maintained their association with prevalent tibial calcification while hypertension, hyperlipidemia and body mass index did not. These associations remained when PAD was added to the model. After adjusting for relevant cardiovascular risk factors, we found that only an abnormal ABI, current PAD symptoms, and lower serum calcium values were associated with the presence of tibial artery calcification. In conclusion, in patients without end-stage renal disease, tibial artery calcification has risk factors that are similar but not identical to those for coronary artery calcification and peripheral atherosclerosis. © The Author(s) 2015.
Vascular calcifications and bone health seem to be etiologically linked via common risk factors such as aging and subclinical chronic inflammation. Epidemiologic studies have shown significant associations between low bone mineral density (BMD), fragility fractures and calcifications of the coronary arteries and the abdominal aorta. In the last decade, high-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as in-vivo research tool for the assessment of peripheral bone geometry, density, and microarchitecture. Although vascular calcifications are frequently observed as incidental findings in HR-pQCT scans, they have not yet been incorporated into quantitative HR-pQCT analyses. We developed a semi-automated algorithm to quantify lower leg arterial calcifications (LLACs), captured by HR-pQCT. The objective of our study was to determine validity and reliability of the LLAC measure.
The aim of this study was to investigate the relationship between aortic calcification (AC) and low bone mineral density (BMD), 25(OH)D, C-terminal telopeptide (CTx), and osteocalcin levels in Asian women. We also tried to find the association between AC and the risk of vertebral fracture. We included 769 patients in this study. All patients underwent QCT. Aortic calcium score (ACS) was quantified by the Agatston scoring method. Spinal fracture was defined by lumbar spine radiography. Among 769 subjects, 96 had at least one vertebral fracture and 345 had AC. ACS positively correlated with age. Osteocalcin, CTx, 25(OH)D, total-hip trabecular BMD (tBMD), femoral neck tBMD, and vertebral tBMD were inversely related with ACS. However, cortical BMD (cBMD) did not correlate with ACS. Among these parameters, only osteocalcin significantly correlated with ACS, even after adjusting for age. We divided the subjects into two groups based on the presence of AC to determine the association between AC and vertebral fracture. Multivariate logistic regression analysis showed that age, tBMD of each site, and AC were associated with vertebral fractures. After adjusting for confounding factors, patients with AC had more than a threefold increased risk of vertebral fracture (OR = 3.29-3.57, P < 0.05 according to site). This study suggests that high ACS is related to low tBMD but not cBMD. Furthermore, our findings indicate that this relationship is definitely age-dependent. Finally, we found that AC is significantly associated with the prevalence of vertebral fracture in Asian women.
: In subtotally nephrectomized rats, we studied to what extent high-dose calcitriol-induced cardiovascular disease can be modulated by almost complete suppression of parathyroid hormone (PTH), mediated by either cinacalcet (CINA) or parathyroidectomy (PTX). : Five groups were studied: sham-operated controls, uremic (U), uremic with calcitriol (U+1,25D), uremic and calcitriol with CINA (U+1,25D+CINA) and uremic and calcitriol with PTX (U+1,25D+PTX). Treatments lasted 14 weeks. : Compared with U group animals, PTH was significantly lower with calcitriol treatment and almost completely suppressed in animals treated with either PTX or CINA. Serum calcium and phosphorus levels were similarly elevated in all groups receiving calcitriol. Renal function in uremic animals was significantly more impaired in the U+1,25D group. Aortic calcifications were pronounced in U+1,25D animals and reduced by more than 50% by concomittant treatment with CINA or PTX. Chondrocytes were observed near areas of calcification (>90%) and endochondral bone formation was confirmed by positive immunofluorescence for chondrocytic transcription factor sox9 and matrix protein collagen X. Altered arterial (aneurysmatic) geometry with a significant increase in wall/lumen and lumen/body weight ratio was found only in the U+1,25D group. Myocardial fibrosis was present in all uremic groups with a significant increase in the U+1,25D group. Connective tissue growth factor messenger RNA was significantly upregulated only in the U+1,25D group. : Submaximal suppression of PTH by either CINA or PTX reduced vascular calcifications, arterial remodeling and myocardial fibrosis to a similar degree and independent of the serum calcium and phosphorus levels. These data do not indicate vasculotropic effects of calcimimetics independent of PTH suppression.
Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events. The relationship between calcium plus vitamin D (calcium/D) supplementation and coronary artery calcium (CAC) has not been previously assessed in a randomized trial setting. We compared CAC scores after trial completion between women randomized to calcium/vitamin D supplementation and women randomized to placebo. In an ancillary substudy of women randomized to calcium carbonate (1,000 mg of elemental calcium daily) plus vitamin D3 (400 IU daily) or placebo, nested within the Women's Health Initiative trial of estrogen among women who underwent hysterectomy, we measured CAC with cardiac CT in 754 women aged 50 to 59 years at randomization. Imaging for CAC was performed at 28 of 40 centers after a mean of 7 years of treatment, and scans were read centrally. CAC scores were measured by a central reading center with masking to randomization assignments. Posttrial CAC measurements were similar in women randomized to calcium/D supplementation and those receiving placebo. The mean CAC score was 91.6 for women receiving calcium/D and 100.5 for women receiving placebo (rank test P value = 0.74). After adjustment for coronary risk factors, multivariate odds ratios for increasing CAC score cutpoints (CAC >0, > or =10, and > or =100) for calcium/D versus placebo were 0.92 (95% CI, 0.64-1.34), 1.29 (0.88-1.87), and 0.90 (0.56-1.44), respectively. Corresponding odds ratios among women with a 50% or higher adherence to study pills and for higher levels of CAC (>300) were similar. Treatment with moderate doses of calcium plus vitamin D3 did not seem to alter coronary artery calcified plaque burden among postmenopausal women. Whether higher or lower doses would affect this outcome remains uncertain.
The rate of calcification within the human thoracic aorta from completion of body growth to advanced old age was examined. Fifty-eight aortae, obtained at necropsy, were dissected into four layers: the complete intima and the separated media, which was subdivided into three tissue samples of equal thickness, defined as the media-inner, -middle, and -outer layers. The sampling sites selected for analysis were from regions of the aortic surface that were free of atherosclerotic plaques. The calcium content within each tissue layer of the aorta was determined. Arterial wall thickness and the cholesterol content of the four layers were also measured. Intimal calcification increased progressively during aging: from 1.6 micrograms Ca/mg tissue at 20 years of age to 5.2 micrograms Ca/mg tissue by 90 years of age. When intima calcium concentration was expressed by tissue volume (w/v), no significant change during aging was found. Medial calcification, as w/v and by w/w, increased throughout aging. Calcium accumulation was most marked in the middle, elastin-rich layer of the media, increasing from 1.4 micrograms Ca/mg tissue at 20 years of age to 49.50 micrograms Ca/mg tissue by 90 years of age. Calcium levels also increased in the other media layers, but at a slower rate than that found within the middle media.
Cross-sectional and follow-up studies on end-stage renal disease patients showed that arterial calcifications are associated with cardiovascular (CV) morbidity and are an independent predictor of all-cause and CV mortality. However, these studies did not examine the impact on prognosis according to the type of calcification, i.e. intimal vs medial. Arterial media calcification (AMC), a non-occlusive condition, affects haemodynamics differently from arterial intima calcification (AIC), which occurs in atherosclerotic plaques. The aim of this study was to investigate the prognostic value of AMC in relationship to all-cause or CV mortality for stable haemodialysis (HD) patients. We included 202 such patients in the present study. At baseline, soft-tissue native radiograms of the pelvis and the thigh were analysed for the presence and type (AMC vs AIC) of arterial calcifications. All patients underwent B-mode ultrasonography of the common carotid artery to determine the presence of atherosclerotic calcified plaques, measurement of aortic pulse wave velocity and echocardiography. AIC was usually observed in older patients with a clinical history of atherosclerosis before starting HD treatment and typical risk factors associated with atherosclerotic disease. AMC was observed in young and middle-aged patients without conventional atherosclerotic risk factors. AMC was closely associated with the duration of HD and calcium-phosphate disorders, including the oral dose of elemental calcium prescribed as phosphate binder (CaCO(3)). Compared to patients with AIC, patients with AMC had a longer survival, but in turn their survival was significantly shorter than that of patients without calcifications. AMC is a strong prognostic marker of all-cause and CV mortality in HD patients, independently of classical atherogenic factors. The principal effect of AMC on arterial function is increased arterial stiffness.
Vascular calcification is a complicating factor observed in advanced atherosclerosis. This review summarises the present knowledge regarding abdominal aortic calcification. Literature review. A literature review was carried using MEDLINE and PUBMED with the search terms 'abdominal', 'aortic' and 'calcification'. Articles were assessed for data regarding mechanisms, measurement, risk factors and outcomes of aortic calcification. Thirty relevant studies were identified. These demonstrated a positive correlation between abdominal aortic calcification and the following factors: older age, hypertension, and smoking. Further studies are required to critically assess other risk factors such as gender, diabetes mellitus and renal failure. Calcification of the abdominal aorta is associated with an increased risk of mortality, coronary heart disease and stroke. Aortic calcification predicts an increased incidence of cardiovascular events, however, the reasons for this association requires further investigation. Accurate measurement of aortic calcification is likely to be increasingly used to determine the risk of cardiovascular events.
Individuals with vascular or valvular calcification are at increased risk for coronary events, but the relationship between calcium consumption and cardiovascular events is uncertain. We evaluated the risk of coronary and cerebrovascular events in the Women's Health Initiative randomized trial of calcium plus vitamin D supplementation. We randomized 36,282 postmenopausal women 50 to 79 years of age at 40 clinical sites to calcium carbonate 500 mg with vitamin D 200 IU twice daily or to placebo. Cardiovascular disease was a prespecified secondary efficacy outcome. During 7 years of follow-up, myocardial infarction or coronary heart disease death was confirmed for 499 women assigned to calcium/vitamin D and 475 women assigned to placebo (hazard ratio, 1.04; 95% confidence interval, 0.92 to 1.18). Stroke was confirmed among 362 women assigned to calcium/vitamin D and 377 assigned to placebo (hazard ratio, 0.95; 95% confidence interval, 0.82 to 1.10). In subgroup analyses, women with higher total calcium intake (diet plus supplements) at baseline were not at higher risk for coronary events (P=0.91 for interaction) or stroke (P=0.14 for interaction) if assigned to active calcium/vitamin D. Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period.
High resolution peripheral quantitative computed tomography (HR-pQCT) is a promising method for detailed in vivo 3D characterization of the densitometric, geometric, and microstructural features of human bone. Currently, a hybrid densitometric, direct, and plate model-based calculation is used to quantify trabecular microstructure. In the present study, this legacy methodology is compared to direct methods derived from a new local thresholding scheme independent of densitometric and model assumptions. Human femoral trabecular bone samples were acquired from patients undergoing hip replacement surgery. HR-pQCT (82 μm isotropic voxels) and micro-tomography (16 μm isotropic voxels) images were acquired. HR-pQCT images were segmented and analyzed in three ways: (1) using the hybrid method provided by the manufacturer based on a fixed global threshold, (2) using direct 3D methods based on the fixed global threshold segmentation, and (3) using direct 3D methods based on a novel local threshold scheme. The results were compared against standard direct 3D indices from μCT analysis. Standard trabecular parameters determined by HR-pQCT correlated strongly to μCT. BV/TV and Tb.Th were significantly underestimated by the hybrid method and significantly overestimated by direct methods based on the global threshold segmentation while the local method yielded optimal intermediate results. The direct-local method also performed favorably for Tb.N (R 2 = 0.85 vs. R 2 = 0.70 for direct-global method) and Tb.Sp (R 2 = 0.93 vs. R 2 = 0.85 for the hybrid method and R 2 = 0.87 for the direct-global method). These results indicate that direct methods, with the aid of advanced segmentation techniques, may yield equivalent or improved accuracy for quantification of trabecular bone microstructure without relying on densitometric or model assumptions.
Peripheral artery calcification on HR-pQCT scans and cardiovascular risk in men
  • P Szulc
  • C Plankaert
  • R Chapurlat
Szulc P, Plankaert C, Chapurlat R (2018) Peripheral artery calcification on HR-pQCT scans and cardiovascular risk in men. Abstract presented at the 2018 American Society for Bone and Mineral Research Annual Meeting, Montreal, Quebec
Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study
  • E J Samelson
  • K E Broe
  • H Xu
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  • D Wong
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  • B Schutte
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  • D C Seedat
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  • S G Servan-Mori
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  • A Shahraz
  • S Shaikh
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  • M Sharma
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  • K Shin
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  • I D Silberberg
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  • S Sykes
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  • R Tabb
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  • R T Tandon
  • N Tavakkoli
  • M Taye
  • B Taylor
  • H R Ao
  • Bjt Tedla
  • B A Tefera
  • W M Have
  • M T Terkawi
  • A S Tesfay
  • F H Tessema
  • G A Thomson
  • A J Thorne-Lyman
  • A L Thrift
  • A G Thurston
  • G D Tillmann
  • T Tirschwell
  • D L Tonelli
  • M Topor-Madry
  • R Topouzis
  • F Towbin
  • J A Traebert
  • J Tran
  • B X Truelsen
  • T Trujillo
  • U Tura
  • A K Tuzcu
  • E M Uchendu
  • U S Ukwaja
  • K N Undurraga
  • E A Uthman
  • O A Dingenen
  • R V Van Donkelaar
  • A Vasankari
  • T Vasconcelos
  • Amn Venketasubramanian
  • N Vidavalur
  • R Vijayakumar
  • L Villalpando
  • S Violante
  • F S Vlassov
  • V V Wagner
  • J A Wagner
  • G R Wallin
  • M T Wang
  • L Watkins
  • D A Weichenthal
  • S Weiderpass
  • E Weintraub
  • R G Werdecker
  • A Westerman
  • R White
  • R A Wijeratne
  • T Wilkinson
  • J D Williams
  • H C Wiysonge
  • C S Woldeyohannes
  • S M Wolfe
  • Cda Won
  • S Wong
  • J Q Woolf
  • A D Xavier
  • D Xiao
  • Q Xu
  • G Yakob
  • B Yalew
  • A Z Yan
  • L L Yano
  • Y Yaseri
  • M Ye
  • P Yebyo
  • H G Yip
  • P Yirsaw
  • B D Yonemoto
  • N Yonga
  • G Younis
  • M Z Yu
  • S Zaidi
  • Z Zaki
  • Mes Zannad
  • F Zavala
  • D E Zeeb
  • H Zeleke
  • B M Zhang
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  • S Zonies
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  • T Lopez
  • A D Murray
M, Schaub MP, Schmidt MI, Schneider IJC, Schöttker B, Schutte AE, Schwebel DC, Seedat S, Sepanlou SG, Servan-Mori EE, Shackelford KA, Shaddick G, Shaheen A, Shahraz S, Shaikh MA, Shakh-Nazarova M, Sharma R, She J, Sheikhbahaei S, Shen J, Shen Z, Shepard DS, Sheth KN, Shetty BP, Shi P, Shibuya K, Shin MJ, Shiri R, Shiue I, Shrime MG, Sigfusdottir ID, Silberberg DH, Silva DAS, Silveira DGA, Silverberg JI, Simard EP, Singh A, Singh GM, Singh JA, Singh OP, Singh PK, Singh V, Soneji S, Søreide K, Soriano JB, Sposato LA, Sreeramareddy CT, Stathopoulou V, Stein DJ, Stein MB, Stranges S, Stroumpoulis K, Sunguya BF, Sur P, Swaminathan S, Sykes BL, Szoeke CEI, Tabarés-Seisdedos R, Tabb KM, Takahashi K, Takala JS, Talongwa RT, Tandon N, Tavakkoli M, Taye B, Taylor HR, Ao BJT, Tedla BA, Tefera WM, Have MT, Terkawi AS, Tesfay FH, Tessema GA, Thomson AJ, Thorne-Lyman AL, Thrift AG, Thurston GD, Tillmann T, Tirschwell DL, Tonelli M, Topor-Madry R, Topouzis F, Towbin JA, Traebert J, Tran BX, Truelsen T, Trujillo U, Tura AK, Tuzcu EM, Uchendu US, Ukwaja KN, Undurraga EA, Uthman OA, Dingenen RV, van Donkelaar A, Vasankari T, Vasconcelos AMN, Venketasubramanian N, Vidavalur R, Vijayakumar L, Villalpando S, Violante FS, Vlassov VV, Wagner JA, Wagner GR, Wallin MT, Wang L, Watkins DA, Weichenthal S, Weiderpass E, Weintraub RG, Werdecker A, Westerman R, White RA, Wijeratne T, Wilkinson JD, Williams HC, Wiysonge CS, Woldeyohannes SM, Wolfe CDA, Won S, Wong JQ, Woolf AD, Xavier D, Xiao Q, Xu G, Yakob B, Yalew AZ, Yan LL, Yano Y, Yaseri M, Ye P, Yebyo HG, Yip P, Yirsaw BD, Yonemoto N, Yonga G, Younis MZ, Yu S, Zaidi Z, Zaki MES, Zannad F, Zavala DE, Zeeb H, Zeleke BM, Zhang H, Zodpey S, Zonies D, Zuhlke LJ, Vos T, Lopez AD, Murray CJL (2016) Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388:1459-1544
Low 25-OH vitamin D levels are not associated with coronary artery calcium or obstructive stenoses
  • J S Ho
  • J J Cannaday
  • C E Barlow
  • D B Reinhardt
  • W A Wade
  • J R Ellis
  • JS Ho