nutrients Review Vitamin K and D Supplementation and Bone Health in Chronic Kidney Disease—Apart or Together? Marta Ziemi ´nska 1, Beata Sieklucka 2 and Krystyna Pawlak 1,* 1 Department of Monitored Pharmacotherapy, Medical University of Bialystok, 15-222 Bialystok, Poland; [email protected] 2 Department of Pharmacodynamics, Medical University of Bialystok, 15-222 Bialystok, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-85-748-5600 Abstract: Vitamin K (VK) and vitamin D (VD) deficiency/insufficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and a higher risk of fractures. CKD patients, with disturbances in VK and VD metabolism, do not have sufficient levels of these vitamins for maintaining normal bone formation and mineralization. So far, there has been no consensus on what serum VK and VD levels can be considered sufficient in this particular population. Moreover, there are no clear guidelines how supplementation of these vitamins should be carried out in the course of CKD. Based on the existing results of preclinical studies and clinical evidence, this review intends to discuss the effect of VK and VD on bone remodeling in CKD. Although the mechanisms of action and the effects of these vitamins on bone are distinct, we try to find evidence for synergy between them in relation to bone metabolism, to answer the question of whether combined supplementation of VK and VD will be more beneficial for bone health in the CKD population than administering each of these vitamins separately. Citation: Ziemi´nska,M.; Sieklucka, B.; Pawlak, K. Vitamin K and D Keywords: vitamin K; vitamin D; chronic kidney disease; bone remodeling; vitamin K and D Supplementation and Bone Health in supplementation Chronic Kidney Disease—Apart or Together? Nutrients 2021, 13, 809. https://doi.org/10.3390/nu13030809 1. Introduction Academic Editor: Chronic kidney disease (CKD) represents a global health issue involving about 13% Vassilios Liakopoulos of the general population, of which about 11% are patients in the 3–5 stage of CKD [1]. Impaired kidney function impacts the quality of bone tissue and results in the development Received: 28 January 2021 of disorders in bone and mineral metabolism, which are defined as Chronic Kidney Disease- Accepted: 24 February 2021 Published: 1 March 2021 Mineral Bone Disorders (CKD-MBD) [2]. Abnormalities in mineral and bone metabolism contribute, in part, to severity of vascular calcification (VC). In this context, CKD-specific Publisher’s Note: MDPI stays neutral risk factors are believed to drive substantially to VC and cardiovascular disease. It is also with regard to jurisdictional claims in established that patients with CKD stage 3–5 will die due to cardiovascular events before published maps and institutional affil- the need of renal replacement therapy [3,4]. iations. CKD-MBD impacts bone remodeling (Figure1)—the dynamic process mediated mainly by the two antagonistically acting cellular populations: osteoblasts (OBs) that control the formation of bone and osteoclasts (OCs), with the ability to resorb mineral- ized bone [5]. This process is tightly regulated by local and systemic hormones, such as parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25D), and vitamin K (VK) [5,6]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. The process of bone remodeling is composed of four phases: the activation phase (the This article is an open access article recruitment of OCs); the resorption phase (the resorption of bone by OCs); the reversal distributed under the terms and phase (the apoptosis of OCs and the recruitment of OBs); and the formation phase (the OBs conditions of the Creative Commons lay down new organic bone matrix that subsequently mineralize) [6]. Bone remodeling Attribution (CC BY) license (https:// together with bone size, geometry, structure, and volume determines bone’s biomechanical creativecommons.org/licenses/by/ properties, integrity, and strength, providing renewal of damaged bone. An imbalance 4.0/). between the amount of resorbed bone and the quantity of new bone formation substantially Nutrients 2021, 13, 809. https://doi.org/10.3390/nu13030809 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 33 Nutrients 2021, 13, 809 2 of 34 imbalance between the amount of resorbed bone and the quantity of new bone formation contributessubstantially to thecontributes increased to risk the of fractures,increased whichrisk of is fractures, associated which with higher is associated mortality with in patientshigher mortality with CKD in [7 patients–9]. with CKD [7–9]. Figure 1. Bone remodeling. Abbreviations: ALP, alkaline phosphatase; BGLAP, bone-Gla-protein; Figure 1. Bone remodeling. Abbreviations: ALP, alkaline phosphatase; BGLAP, bone-Gla-protein; BMP, bone morphogenic protein; BSP, bone sialoprotein; c-fms, colony-stimulating factor-1 BMP, bone morphogenic protein; BSP, bone sialoprotein; c-fms, colony-stimulating factor-1 receptor; receptor; COL1, collagen type 1; CTSK, cathepsin K; HSC, hemapoietic stem cells; MAPKs, COL1,mitogen collagen-activated type protein 1; CTSK, kinases; cathepsin M-CSF, K; HSC, macrophage hemapoietic colony stem-stimulating cells; MAPKs, factor; mitogen-activated MMP-9, matric proteinmetalloproteinase kinases; M-CSF, 9; Msc, macrophage mesenchymal colony-stimulating stem cell; NFATc, factor; nuclear MMP-9, factor matric of activated metalloproteinase T-cells; NFkB, 9; Msc,nuclear mesenchymal factor-kappa stem B; cell; OPN, NFATc, osteopontin; nuclear factorOCPs, of osteoclast activated precursors; T-cells; NFkB, RANK, nuclear receptor factor-kappa activator B; OPN,of nuclear osteopontin; factor kappa OCPs, B; osteoclast RANKL, precursors; receptor activator RANK, of receptor nuclear activator factor kappa of nuclear B ligand; factor Runx2, kappa B; RANKL,runt-related receptor transcription activator of factor nuclear 2; TRAF6, factor kappa Tumor B ligand;necrosis Runx2, factor runt-related receptor associated transcription factor factor 6; 2; TRAF6,TRAP, Tumortartare necrosis-resistant factor acid phosphatase. receptor associated factor 6; TRAP, tartare-resistant acid phosphatase. ManyMany clinical clinical studies studies reported reported on VKon VK and and vitamin vitamin D (VD) D (VD) deficiency deficiency in patients in patients with CKDwith or CKD undergoing or undergoing dialysis dialysis [3,10–12 [3,10]. These–12]. vitaminThese vitamin deficiencies deficiencies could resultcould fromresult both from dietaryboth dietary and nondietary and nondietary determinants. determinants Dietary. Dietary recommendations recommendation for CKDs for patients, CKD suchpatients, as dietssuch low as diets in potassium low in potassium (fewer leafy (fewer green leafy vegetables green vegetables rich in vitamin rich in K1,vitamin VK1) K1 and, VK1) low and in phosphatelow in phosphate (fewer dairy (fewer products dairy products rich in vitamin rich in vitamin K2, VK2) K2 could, VK2) promote could promote VK deficiency. VK de- Holdenficiency. et Holden al. [3] showed et al. [ that3] showed patients that with patients stage 3–5with CKD stage have 3–5 higher CKD VK1have levelshigher than VK1 thoselevels on than maintenance those on maintenance dialysis. They dialysis. concluded They that concluded patients that who patients were clinically who were better clini- nourishedcally better have nourished also better have vitamin also better K status. vitamin Nutritional K status. factors Nutritional may alsofactors affect may the also defi- af- ciencyfect the of VDdeficiency status in of CKD. VD status The low in foodCKD. intake The low was food frequently intake noticed was frequently in this population, noticed in duethis to population, numerous due reasons, to numerous such as reduced reasons, appetite, such as reduced dietaryrestrictions, appetite, dietary i.e., low restrictions, protein andi.e., phosphate low protein diets, and uremic-related phosphate diets, gastrointestinal uremic-related symptoms, gastrointestinal and impaired symptoms gastrointesti-, and nalimpaired absorption gastrointestinal of VD [13]. The absorption nondietary of VD determinants [13]. The nondietary of VD in a determinants cohort of patients of VD with in a CKDcohort included of patients age, gender,with CKD low included physical age, activity, gender, less sunlightlow physical exposure, activity, blunted less sunlight the re- sponseexposure, of plasma blunted VD the to ultravioletresponse of (UVB) plasma irradiation, VD to ultraviolet and hyperpigmentation, (UVB) irradiation which, and may hy- playperpigmentation, a role in the impaired which may endogenous play a role VD in synthesis the impaired [14]. Additionally, endogenous withVD synthesis an increased [14]. lossAdditionally, of renal tissue, with the an availability increased loss and functionalityof renal tissue, of the 1-α availabilityhydroxylase and decreases, functionality thereby of reducing1-α hydroxylase 1,25D [15 decreases,]. Proteinuria thereby has alsoreducing been described1,25D [15] as. Proteinuria a contributing has factoralso been in the de- pathogenesisscribed as a contributing of VD deficiency facto [r3 ,in13 the,14]. pathogenesis Vitamin D binding of VD def proteiniciency (VDBP) [3,13,14] carries. Vitamin about D 85%binding of the protein circulating (VDBP) 25-hydroxyvitamin carries about 85% D (25D), of the VDBP–25Dcirculating complexes25-hydroxyvitamin are filtered D in (25D the), glomerulus. Patients