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      A Magnesium Based Phosphate Binder Reduces Vascular Calcification without Affecting Bone in Chronic Renal Failure Rats

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          Abstract

          The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover.

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          Arterial calcifications and bone histomorphometry in end-stage renal disease.

          Arterial calcification (AC) is a common complication of end-stage renal disease (ESRD). The mechanisms responsible are complex, including disturbances of mineral metabolism and active expression of various mineral-regulating proteins. An inverse relationship between AC and bone density has been documented in uremic patients. In the study presented here, which included 58 patients with ESRD on hemodialysis (HD), bone-histomorphometry characteristics were compared with the AC scores (0 to 4) determined according to the number of arterial sites with calcifications. Patients with AC scores of 0 (no calcifications), or 1 or 2 (mild calcifications) had similar serum parathyroid hormone levels and bone histomorphometry, with larger osteoclast resorption, higher osteoclast numbers, and larger osteoblastic and double tertracycline-labeled surfaces. In contrast, patients with high AC scores (3 and 4) were characterized by lower serum parathyroid hormone, low osteoclast numbers and osteoblastic surfaces, smaller or absent double tetracycline-labeled surfaces, and high percentages of aluminum-stained surfaces. According to multivariate analysis, AC score was positively associated with age (P < 0.0001), daily dose of calcium-containing phosphate binders (P = 0.009), and bone aluminum-stained surfaces (P = 0.037), and an inverse correlation was observed with osteoblastic surfaces (P = 0.001). A high AC score is associated with bone histomorphometry suggestive of low bone activity and adynamic bone disease. These findings suggest that therapeutic interventions associated with excessive lowering of parathyroid activity (parathyroidectomy, excessive calcium or aluminum load) favor lower bone turnover and adynamic bone disease, which could influence the development and progression of AC.
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            Association of changes in bone remodeling and coronary calcification in hemodialysis patients: a prospective study.

            Vascular calcification is common and constitutes a prognostic marker of mortality in the hemodialysis population. Derangements of mineral metabolism may influence its development. The aim of this study is to prospectively evaluate the association between bone remodeling disorders and progression of coronary artery calcification (CAC) in hemodialysis patients. Cohort study nested within a randomized controlled trial. 64 stable hemodialysis patients. Bone-related laboratory parameters and bone histomorphometric characteristics at baseline and after 1 year of follow-up. Progression of CAC assessed by means of coronary multislice tomography at baseline and after 1 year of follow-up. Baseline calcification score of 30 Agatston units or greater was defined as calcification. Change in calcification score of 15% or greater was defined as progression. Of 64 patients, 38 (60%) of the patients had CAC and 26 (40%) did not [corrected]. Participants without CAC at baseline were younger (P < 0.001), mainly men (P = 0.03) and nonwhite (P = 0.003), and had lower serum osteoprotegerin levels (P = 0.003) and higher trabecular bone volume (P = 0.001). Age (P = 0.003; beta coefficient = 1.107; 95% confidence interval [CI], 1.036 to 1.183) and trabecular bone volume (P = 0.006; beta coefficient = 0.828; 95% CI, 0.723 to 0.948) were predictors for CAC development. Of 38 participants who had calcification at baseline, 26 (68%) had CAC progression in 1 year. Progressors had lower bone-specific alkaline phosphatase (P = 0.03) and deoxypyridinoline levels (P = 0.02) on follow-up, and low turnover was mainly diagnosed at the 12-month bone biopsy (P = 0.04). Low-turnover bone status at the 12-month bone biopsy was the only independent predictor for CAC progression (P = 0.04; beta coefficient = 4.5; 95% CI, 1.04 to 19.39). According to bone histological examination, nonprogressors with initially high turnover (n = 5) subsequently had decreased bone formation rate (P = 0.03), and those initially with low turnover (n = 7) subsequently had increased bone formation rate (P = 0.003) and osteoid volume (P = 0.001). Relatively small population, absence of patients with severe hyperparathyroidism, short observational period. Lower trabecular bone volume was associated with CAC development, whereas improvement in bone turnover was associated with lower CAC progression in patients with high- and low-turnover bone disorders. Because CAC is implicated in cardiovascular mortality, bone derangements may constitute a modifiable mortality risk factor in hemodialysis patients.
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              Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability

              Background. Phosphate binders are required to control serum phosphorus in dialysis patients. A phosphate binder combining calcium and magnesium offers an interesting therapeutic option. Methods. This controlled randomized, investigator-masked, multicentre trial investigated the effect of calcium acetate/magnesium carbonate (CaMg) on serum phosphorus levels compared with sevelamer hydrochloride (HCl). The study aim was to show non-inferiority of CaMg in lowering serum phosphorus levels into Kidney Disease Outcome Quality Initiative (K/DOQI) target level range after 24 weeks. Three hundred and twenty-six patients from five European countries were included. After a phosphate binder washout period, 255 patients were randomized in a 1:1 fashion. Two hundred and four patients completed the study per protocol (CaMg, N = 105; dropouts N = 18; sevelamer-HCl, N = 99; dropouts N = 34). Patient baseline characteristics were similar in both groups. Results. Serum phosphorus levels had decreased significantly with both drugs at week 25, and the study hypothesis of CaMg not being inferior to sevelamer-HCl was confirmed. The area under the curve for serum phosphorus (P = 0.0042) and the number of visits above K/DOQI (≤1.78 mmol/L, P = 0.0198) and Kidney disease: Improving global outcomes (KDIGO) targets (≤1.45 mmol/L, P = 0.0067) were significantly lower with CaMg. Ionized serum calcium did not differ between groups; total serum calcium increased in the CaMg group (treatment difference 0.0477 mmol/L; P = 0.0032) but was not associated with a higher risk of hypercalcaemia. An asymptomatic increase in serum magnesium occurred in CaMg-treated patients (treatment difference 0.2597 mmol/L, P < 0.0001). There was no difference in the number of patients with adverse events. Conclusion. CaMg was non-inferior to the comparator at controlling serum phosphorus levels at Week 25. There was no change in ionized calcium; there was minimal increase in total serum calcium and a small increase in serum magnesium. It had a good tolerability profile and thus may represent an effective treatment of hyperphosphataemia.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                17 September 2014
                : 9
                : 9
                : e107067
                Affiliations
                [1 ]Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
                [2 ]Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany
                [3 ]Department of Nephrology, University of Düsseldorf, Düsseldorf, Germany
                University of Milan, Italy
                Author notes

                Competing Interests: Ellen Neven has read the journal's policy and the authors of this manuscript have the following competing interests: S. Steppan, K. Gündlach and J. Büchel are current employees of Fresenius Medical Care Deutschland GmbH. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: EN TDS GD KG SS JB JPD PD GB. Performed the experiments: EN TDS GD GB. Analyzed the data: EN TDS GB. Contributed to the writing of the manuscript: EN KG SS JB JPD PD GB.

                Article
                PONE-D-14-21161
                10.1371/journal.pone.0107067
                4167554
                25229549
                b8553457-866d-474b-b39d-a68ebeef0484
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 May 2014
                : 7 August 2014
                Page count
                Pages: 9
                Funding
                This study was supported by a research grant (grant number: A11/0819) from Fresenius Medical Care Deutschland GmbH (Bad Homburg, Germany). K. Gundlach, S. Steppan and J. Büchel are current employees of Fresenius Medical Care Deutschland GmbH and contributed to the study design and proofreading of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Bone and Mineral Metabolism
                Medicine and Health Sciences
                Cardiology
                Cardiovascular Diseases
                Nephrology
                Mineral Metabolism and the Kidney
                Vascular Medicine
                Vascular Diseases
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

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