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Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Patients with Colorectal Adenoma in a Clinical Trial.
Gibbs, DC, Fedirko, V, Baron, JA, Barry, EL, Flanders, WD, McCullough, ML, Yacoub, R, Raavi, T, Rutherford, RE, Seabrook, ME, et al
Cancer prevention research (Philadelphia, Pa.). 2021;(1):65-76
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Abstract
Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.
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A Randomized Trial of Calcium Plus Vitamin D Supplementation and Risk of Ductal Carcinoma In Situ of the Breast.
Peila, R, Xue, X, Cauley, JA, Chlebowski, R, Manson, JE, Nassir, R, Saquib, N, Shadyab, AH, Zhang, Z, Wassertheil-Smoller, S, et al
JNCI cancer spectrum. 2021;(4)
Abstract
BACKGROUND The effect of calcium plus vitamin D (CaD) supplementation on risk of ductal carcinoma in situ (DCIS) of the breast, a nonobligate precursor of invasive ductal carcinoma, is not well understood. In this secondary analysis, we examined this association in the Women's Health Initiative CaD trial over approximately 20 years of follow-up. METHODS A total of 36 282 cancer-free postmenopausal women (50-79 years) were randomly assigned to daily (d) calcium (1000 mg) plus vitamin D (400 IU) supplementation or to a placebo. Personal supplementation with vitamin D (≤600 IU/d, subsequently raised to 1000 IU/d) and calcium (≤1000 mg/d) was allowed. The intervention phase (median = 7.1 years), was followed by a postintervention phase (additional 13.8 years), which included 86.0% of the surviving women. A total of 595 incident DCIS cases were ascertained. Hazard ratios (HRs) plus 95% confidence intervals (CIs) were calculated. RESULTS The intervention group had a lower risk of DCIS throughout follow-up (HR = 0.82, 95% CI = 0.70 to 0.96) and during the postintervention phase (HR = 0.76, 95% CI = 0.61 to 0.94). The group that used CaD personal supplements in combination with the trial intervention had a lower risk of DCIS compared with the trial placebo group that did not use personal supplementation (HR = 0.72, 95% CI = 0.56 to 0.91). CONCLUSIONS CaD supplementation in postmenopausal women was associated with reduced risk of DCIS, raising the possibility that consistent use of these supplements might provide long-term benefits for the prevention of DCIS.
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Vitamin D and Calcium Supplement Attenuate Bone Loss among HIVInfected Patients Receiving Tenofovir Disoproxil Fumarate/Emtricitabine/ Efavirenz: An Open-Label, Randomized Controlled Trial.
Boontanondha, P, Nimitphong, H, Musikarat, S, Ragkho, A, Kiertiburanakul, S
Current HIV research. 2020;(1):52-62
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Abstract
BACKGROUND Antiretroviral therapy (ART), especially with tenofovir disoproxil fumarate (TDF), has been associated with accelerated bone turnover and leads to significant bone loss. OBJECTIVE We aimed to determine the effect of vitamin D2 and calcium on bone mineral density (BMD) in HIV-infected patients receiving TDF/emtricitabine (FTC)/efavirenz (EFV). METHODS A prospective, open-label, randomized controlled study was conducted. Eligible patients were ART naïve HIV individuals who initiated TDF/FTC/EFV. The study group received supplementation with vitamin D2 and calcium carbonate, whereas the control group was administered only ART. The primary outcome was the percentage change in total hip BMD at week 24 compared with baseline. RESULTS A total of 18 patients were randomized (9 in each group). The mean (standard deviation; SD) total hip BMD significantly decreased from baseline in both groups, from 0.96 (0.14) g/cm2 to 0.93 (0.13) g/cm2 in the study group (p = 0.006) and from 0.87 (0.11) g/cm2 to 0.84 (0.11) g/cm2 in the control group (p = 0.004). The mean (SD) lumbar spine BMD significantly decreased from baseline in both groups, from 1.00 (0.13) g/cm2 to 0.97 (0.13) g/cm2 (p = 0.004) in the study group and from 0.90 (0.09) g/cm3 to 0.86 (0.08) g/cm2 in the control group (p = 0.006). At week 24, the mean (SD) lumbar spine BMD was significantly greater in the study group than in the control group (p = 0.042). However, there were no significant differences in the percentage change of total hip, lumbar spine, and femoral neck BMD between both groups. No adverse events were reported. In conclusion, as early as 24 weeks after TDF initiation, a significant decline in BMD was detected. CONCLUSION Vitamin D2 and calcium supplements should be considered for HIV-infected patients receiving TDF/FTC/EFV in a resource-limited setting where there are limited ART options (Clinicaltrials. gov NCT0287643).
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Prevention of benign paroxysmal positional vertigo with vitamin D supplementation: A randomized trial.
Jeong, SH, Kim, JS, Kim, HJ, Choi, JY, Koo, JW, Choi, KD, Park, JY, Lee, SH, Choi, SY, Oh, SY, et al
Neurology. 2020;(9):e1117-e1125
Abstract
OBJECTIVE To assess the effect of vitamin D and calcium supplementation in preventing recurrences of benign paroxysmal positional vertigo (BPPV). METHODS We performed an investigator-initiated, blinded-outcome assessor, parallel, multicenter, randomized controlled trial in 8 hospitals between December 2013 and May 2017. Patients with confirmed BPPV were randomly assigned to the intervention (n = 518) or the observation (n = 532) group after successful treatment with canalith repositioning maneuvers. The primary outcome was the annual recurrence rate (ARR). Patients in the intervention group had taken vitamin D 400 IU and 500 mg of calcium carbonate twice a day for 1 year when serum vitamin D level was lower than 20 ng/mL. Patients in the observation group were assigned to follow-ups without further vitamin D evaluation or supplementation. RESULTS The intervention group showed a reduction in the ARR (0.83 [95% confidence interval (CI), 0.74-0.92] vs 1.10 [95% CI, 1.00-1.19] recurrences per 1 person-year) with an incidence rate ratio of 0.76 (95% CI, 0.66-0.87, p < 0.001) and an absolute rate ratio of -0.27 (-0.40 to -0.14) from intention-to-treat analysis. The number needed to treat was 3.70 (95% CI, 2.50-7.14). The proportion of patients with recurrence was also lower in the intervention than in the observation group (37.8 vs 46.7%, p = 0.005). CONCLUSIONS Supplementation of vitamin D and calcium may be considered in patients with frequent attacks of BPPV, especially when serum vitamin D is subnormal. CLASSIFICATION OF EVIDENCE This study provides Class III evidence that for patients with BPPV, vitamin D and calcium supplementation reduces recurrences of BPPV.
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Fall Prevention and Anti-Osteoporosis in Osteopenia Patients of 80 Years of Age and Older: A Randomized Controlled Study.
Zhou, J, Liu, B, Qin, MZ, Liu, JP
Orthopaedic surgery. 2020;(3):890-899
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Abstract
UNLABELLED To evaluate the effects of two fall-prevention and anti-osteoporotic protocols in elderly patients with osteopenia (OPA). METHODS The present randomized controlled study included patients with OPA (n =123). The age of these patients was ≥80 years old, with the mean age of 83.54 ± 2.99 years, and the male-to-female ratio was 2.97:1.00. Fall-prevention guidance was given to all patients. Patients in the experiment group (n = 62) orally received 600 mg/d of calcium carbonate, 0.5 μg/d of alfacalcidol, and 70 mg/week of alendronate, while patients in the control group (n = 61) orally received 600 mg/d of calcium carbonate and 0.5 μg/d of alfacalcidol for 18 months. The grip strength, gait speed, bone turnover markers, serum calcium, serum phosphorus, parathyroid hormone (PTH), and bone mineral density were measured, and the Timed Up and Go (TUG) test and the chair rising test (CRT) were performed. Falls, fragility fractures, medication compliance, and side effects of the drugs were recorded. RESULTS The serum levels of bone turnover markers (type I procollagen amino-terminal peptide [P1NP], type I collagen carboxyl terminal peptide [β-CTx], and osteocalcin [OC]) decreased, while the bone mineral density of the lumbar spine and bilateral femoral neck increased after treatment in the experiment group (P < 0.05, P < 0.01). The rate of change in bone mineral density of the bilateral femoral neck was higher in the experiment group than the control group (3.43% vs 0.03%, P < 0.05; 2.86% vs -0.02%, P < 0.01). After treatment, the proportion of patients with increased hip T scores in the experiment group (66.1%, 41/62) was significantly higher than the proportion (35.0%, 21/60) in the control group (P = 0.001). The incidence of fall decreased in both groups after treatment compared to that before treatment (54.8% vs 33.9% and 54.1% vs 36.7%, respectively; P < 0.05). The incidence of fragility fractures was lower in the experiment group than the control group (8.1% vs 20.0%, P = 0.057). During the intervention period, the incidence of fragility fractures in patients who did not fall (3.8%, 3/79) was significantly lower than that in patients who fell (32.6%, 14/43) (P = 0.000). The risk of fragility fractures was significantly lower in patients who did not fall compared to patients who fell (relative risk: 0.117, 95% confidence interval: 0.035-0.384). CONCLUSION The combination of alendronate sodium with alfacalcidol and calcium can significantly improve the bone mineral density of the lumbar spine and femoral neck. For older patients with OPA, subjectively paying attention to avoiding falls can significantly reduce the risk of fragility fractures.
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Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.
Shen, Z, Lee, CA, Valdez, S, Yang, X, Wilson, DM, Flanagan, T, Gillen, M
Clinical pharmacology in drug development. 2019;(5):647-656
Abstract
Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.
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Body mass index, calcium supplementation and risk of colorectal adenomas.
Barry, EL, Lund, JL, Westreich, D, Mott, LA, Ahnen, DJ, Beck, GJ, Bostick, RM, Bresalier, RS, Burke, CA, Church, TR, et al
International journal of cancer. 2019;(3):448-458
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Abstract
Calcium supplementation (1,200 mg/day) did not significantly reduce colorectal adenomas in our recent randomized, controlled trial (Vitamin D/Calcium Polyp Prevention Study, VCPPS, 2004-2013) in contrast to our previous trial (Calcium Polyp Prevention Study, CPPS, 1988-1996). To reconcile these findings, we identified participant characteristics that differed between the study populations and modified the effect of calcium supplementation on adenomas or high-risk findings (advanced or multiple adenomas). Compared to the CPPS, more participants in the VCPPS were obese (body mass index (BMI) ≥30 kg/m2 ; 37.5% vs. 24.4%) and fewer had normal BMI (BMI <25 kg/m2 ; 18.5% vs. 31%). BMI appeared to modify the effect of calcium supplementation on adenomas and especially on high risk-findings: in the VCPPS, there was a 44% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.56, 95% CI = 0.26-1.23), but not among overweight (RR = 1.09, 95% CI = 0.62-1.91) or obese (RR = 1.54, 95% CI = 0.92-2.57) individuals (pinteraction = 0.03). Similarly, in the CPPS, there was a 56% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.44, 95% CI = 0.26-0.74), but not among overweight (RR = 0.87, 95% CI = 0.55-1.39) or obese (RR = 1.02, 95% CI = 0.57-1.82) individuals (pinteraction = 0.02). Standardization of each trial's findings to the BMI distribution in the other attenuated calcium's protective effect on adenomas in the CPPS but enhanced it in the VCPPS. In conclusion, 1,200 mg/day calcium supplementation may reduce risk of colorectal adenomas among those with normal BMI but not in overweight or obese individuals; and differences in BMI distribution partially account for the apparent difference in calcium efficacy between the two trials.
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Pregnancy supplementation of Gambian mothers with calcium carbonate alters mid-childhood IGF1 in a sex-specific manner.
Prentice, A, Ward, KA, Nigdikar, S, Hawkesworth, S, Moore, SE
Bone. 2019;:314-320
Abstract
CONTEXT Sex-specific effects of pregnancy calcium carbonate supplementation have been reported in 8-12 year old Gambian children, indicating faster growth in boys but slower growth in girls born to calcium-supplemented mothers. OBJECTIVE To determine whether the pregnancy supplement resulted in sex-specific effects on offspring IGF1 and other growth-related indices in mid-childhood. DESIGN Analysis of archived data obtained in mid-childhood from the children of rural Gambian mothers who had been randomised to 1500 mgCa/d (Ca) or placebo (P) from 20 weeks pregnancy to delivery (ISRCTN96502494). PARTICIPANTS AND METHODS Of the 526 children born and followed in infancy, 290 had early-morning, fasting plasma assayed for IGF1, IGFBP3, leptin, insulin and calcium-related indices and had anthropometry performed at age 7.5 (SD1.2) years (N/group: Males(M)-Ca = 64, Females(F)-Ca = 77; M-P = 76, F-P = 73). Sex-specific effects of maternal supplementation were considered using regression with sexes separated and together to test for sex ∗ supplement interactions. RESULTS Boys had lower IGF1, IGFBP3, leptin and insulin than girls (P ≤ 0.004). IGF1 was higher in M-Ca than M-P (+14.2 (SE7.7)%, P = 0.05) but lower in F-Ca than F-P (-17.8 (SE7.4)%, P = 0.01); sex ∗ supplement interaction P = 0.001. IGF1 concentrations (ng/ml, geometric mean [-1SE,+1SE]) were M-Ca = 78.1[4.3,4.5], M-P = 67.8[3.4,3.6]; F-Ca = 99.5[4.8,5.1], F-P = 118.9[6.4,6.8]. Similar sex ∗ supplement interactions were seen for IGFBP3 and IGF1-adjusted-for-IGFBP3 but group differences were smaller. There were no significant supplement effects on the other biochemical indices. CONCLUSIONS Calcium carbonate supplementation of pregnant Gambian mothers resulted in higher IGF1 in boys and lower IGF1 in girls during mid-childhood, consistent with the reported maternal supplement effects on growth of the offspring in later childhood.
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Effect of calcium citrate vs calcium carbonate on elevated parathyroid hormone after Roux-en-Y gastric bypass. A double-blinded, randomized trial.
Ring Madsen, L, Espersen, R, Rejnmark, L, Richelsen, B
Clinical endocrinology. 2018;(6):734-741
Abstract
OBJECTIVE Following Roux-en-Y gastric bypass (RYGB), elevated parathyroid hormone (PTH) levels potentially harmful to bone health are commonly observed. Owing to assumed superior absorption, calcium citrate is often recommended over calcium carbonate following RYGB for the treatment of elevated PTH. We aimed to investigate the impact of either calcium carbonate or calcium citrate (1200 mg elementary calcium) in patients with elevated PTH levels following RYGB. DESIGN Clinical, double-blinded, randomized controlled trial of a 12-week duration at a Danish University Hospital. PATIENTS AND MEASUREMENTS Thirty-nine (no drop out) RYGB operated patients with elevated PTH levels (PTH > 6.9 pmol/L) and normal plasma levels of calcium and 25-hydroxyvitamin D were randomized to either calcium carbonate or calcium citrate (1200 mg elementary calcium/daily). We assessed change in PTH as the primary outcome. RESULTS The effect of the two calcium formulations on change in PTH was comparable and neutral: -1.9% (calcium citrate) vs +0.9% (calcium carbonate), P = 0.680. Compared to the carbonate-treated group, the following bone turnover markers decreased significantly in the citrate-treated group: procollagen I N-terminal propeptide (-16.6% vs -3.2%, P = 0.021), osteocalcin (-17.2% vs -4.3%, P = 0.007) and bone-specific alkaline phosphatase (-5.9% vs 3.7%, P = 0.027) and remained significantly decreased after multivariable adjustment. CONCLUSION Increasing the dose of calcium supplementation in RYGB operated patients with slightly elevated PTH levels does not normalize PTH levels, regardless of the type of supplement. Our results do not support recommending supplementation with calcium citrate over calcium carbonate in RYGB patients.
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Effect of adding B-vitamins to vitamin D and calcium supplementation on CpG methylation of epigenetic aging markers.
Obeid, R, Hübner, U, Bodis, M, Graeber, S, Geisel, J
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2018;(4):411-417
Abstract
BACKGROUND AND AIM B-vitamins may influence DNA methylation. We studied the effects of vitamin D + Ca + B versus D + Ca on epigenetic age markers and biological age. METHODS AND RESULTS Participants (mean ± SD of age = 68.4 ± 10.1 years) were randomized to receive 1200 IE vitamin D3 plus 800 mg Ca-carbonate alone (n = 31) or with 0.5 mg B9, 50 mg B6, and 0.5 mg B12 (n = 32). The CpG methylation of 3 genes (ASPA, ITGA2B, and PDE4C) and the changes in methylation were compared between the groups after 1 year. The changes of ASPA methylation from baseline were higher in the D + Ca + B than in the D + Ca group (1.40 ± 4.02 vs. -0.96 ± 5.12, respectively; p = 0.046, adjusted for age, sex, and baseline methylation). The changes in PDE4C from baseline were slightly higher in the D + Ca + B group (1.95 ± 3.57 vs. 0.22 ± 3.57; adjusted p = 0.062). Methylation of ITGA2B and its changes from baseline were not different between the intervention groups. Sex-adjusted odds ratio of accelerated aging (chronological age < biological age at 1 year) was 5.26 (95% confidence interval 1.51-18.28) in the D + Ca + B compared with the D + Ca group. Accelerated aging in both groups was associated with younger age. In the D + Ca + B group, it was additionally associated with lower baseline homocysteine. CONCLUSIONS Vitamin D + Ca + B and D + Ca differentially affected epigenetic age markers, although the effect size appeared to be small after 1 year. B-vitamins effect in young subjects with low homocysteine requires further investigation. ClinicalTrials.gov ID: NCT02586181.