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Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutrition and Public Health".

Deadline for manuscript submissions: closed (20 September 2021) | Viewed by 49046

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Special Issue Editors

Dr. Maria Fusaro

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Guest Editor

1. National Research Council (CNR)—Institute of Clinical Physiology (IFC), Pisa Via G. Moruzzi 1, 56124 Pisa, PI, Italy
2. Department of Medicine, University of Padova Italy, Via Giustiniani 2, 35128 Padova, PD, Italy
Interests: vitamin K; vitamin D; mineral bone disorders, CKD; bone fractures; vascular calcifications; nutrition
Special Issues, Collections and Topics in MDPI journals

Dr. Giovanni Tripepi

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Co-Guest Editor

National Research Council (CNR) – Institute of Clinical Physiology (IFC), Section of Reggio Calabria, c/o Grande Ospedale Metropolitano BMM – Via Vallone Petrara, Reggio Calabria, Italy
Interests: Vitamin K; Vitamin D; CKD; Bone Fractures; Vascular calcifications; Biostatistics; Epidemiology

Prof. Dr. Maurizio Gallieni

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Co-Guest Editor

1. Department of Biomedical and Clinical Sciences, Università di Milano, 20157 Milano, Italy
2. Nephrology Unit, ASST Fatebenefratelli Sacco, 20157 Milano, Italy
Interests: vitamin K; vitamin D; phosphate; chronic kidney disease; nephrolithiasis; electrolyte disorders; peritoneal dialysis; hemodialysis; onconephrology

Special Issue Information

Dear Colleagues,

Bone disease involving fragility fractures (FFs) from osteoporosis and cardiovascular disease (CVD) are the two major causes of death worldwide. Therefore, it is very important to maintain bone and the vascular system in good status in order to adopt better strategies to prevent FFs and CVD. In this context, the association with chronic kidney disease (CKD) amplifies both fractures and CVD, especially in patients in end-stage renal disease (ESRD).

A healthy diet combined with exercise represents the best preventive approach. It is well-established that a dietary supplementation with calcium and vitamin D in postmenopausal women can decrease fracture risk. Furthermore, adequate vitamin K intake, combined with calcium and vitamin D, not only improves bone health (especially in terms of bone quality) but also prevents soft tissue calcifications through the action of the matrix Gla protein (MGP: a vitamin-K-dependent protein). Magnesium is another relevant player both for the formation of hydroxyapatite and also to reduce vascular calcifications (VCs).

This supplement will collect reviews aimed at describing the best available evidence in the field.

Dr. Maria Fusaro
Dr. Giovanni Tripepi
Prof. Dr. Maurizio Gallieni
Guest Editor

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Keywords

Vitamin D
Calcium
Magnesium
Vitamin K
Mineral bone disorders
Osteoporosis
Osteopenia
Bone fractures
Bone quality
Vascular calcifications
Cardiovascular disease

Published Papers (8 papers)

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Research

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13 pages, 1161 KiB

Open AccessArticle

A Novel Quantitative Computer-Assisted Score Can Improve Repeatability in the Estimate of Vascular Calcifications at the Abdominal Aorta

by Maria Fusaro, Enrico Schileo, Gianluigi Crimi, Andrea Aghi, Alberto Bazzocchi, Giovanni Barbanti Brodano, Marco Girolami, Stefania Sella, Cristina Politi, Serge Ferrari, Chiara Gasperini, Giovanni Tripepi and Fulvia Taddei

Nutrients 2022, 14(20), 4276; https://doi.org/10.3390/nu14204276 - 13 Oct 2022

Cited by 6 | Viewed by 1242

Abstract

In CKD and in the elderly, Vascular Calcifications (VC) are associated to cardiovascular events and bone fractures. VC scores at the abdominal aorta (AA) from lateral spine radiographs are widely applied (the 0–24 semiquantitative discrete visual score (SV) being the most used). We hypothesised that a novel continuum score based on quantitative computer-assisted tracking of calcifications (QC score) can improve the precision of the SV score. This study tested the repeatability and reproducibility of QC score and SV score. In forty-four patients with VC from an earlier study, five experts from four specialties evaluated the data twice using a dedicated software. Test–retest was performed on eight subjects. QC results were reported in a 0–24 scale to readily compare with SV. The QC score showed higher intra-operator repeatability: the 95% CI of Bland–Altman differences was almost halved in QC; intra-operator R² improved from 0.67 for SV to 0.79 for QC. Inter-observer repeatability was higher for QC score in the first (Intraclass Correlation Coefficient 0.78 vs. 0.64), but not in the second evaluation (0.84 vs. 0.82), indicating a possible heavier learning artefact for SV. The Minimum Detectable Difference (MDD) was smaller for QC (2.98 vs. 4 for SV, in the 0–24 range). Both scores were insensitive to test–retest procedure. Notably, QC and SV scores were discordant: SV showed generally higher values, and an increasing trend of differences with VC severity. In summary, the new QC score improved the precision of lateral spine radiograph scores in estimating VC. We reported for the first time an estimate of MDD in VC assessment that was 25% lower for the new QC score with respect to the usual SV score. An ongoing study will determine whether this lower MDD may reduce follow-up times to check for VC progression. Full article

(This article belongs to the Special Issue Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment)

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14 pages, 1322 KiB

Open AccessArticle

The Novel Bone Alkaline Phosphatase Isoform B1x Is Associated with Improved 5-Year Survival in Chronic Kidney Disease

by Mathias Haarhaus, Anders Fernström, Abdul Rashid Qureshi and Per Magnusson

Nutrients 2021, 13(12), 4402; https://doi.org/10.3390/nu13124402 - 09 Dec 2021

Cited by 2 | Viewed by 2518

Abstract

Circulating alkaline phosphatase (ALP) is an independent cardiovascular risk marker. Serum bone ALP (BALP) isoforms indicate bone turnover and comprise approximately 50% of total circulating ALP. In chronic kidney disease (CKD), mortality is highest in patients with increased ALP and BALP and low bone turnover. However, not all low bone turnover states are associated with increased mortality. Chronic inflammation and oxidative stress, features of protein energy wasting syndrome, induce cardiovascular BALP activity and fibro-calcification, while bone turnover is suppressed. Circulating BALP isoform B1x is associated with low ALP and low bone turnover and has been exclusively detected in CKD. We investigated the association of serum B1x with survival, abdominal aortic calcification (AAC) score, and aortic pulse wave velocity (PWV) in CKD. Serum ALP, BALP isoforms, parathyroid hormone (PTH), PWV, and AAC were measured repeatedly over 2 years in 68 prevalent dialysis patients. Mortality was assessed after 5 years. B1x was detected in 53 patients. A competing risk analysis revealed an association of B1x with improved 5-year survival; whereas, baseline PWV, but not AAC score, predicted mortality. However, PWV improved in 26 patients (53%), and B1x was associated with variation of PWV over time (p = 0.03). Patients with B1x had lower PTH and total ALP, suggesting an association with lower bone turnover. In conclusion, B1x is associated with time-varying PWV, lower circulating ALP, and improved survival in CKD, and thus may be an indicator of a reduced cardiovascular risk profile among patients with low bone turnover. Full article

(This article belongs to the Special Issue Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment)

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12 pages, 1621 KiB

Open AccessArticle

The Vessels-Bone Axis: Iliac Artery Calcifications, Vertebral Fractures and Vitamin K from VIKI Study

by Maria Fusaro, Giovanni Tripepi, Mario Plebani, Cristina Politi, Andrea Aghi, Fulvia Taddei, Enrico Schileo, Martina Zaninotto, Gaetano La Manna, Giuseppe Cianciolo, Maurizio Gallieni, Laura Cosmai, Piergiorgio Messa, Maura Ravera, Thomas L. Nickolas, Serge Ferrari, Markus Ketteler, Giorgio Iervasi, Maria Cristina Mereu, Roberto Vettor, Sandro Giannini, Lorenzo Gasperoni, Stefania Sella, Maria Luisa Brandi, Luisella Cianferotti and Raffaele De Caterina Show full author list Hide full author list

Nutrients 2021, 13(10), 3567; https://doi.org/10.3390/nu13103567 - 12 Oct 2021

Cited by 6 | Viewed by 2659

Abstract

Vascular calcification and fragility fractures are associated with high morbidity and mortality, especially in end-stage renal disease. We evaluated the relationship of iliac arteries calcifications (IACs) and abdominal aortic calcifications (AACs) with the risk for vertebral fractures (VFs) in hemodialysis patients. The VIKI study was a multicenter cross-sectional study involving 387 hemodialysis patients. The biochemical data included bone health markers, such as vitamin K levels, vitamin K-dependent proteins, vitamin 25(OH)D, alkaline phosphatase, parathormone, calcium, and phosphate. VF, IACs and AACs was determined through standardized spine radiograms. VF was defined as >20% reduction of vertebral body height, and VC were quantified by measuring the length of calcium deposits along the arteries. The prevalence of IACs and AACs were 56.1% and 80.6%, respectively. After adjusting for confounding variables, the presence of IACs was associated with 73% higher odds of VF (p = 0.028), whereas we found no association (p = 0.294) for AACs. IACs were associated with VF irrespective of calcification severity. Patients with IACs had lower levels of vitamin K2 and menaquinone 7 (0.99 vs. 1.15 ng/mL; p = 0.003), and this deficiency became greater with adjustment for triglycerides (0.57 vs. 0.87 ng/mL; p < 0.001). IACs, regardless of their extent, are a clinically relevant risk factor for VFs. The association is enhanced by adjusting for vitamin K, a main player in bone and vascular health. To our knowledge these results are the first in the literature. Prospective studies are needed to confirm these findings both in chronic kidney disease and in the general population. Full article

(This article belongs to the Special Issue Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment)

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15 pages, 796 KiB

Open AccessArticle

Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study

by Sandro Giannini, Giovanni Passeri, Giovanni Tripepi, Stefania Sella, Maria Fusaro, Gaetano Arcidiacono, Marco Onofrio Torres, Alberto Michielin, Tancredi Prandini, Valeria Baffa, Andrea Aghi, Colin Gerard Egan, Martina Brigo, Martina Zaninotto, Mario Plebani, Roberto Vettor, Paola Fioretto, Maurizio Rossini, Alessandro Vignali, Fabrizio Fabris and Francesco Bertoldo Show full author list Hide full author list

Nutrients 2021, 13(1), 219; https://doi.org/10.3390/nu13010219 - 14 Jan 2021

Cited by 53 | Viewed by 19627

Abstract

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67–0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients. Full article

(This article belongs to the Special Issue Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment)

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Review

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14 pages, 876 KiB

Open AccessReview

Cardiovascular Safety and Effectiveness of Bisphosphonates: From Intervention Trials to Real-Life Data

by Chiara Delli Poggi, Maria Fusaro, Maria Cristina Mereu, Maria Luisa Brandi and Luisella Cianferotti

Nutrients 2022, 14(12), 2369; https://doi.org/10.3390/nu14122369 - 07 Jun 2022

Cited by 4 | Viewed by 2614

Abstract

Both osteoporosis with related fragility fractures and cardiovascular diseases are rapidly outspreading worldwide. Since they are often coexistent in elderly patients and may be related to possible common pathogenetic mechanisms, the possible reciprocal effects of drugs employed to treat these diseases have to be considered in clinical practice. Bisphosphonates, the agents most largely employed to decrease bone fragility, have been shown to be overall safe with respect to cardiovascular diseases and even capable of reducing cardiovascular morbidity in some settings, as mainly shown by real life studies. No randomized controlled trials with cardiovascular outcomes as primary endpoints are available. While contradictory results have emerged about a possible BSP-mediated reduction of overall mortality, it is undeniable that these drugs can be employed safely in patients with high fracture risk, since no increased mortality has ever been demonstrated. Although partial reassurance has emerged from meta-analysis assessing the risk of cardiac arrhythmias during bisphosphonates treatment, caution is warranted in administering this class of drugs to patients at risk for atrial fibrillation, possibly preferring other antiresorptives or anabolics, according to osteoporosis guidelines. This paper focuses on the complex relationship between bisphosphonates use and cardiovascular disease and possible co-management issues. Full article

(This article belongs to the Special Issue Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment)

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25 pages, 1885 KiB

Open AccessReview

Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease

by Mathias Haarhaus, Giuseppe Cianciolo, Simona Barbuto, Gaetano La Manna, Lorenzo Gasperoni, Giovanni Tripepi, Mario Plebani, Maria Fusaro and Per Magnusson

Nutrients 2022, 14(10), 2124; https://doi.org/10.3390/nu14102124 - 19 May 2022

Cited by 23 | Viewed by 9485

Abstract

Alkaline phosphatase (ALP) is an evolutionary conserved enzyme and widely used biomarker in clinical practice. Tissue-nonspecific alkaline phosphatase (TNALP) is one of four human isozymes that are expressed as distinct TNALP isoforms after posttranslational modifications, mainly in bone, liver, and kidney tissues. Beyond the well-known effects on bone mineralization, the bone ALP (BALP) isoforms (B/I, B1, B1x, and B2) are also involved in the pathogenesis of ectopic calcification. This narrative review summarizes the recent clinical investigations and mechanisms that link ALP and BALP to inflammation, metabolic syndrome, vascular calcification, endothelial dysfunction, fibrosis, cardiovascular disease, and mortality. The association between ALP, vitamin K, bone metabolism, and fracture risk in patients with chronic kidney disease (CKD) is also discussed. Recent advances in different pharmacological strategies are highlighted, with the potential to modulate the expression of ALP directly and indirectly in CKD–mineral and bone disorder (CKD-MBD), e.g., epigenetic modulation, phosphate binders, calcimimetics, vitamin D, and other anti-fracture treatments. We conclude that the significant evidence for ALP as a pathogenic factor and risk marker in CKD-MBD supports the inclusion of concrete treatment targets for ALP in clinical guidelines. While a target value below 120 U/L is associated with improved survival, further experimental and clinical research should explore interventional strategies with optimal risk–benefit profiles. The future holds great promise for novel drug therapies modulating ALP. Full article

(This article belongs to the Special Issue Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment)

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15 pages, 1629 KiB

Open AccessReview

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism

by Maria Fusaro, Giulia Vanessa Re Sartò, Maurizio Gallieni, Laura Cosmai, Piergiorgio Messa, Maurizio Rossini, Iacopo Chiodini, Mario Plebani, Pieter Evenepoel, Nicholas Harvey, Serge Ferrari, Jorge Cannata-Andía, Andrea Trombetti, Maria Luisa Brandi, Markus Ketteler, Thomas L. Nickolas, John Cunningham, Syazrah Salam, Carlo Della Rocca, Aldo Scarpa, Salvatore Minisola, Fabio Malberti, Filomena Cetani, Mario Cozzolino, Sandro Mazzaferro, Luigi Morrone, Giovanni Tripepi, Martina Zaninotto, Maria Cristina Mereu, Maura Ravera, Giuseppe Cianciolo, Gaetano La Manna, Andrea Aghi, Sandro Giannini, Luca Dalle Carbonare and on behalf of the SIN-SIOMMMS Bone Biopsy Promoting Group Show full author list Hide full author list

Nutrients 2022, 14(9), 1742; https://doi.org/10.3390/nu14091742 - 22 Apr 2022

Cited by 8 | Viewed by 3265

Abstract

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis. Full article

(This article belongs to the Special Issue Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment)

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14 pages, 1544 KiB

Open AccessReview

Pathophysiology of Vascular Calcification and Bone Loss: Linked Disorders of Ageing?

by Jorge B. Cannata-Andía, Natalia Carrillo-López, Osvaldo D. Messina, Neveen A. T. Hamdy, Sara Panizo, Serge L. Ferrari and on behalf of the International Osteoporosis Foundation (IOF) Working Group on Bone and Cardiovascular Diseases

Nutrients 2021, 13(11), 3835; https://doi.org/10.3390/nu13113835 - 27 Oct 2021

Cited by 19 | Viewed by 5462

Abstract

Vascular Calcification (VC), low bone mass and fragility fractures are frequently observed in ageing subjects. Although this clinical observation could be the mere coincidence of frequent age-dependent disorders, clinical and experimental data suggest that VC and bone loss could share pathophysiological mechanisms. Indeed, VC is an active process of calcium and phosphate precipitation that involves the transition of the vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Among the molecules involved in this process, parathyroid hormone (PTH) plays a key role acting through several mechanisms which includes the regulation of the RANK/RANKL/OPG system and the Wnt/ß-catenin pathway, the main pathways for bone resorption and bone formation, respectively. Furthermore, some microRNAs have been implicated as common regulators of bone metabolism, VC, left ventricle hypertrophy and myocardial fibrosis. Elucidating the common mechanisms between ageing; VC and bone loss could help to better understand the potential effects of osteoporosis drugs on the CV system. Full article

(This article belongs to the Special Issue Nutrition in Bone and Vascular Health: The Journey from Pathophysiology to Treatment)

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