Calcium And Vitamin D Supplementation Research Articles

Adequacy of calcium and vitamin D reduces inflammation, β-catenin signaling, and dysbiotic Parasutterela bacteria in the colon of C57BL/6 mice fed a western-style diet

Adoption of an obesogenic diet low in calcium and vitamin D (CaD) leads to increased obesity, colonic inflammation, and cancer. However, the underlying mechanisms remain to be elucidated. We tested the hypothesis that CaD supplementation (from inadequacy to adequacy) may reduce colonic inflammation, oncogenic signaling, and dysbiosis in the colon of C57BL/6 mice fed a Western diet. Male C57/BL6 mice (4-weeks old) were assigned to 3 dietary groups for 36 weeks: (1) AIN76A as a control diet (AIN); (2) a defined rodent “new Western diet” (NWD); or (3) NWD with CaD supplementation (NWD/CaD). Compared to the AIN, mice receiving the NWD or NWD/CaD exhibited more than 0.2-fold increase in the levels of plasma leptin, tumor necrosis factor α (TNF-α) and body weight. The levels of plasma interleukin 6 (IL-6), inflammatory cell infiltration, and β-catenin/Ki67 protein (oncogenic signaling) were increased more than 0.8-fold in the NWD (but not NWD/CaD) group compared to the AIN group. Consistent with the inflammatory phenotype, colonic secondary bile acid (inflammatory bacterial metabolite) levels increased more than 0.4-fold in the NWD group compared to the NWD/CaD and AIN groups. Furthermore, the abundance of colonic Proteobacteria (e.g., Parasutterela), considered signatures of dysbiosis, was increased more than four-fold; and the α diversity of colonic bacterial species, indicative of health, was decreased by 30% in the NWD group compared to the AIN and NWD/CaD groups. Collectively, CaD adequacy reduces colonic inflammation, β-catenin oncogenic signaling, secondary bile acids, and bacterial dysbiosis in mice fed with a Western diet.

Supplementation of Calcium and Vitamin D Reduces Colonic Inflammation and Beta-Catenin Signaling in C57BL/6 Mice Fed a Western Diet

Abstract Objectives Adoption of a Western diet, low in calcium and vitamin D (CaD), is a global problem leading to increased obesity, colonic inflammation and neoplasia. However, the mechanisms underlying this relationship remains to be elucidated. We tested the hypothesis that CaD supplementation may reduce colonic inflammation, oncogenic signaling and dysbiosis in the colon of C57BL/6 mice fed a Western diet. Methods Male C57/BL6 mice (4-week old) were assigned to 3 dietary groups (n = 20/group) for 36 weeks: (1) AIN76A as a control diet (AIN); (2) a defined rodent “new Western diet” (NWD); or (3) NWD with CaD supplementation (NWD/CaD). We used biochemical, mass spectrometry, histological and multi-omics approaches to determine the interplay between CaD supplementation, colonic inflammation and microbiome composition. Results Mice receiving the NWD or NWD/CaD exhibited >0.2- fold increase in the concentrations of plasma leptin, tumor necrosis factor α (TNF-α) and body weight when compared with those on the AIN diet. However, the concentrations of plasma interleukin 6 (IL6), inflammatory cell infiltration and b-catenin/Ki67 protein (oncogenic signaling) were increased >0.8 - fold in the NWD (but not NWD/CaD) group when compared with the AIN group. Consistent with the inflammatory phenotype: (1) colonic secondary bile acid (an inflammatory bacterial metabolite) concentrations increased >0.4 - fold in the NWD group when compared with the NWD/CaD and AIN groups; (2) in contrast, α diversity of colonic bacterial species, a healthy gut microbiome marker, was decreased by 30% in the NWD group when compared with the AIN and NWD/CaD groups. Conclusions This study demonstrates that, in a mouse model, CaD supplementation reduces colonic inflammation, oncogenic signaling and bacterial dysbiosis in the context of Western diet consumption. Funding Sources This work was supported by U.S. Department of Agriculture, Agricultural Research Service, research project 3062–51,000-056–00D.

Vitamin D with calcium supplementation and risk of atrial fibrillation in postmenopausal women

Atrial fibrillation (AF) is the most common arrhythmia in adults. Although vitamin D deficiency is associated with AF risk factors, retrospective studies of association with AF have shown mixed results. We sought to determine the efficacy of calcium and vitamin D (CaD) supplementation for AF prevention in a randomized trial. We performed a secondary analysis of the Women's Health Initiative trial on CaD supplementation versus placebo. We linked participants to their Medicare claims to ascertain incident AF. Among 16,801 included participants, there were 1,453 (8.6%) cases of incident AF over an average of 4.5 years, at an average rate of 19.9 events per 1,000 person-years. We found no significant difference in incident AF rates between the CaD and placebo arms (hazard ratio 1.02 for CaD vs placebo, 95% CI 0.92-1.13). After multivariate adjustment, there was no significant association between baseline 25-hydroxyvitamin D serum levels and incident AF (hazard ratio 0.92 for lowest subgroup vs highest subgroup, 95% CI 0.66-1.28). We present the first analysis of a large randomized trial of daily vitamin D supplementation for AF prevention. We found that CaD had no effect on incidence of AF in Women's Health Initiative CaD trial participants. We also found that baseline serum 25-hydroxyvitamin D level was not predictive of long-term incident AF risk.

The calcium and vitamin D controversy.

Areas of the world where vitamin D levels are low for months of the year and intakes of calcium are high have a high prevalence of osteoporosis and cardiovascular disease. This suggests a public health message of avoiding calcium supplements and increasing vitamin D intake. No message could be more welcome as vitamin D can be given as a bolus while calcium must be taken daily and may be poorly tolerated. This approach is based on no evidence from intervention studies. Randomized controlled trials (RCTs) suggest that vitamin D given with calcium elicits a small reduction in fracture risk and deaths. This has not been demonstrated for D given alone. The cardiovascular safety of calcium and vitamin D (CaD) supplements is difficult to ascertain due to weaknesses in RCT designs and adjudication that cannot be remedied by subanalysis. Moreover, no major new RCTs are in process to provide better evidence. It remains unclear that calcium from dietary sources has health advantages over supplements. Benefits may be confined to patients with poor nutritional intake and the small effects at societal levels may be derived from large effects in a small number of patients. This has been impossible to confirm given the limited information about baseline vitamin D and calcium status at entry into trials. Future intervention studies should carefully capture baseline characteristics as these may determine the strength of the response, and make more efficient use of randomization strategies allowing subsequent disassembly or subanalyses while maintaining balancing. Though large clinical RCTs currently evaluate the effects of higher vitamin D doses (equivalent to 50-83 µg/d) there is no current research effort regarding the calcium controversy. In the absence of such studies it is not possible to provide clinicians with evidence-based recommendations regarding the best use of CaD supplementation.

Zoledronic Acid and Its Calcium-contain Complexes in Treatment of Experimental Osteoporosis in Wistar Female Rats

The aim was to assess the composition, stability and biological activity of the complexes that are formed in the solution on the interaction of calcium ions with Zolendronic acid (Zol) and study their effects on bone mineral density (BMD) indexes in female rats with experimental osteoporosis. 40 reproductive Wistar rats with systemic osteoporosis which was modeled by oophorectomy were under the study. Animals were divided into 4 groups (I – did not receive any treatment with bisphosphonates, only sufficient consumption of calcium and vitamin D (Ca-D); II – receive single dose of Zol and Ca-D; III – soluble calcium complexes of Zol (Ca-Zol) without additional use of Ca-D; IV – soluble calcium complexes of Zol with Ca-D). BMD and bone mineral content (BMC) of total body and spine were measured before treatment, after 1 and 3 months of observation by X-ray densitometer Prodigy. Our study showed the significant positive changes in total body BMD in 1 and 3 months and spine BMD in 3 months of observation 2d group. Analysis of BMD in rats of 3d group has not shown any significant changes of spine and total body in 1 and 3 months after its injection. However, the administration of complexes calcium and Zol with Ca-D has positive effects on total body BMDs in 1 and 3 months’ follow-up and spine BMD in 3 months of observation. Analysis of BMC indices in rats of 4th group showed the positive changes in spine and total body indexes in 1 and 3 month of follow-up, however it was not found any significant differences with animal of 2d group. Conclusion investigated soluble complexes of calcium and Zol in combination with Ca-D supplementation showed positive effect on BMD and BMC indices however did not have any benefits in comparison standard administration of Zol with Ca-D supplementation.

Клиническое исследование «Инициатива во имя здоровья женщин»: взаимосвязь кальция и витамина D с гормональной терапией

This study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT). This is a prospective, partial-factorial, randomized, controlled, double-blind trial among Women’s Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density. Interaction between HT and CaD on hip fracture (р interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38–0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85–1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28–0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60–1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake. There was no interaction between HT and CaD on change in hip or spine bone mineral density. Conclusions: Postmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake.

Calcium and Vitamin D in Sarcoidosis: Is Supplementation Safe?

Granulomas in sarcoidosis express high levels of 1α-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1α-hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first-line treatment in organ-threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25-hydroxy vitamin D (25-(OH)D), 1,25-dihydroxy vitamin D (1,25(OH)2 D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25-(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD-supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D-deficient sarcoidosis patients should be supplemented.

Women’s Health Initiative clinical trials

This study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT). This is a prospective, partial-factorial, randomized, controlled, double-blind trial among Women's Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density. Interaction between HT and CaD on hip fracture (P interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38-0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85-1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28-0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60-1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake. There was no interaction between HT and CaD on change in hip or spine bone mineral density. Postmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake.

Effect of 5 y of calcium plus vitamin D supplementation on change in circulating lipids: results from the Women’s Health Initiative

Dietary calcium and vitamin D intakes may be inversely associated with cardiovascular disease (CVD) risk, possibly because of their potential beneficial effects on circulating lipids. Clinical trials that have evaluated the effect of calcium supplementation on lipids are limited by a short follow-up, and data on vitamin D are scarce. The objective was to evaluate the effect of a longer-term effect (over 5 y) of calcium and vitamin D (CaD) supplementation on changes in the concentrations of several lipids: LDL, HDL, non-HDL, total cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]. The study was conducted in 1259 postmenopausal women in the Calcium plus Vitamin D Trial (1 g elemental Ca as carbonate plus 400 IU vitamin D(3)/d compared with placebo) of the Women's Health Initiative. Analyses were conducted by intention-to-treat. Repeated measurements on lipids during follow-up were analyzed by linear mixed-effects models. Overall, the change in lipids was relatively small [< or =5% except for Lp(a), which was 20-25%], and there was no significant difference in the mean change of any lipid variable between the active and placebo groups. Our results indicate that CaD supplementation is not associated with lipid changes over 5 y. Existing and future CaD trials should consider evaluating this association for different doses of supplements. This study was registered at clinicaltrials.gov as NCT00000611.

Persistence with calcium and vitamin D in elderly patients after hip fracture

All hip fracture (HF) subjects are candidates for calcium and vitamin D (CaD) supplementation. Up to 50% of HF older adults present with secondary hyperparathyroidism (HPTH) resulting from hypovitaminosis D on hospital admission. To investigate the patterns and predictors of persistence with CaD supplementation in the elderly after HF, we considered all patients aged 70 years or older who were discharged alive after surgical repair of HF in the period of 1 year from an Orthopaedic Unit. Baseline characteristics of the subjects and osteoporosis treatment prescribed at discharge were retrieved from medical record review. A telephone interview at 6 months evaluated whether patients were currently taking CaD supplementation. Nonpersistence was defined when subjects ceased therapy within 6 months. Univariate and multivariate models were applied to determine the relationship between 6 months persistence with CaD and the variables collected: age, living situation, prescription of a bisphosphonate, baseline walking ability, number of drugs used, presence of dementia, number of active clinical issues at discharge (ACIs), discharge location, and being referred to a center for metabolic bone diseases (preplanned visit) at discharge. Of 428 subjects enrolled, 117 were excluded for different reasons (incomplete data, no therapy, death). A total of 311 subjects were discharged with a prescription of CaD (calcium 1,000 mg, cholecalciferol 800 UI, once daily) and were considered for the analysis. At 6 months, only 114 patients (36.7%) were currently taking CaD supplementation. In a univariate analysis, the following variables were significantly related with persistence: absence of dementia, prescription of a bisphosphonate, six or fewer drugs being used (drugs used <or=6), two or less ACIs (<or=2 ACIs) at discharge, ability to walk without aid at baseline, being discharged home, and being referred to a preplanned visit. In a multivariate model, the prescription of a bisphosphonate at discharge (OR 3.178, 95% CI 1.477-6.836, P = 0.003), a preplanned visit (OR 1.953, 95% CI 1.066-3.514, P = 0.03), the absence of dementia (OR 1.877, 95% CI 1.021-3.451, P = 0.043), and <or=6 drugs used (OR 1.842, 95% CI 1.066-3.182, P = 0.029) remained the most significant predictors of persistence with CaD. In HF elderly, who are at high risk of hypovitaminosis D and HPTH, persistence with CaD supplementation is very low. The enrolment in a postsurgical program for the management of bone disease can significantly increase persistence. Moreover, factors related to the complexity of older adult patients (polypharmacotherapy, dementia) seem to be particularly important in compliance with prescribed drugs.

Low bone mineral density measurements in care home residents—a treatable cause of fractures

to assess predictors of fracture risk and treatment for osteoporosis among elderly care home residents. cross-sectional survey; residents of care homes in Newcastle upon Tyne, UK; representative sample from residential care (87), nursing homes (105) and specialist homes for elderly people with dementia [elderly mentally infirm (EMI)]: residential (124) and nursing (76); dual-energy X-ray absorptiometry bone mineral density (BMD) at calcaneum; functional assessments, including cognition, using Mini-Mental State Examination (MMSE), Clifton Assessment Procedure for the Elderly-Behaviour Rating Score (CAPE-BRS) and Functional Assessment Staging Test (FAST) scores; current drug prescription. MMSE, CAPE, FAST (all ANOVA P < 0.001) and weight (ANOVA P < 0.02) were lower in EMI homes. Drugs with sedative effects (chi-square, P < 0.0001) were more likely and calcium and vitamin D (CaD) supplementation (chi-square, P < 0.02) less likely in EMI care. For residential care, the odds ratio (OR) for sedative drugs in EMI was 2.13 (95% CI 1.11-4.06) with no significant difference between nursing homes. For CaD supplementation, the OR for EMI nursing homes was 0.19 (95% CI 0.05-0.72) and for EMI residential homes 0.38 (NS to 95% CI 0.12-1.27). BMD was low: mean T-score was -2.29 (95% CI -2-48 to -2.09) and Z-score -0.96 (95% CI -1.16 to -0.76) with a prevalence of osteoporosis (T-score < -1.6) of 69.2%. MMSE and FAST scores did not predict BMD. In EMI residential care, a decrease of CAPE score by 5 points was associated with a decrease in T-score by 0.6 (95% CI 0.15-1.1). of the tools used to assess function, only CAPE predicted low BMD in EMI residential care. Rates of CaD supplementation are particularly low in EMI care, where risk factors for fracture were the greatest. We conclude that fracture risk is neglected in these homes, and targeted education and treatment are warranted.

Does a Distal Forearm Fracture Lead to Evaluation for Osteoporosis?

In postmenopausal women, a low-trauma distal forearm fracture is a risk factor for osteoporosis and future fracture, which indicates osteoporosis follow-up according to prevailing guidelines. We decided to determine how often women over 45 yr presenting with a low-trauma distal forearm fracture to a Danish emergency department during a 1-yr period were followed up for osteoporosis. We performed a retrospective review of hospital records and we sent the women and their general practitioners (GPs) questionnaires regarding the follow-up undertaken in primary care. Finally, we invited the women for a densitometry to estimate the prevalence of osteoporosis. From May 1, 2001 to April 30, 2002, 147 women presented with a low-trauma distal forearm fractures. According to the review of hospital records, none of the women was referred for bone densitometry or spine X-rays. One woman had calcium and vitamin D supplementation (CVDS) prescribed and two were recommended to consult their GPs for osteoporosis follow-up. In primary care, 12 women were referred for densitometry or spine X-rays, and 11 women started CVDS after the fracture. Women with risk factors for osteoporosis in addition to the forearm fracture were not more likely to be referred for densitometry or spine X-rays (p = 0.10). The prevalence of osteoporosis was 24% among the 79 women who underwent densitometry. Our study demonstrates a low use of available measures to reduce the risk of future fracture in women with a low-trauma distal forearm fracture, and it emphasizes the need to decide on a local level how to provide osteoporosis follow-up for women with fragility fractures.