Katharina Kienreich

Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality—A review of recent evidence

BACKGROUND Optimal vitamin D intake and its status are important not only for bone and calcium-phosphate metabolism, but also for overall health and well-being. Vitamin D deficiency and insufficiency as a global health problem are likely to be a risk for wide spectrum of acute and chronic illnesses. METHODS A review of randomized controlled trials, meta-analyses, and other evidence of vitamin D action on various health outcomes. RESULTS Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is associated with all-cause mortality. CONCLUSIONS Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for the spectrum of disorders. Supplementation guidance and population strategies for the eradication of vitamin D deficiency must be included in the priorities of physicians, medical professionals and healthcare policy-makers.

Aldosterone and parathyroid hormone: a precarious couple for cardiovascular disease.

Animal and human studies support a clinically relevant interaction between aldosterone and parathyroid hormone (PTH) levels and suggest an impact of the interaction on cardiovascular (CV) health. This review focuses on mechanisms behind the bidirectional interactions between aldosterone and PTH and their potential impact on the CV system. There is evidence that PTH increases the secretion of aldosterone from the adrenals directly as well as indirectly by activating the renin-angiotensin system. Upregulation of aldosterone synthesis might contribute to the higher risk of arterial hypertension and of CV damage in patients with primary hyperparathyroidism. Furthermore, parathyroidectomy is followed by decreased blood pressure levels and reduced CV morbidity as well as lower renin and aldosterone levels. In chronic heart failure, the aldosterone activity is inappropriately elevated, causing salt retention; it has been argued that the resulting calcium wasting causes secondary hyperparathyroidism. The ensuing intracellular calcium overload and oxidative stress, caused by PTH and amplified by the relative aldosterone excess, may increase the risk of CV events. In the setting of primary aldosteronism, renal and faecal calcium loss triggers increased PTH secretion which in turn aggravates aldosterone secretion and CV damage. This sequence explains why adrenalectomy and blockade of the mineralocorticoid receptor tend to decrease PTH levels in patients with primary aldosteronism. In view of the reciprocal interaction between aldosterone and PTH and the potentially ensuing CV damage, studies are urgently needed to evaluate diagnostic and therapeutic strategies addressing the interaction between the two hormones.

Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease

Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon.

Role of Vitamin D in the Development of Insulin Resistance and Type 2 Diabetes

Vitamin D deficiency is mainly a consequence of insufficient sunlight induced vitamin D production in the skin and has been associated with various chronic diseases including type 2 diabetes. Experimental data have shown that vitamin D is important for glucose induced insulin secretion, improves insulin resistance, and exerts anti-inflammatory actions. Epidemiological studies have largely documented that a poor vitamin D status is associated with higher risk of insulin resistance and type 2 diabetes. The majority of randomized controlled trials (RCTs) in healthy or prediabetic individuals have, however, failed to demonstrate relevant vitamin D effects on insulin resistance or diabetes incidence. In patients with type 2 diabetes, a few RCTs reported some moderate effects of vitamin D on glycemic control and insulin resistance. While these findings warrant further in-depth studies, the current evidence is insufficient to recommend vitamin D supplementation for the prevention or treatment of type 2 diabetes.

Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial.

Vitamin D deficiency is a risk factor for arterial hypertension, but randomized controlled trials showed mixed effects of vitamin D supplementation on blood pressure (BP). We aimed to evaluate whether vitamin D supplementation affects 24-hour systolic ambulatory BP monitoring values and cardiovascular risk factors. The Styrian Vitamin D Hypertension Trial is a single-center, double-blind, placebo-controlled study conducted from June 2011 to August 2014 at the endocrine outpatient clinic of the Medical University of Graz, Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxyvitamin D levels below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for 8 weeks. Primary outcome measure was 24-hour systolic BP. Secondary outcome measures were 24-hour diastolic BP, N-terminal-pro-B-type natriuretic peptide, QTc interval, renin, aldosterone, 24-hour urinary albumin excretion, homeostasis model assessment-insulin resistance, triglycerides, high-density lipoprotein cholesterol, and pulse wave velocity. A total of 188 participants (mean [SD] age, 60.1 [11.3] years; 47% women; 25-hydroxyvitamin D, 21.2 [5.6] ng/mL) completed the trial. The mean treatment effect (95% confidence interval) for 24-hour systolic BP was −0.4 (−2.8 to 1.9) mm Hg (P=0.712). Triglycerides increased significantly (mean change [95% confidence interval], 17 [1–33] mg/dL; P=0.013), but no further significant effects were observed for secondary outcomes. Vitamin D supplementation in hypertensive patients with low 25-hydroxyvitamin D has no significant effect on BP and several cardiovascular risk factors, but it was associated with a significant increase in triglycerides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02136771.

Vitamin D and cardiovascular disease.

Vitamin D deficiency, as well as cardiovascular diseases (CVD) and related risk factors are highly prevalent worldwide and frequently co-occur. Vitamin D has long been known to be an essential part of bone metabolism, although recent evidence suggests that vitamin D plays a key role in the pathophysiology of other diseases, including CVD, as well. In this review, we aim to summarize the most recent data on the involvement of vitamin D deficiency in the development of major cardiovascular risk factors: hypertension, obesity and dyslipidemia, type 2 diabetes, chronic kidney disease and endothelial dysfunction. In addition, we outline the most recent observational, as well as interventional data on the influence of vitamin D on CVD. Since it is still an unresolved issue whether vitamin D deficiency is causally involved in the pathogenesis of CVD, data from randomized controlled trials (RCTs) designed to assess the impact of vitamin D supplementation on cardiovascular outcomes are awaited with anticipation. At present, we can only conclude that vitamin D deficiency is an independent cardiovascular risk factor, but whether vitamin D supplementation can significantly improve cardiovascular outcomes is still largely unknown.

Hyperparathyroidism in Patients with Primary Aldosteronism: Cross-Sectional and Interventional Data from the GECOH Study

CONTEXT Experimental studies suggest that aldosterone induces hypercalciuria and might contribute to hyperparathyroidism. OBJECTIVE We aimed to test for differences in PTH levels and parameters of calcium and vitamin D metabolism in patients with primary aldosteronism (PA) compared with patients with essential hypertension (EH) and to evaluate the impact of PA treatment on these laboratory values. DESIGN, SETTING, AND PARTICIPANTS The Graz Endocrine Causes of Hypertension study includes hypertensive patients referred for screening for endocrine hypertension at a tertiary care center in Graz, Austria. MAIN OUTCOME MEASURES Differences in PTH levels between patients with PA and EH. RESULTS Among 192 patients, we identified 10 patients with PA and 182 with EH. PTH levels (mean ± sd in picograms per milliliter) were significantly higher in PA patients compared with EH (67.8 ± 26.9 vs. 46.5 ± 20.9; P = 0.002). After treatment of PA with either adrenal surgery (n = 5) or mineralocorticoid receptor antagonists (n = 5), PTH concentrations decreased to 43.9 ± 14.9 (P = 0.023). Serum 25-hydroxyvitamin D concentrations were similar in both groups. Compared with EH, serum calcium concentrations were significantly lower (2.35 ± 0.10 vs. 2.26 ± 0.10 mmol/liter; P = 0.013), and there was a nonsignificant trend toward an increased spot urine calcium to creatinine ratio in PA [median (interquartile range) 0.19 (0.11-0.31) vs. 0.33 (0.12-0.53); P = 0.094]. CONCLUSIONS Our results suggest that PA contributes to secondary hyperparathyroidism. Further studies are warranted to evaluate whether PTH has implications for PA diagnostics and whether mineralocorticoid receptor antagonists have a general impact on PTH and calcium metabolism.

Low 25-Hydroxyvitamin D Is Associated with Increased Mortality in Female Nursing Home Residents

CONTEXT Vitamin D deficiency contributes to skeletal diseases and is highly prevalent among institutionalized elderly patients. Whether low 25-hydroxyvitamin D (25[OH]D) concentrations are an independent risk factor for mortality in these patients is, however, unclear. OBJECTIVE We aimed to evaluate whether 25(OH)D concentrations are associated with mortality. DESIGN, SETTING, AND PARTICIPANTS This is a prospective cohort study among elderly female patients (age >70 yr) recruited from 95 nursing homes in Austria. MAIN OUTCOME MEASURES We calculated Cox proportional hazard ratios (HR) for all-cause mortality according to 25(OH)D quartiles. RESULTS We examined 961 study participants (age 83.7 ± 6.1 yr). Median 25(OH)D concentration was 17.5 (interquartile range 13.7-25.5) nmol/liter, and 93% of our cohort had 25(OH)D levels below 50 nmol/liter. During a mean follow-up time of 27 ± 8 months, 284 patients died. Compared with the fourth quartile (25[OH]D >25.5 nmol/liter), the age-adjusted HR (with 95% confidence interval) was 1.49 (1.07-2.10) in the first 25(OH)D quartile (25[OH]D <14.0 nmol/liter), and this association remained significant after multivariate adjustments (HR = 1.56; 95% confidence interval = 1.01-2.40). CONCLUSIONS This Austrian study suggests that the majority of institutionalized female patients are vitamin D deficient during winter and that there was an inverse association of 25(OH)D and mortality. These data underscore the urgent need for effective strategies for the prevention and treatment of vitamin D deficiency, in particular in the setting of nursing homes.

Vitamin D and Cancer Mortality: Systematic Review of Prospective Epidemiological Studies

Accumulating evidence from experimental and epidemiological studies suggests that vitamin D deficiency might be a causal risk factor for cancer and therewith associated mortality. We performed a systematic review in Medline up to February 2012 to identify prospective studies on 25-hydroxyvitamin D (25[OH]D) and cancer mortality as well as on 25(OH)D and survival in cancer patients. Our search retrieved 13 studies on cancer-specific mortality and 20 studies on overall mortality in cancer patients. Data on 25(OH)D and cancer mortality were mainly derived from general populations. The results were inconsistent and yielded either no, inverse or positive associations. By contrast, the majority of studies in cancer patients showed that patients with higher 25(OH)D levels had a decreased risk of mortality. This relationship was particularly evident in cohorts of colorectal cancer patients. In contrast, there was no indication for increased mortality risk with higher vitamin D levels in any cancer cohort. In conclusion, the relationship of vitamin D status and cancerspecific mortality is still unclear and warrants further studies. Our results provide a strong rationale to perform prospective randomized controlled studies to document a potential effect of vitamin D supplementation on survival in cancer patients.

Vitamin D and cardiovascular disease: Update and outlook

Abstract Accumulating evidence suggests that vitamin D may play a role for cardiovascular health. Expression of the vitamin D receptor (VDR) and enzymes for vitamin D metabolism have been identified in the vasculature as well as in the heart. VDR knock-out mice suffer from cardiovascular disease (CVD) and even selective VDR deletion in cardiomyocytes causes myocardial hypertrophy. Many, but not all observational studies showed that vitamin D deficiency is associated with CVD and its risk factors. Low concentrations of 25-hydroxyvitamin D (25(OH)D) are an independent risk factor for cardiovascular events, in particular for strokes and sudden cardiac deaths. Only few randomized controlled trials (RCTs) are available on this topic. These RCTs are frequently limited by the additional supplementation of calcium which may increase the risk of CVD events. RCTs with pure vitamin D supplementation have partially but not consistently shown beneficial effects on cardiovascular risk factors such as arterial hypertension. A number of large RCTs on the impact of vitamin D supplementation on cardiovascular events and mortality have already started but limitations of the study designs such as inclusion of individuals with relatively high 25(OH)D concentrations have to be considered. At present, the evidence is not sufficient for general recommendations to supplement vitamin D in order to prevent and treat CVD. It should, however, be noted that justification for the prevention and treatment of vitamin D deficiency comes from evidence based benefits of vitamin D supplementation on musculoskeletal health.