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REVIEWpublished:05 February 2019doi:10.3389/fcvm.2019.00006Frontiers in Cardiovascular Medicine|www.frontiersin.org1February 2019|Volume 6|Article 6Edited by:Dwight A.Towler,University of Texas SouthwesternMedical Center,United StatesReviewed by:Yabing Chen,University of Alabama at Birmingham,United StatesJoshua D.Hutcheson,Florida International University,United StatesSasha Anna Singh,Harvard Medical School,United StatesAlexander N.Kapustin,AstraZeneca,United Kingdom*Correspondence:Leon J.Schurgersl.schurgersmaastrichtuniversity.nlSpecialty section:This article was submitted toAtherosclerosis and VascularMedicine,a section of the journalFrontiers in Cardiovascular MedicineReceived:21 September 2018Accepted:14 January 2019Published:05 February 2019Citation:Wasilewski GB,Vervloet MG andSchurgers LJ(2019)TheBoneVasculature Axis:CalciumSupplementation and the Role ofVitamin K.Front.Cardiovasc.Med.6:6.doi:10.3389/fcvm.2019.00006The BoneVasculature Axis:Calcium Supplementation and theRole of Vitamin KGrzegorz B.Wasilewski1,2,Marc G.Vervloet3and Leon J.Schurgers1*1Department of Biochemistry,Cardiovascular Research Institute Maastricht,Maastricht University,Maastricht,Netherlands,2Nattopharma ASA,Hovik,Norway,3Department of Nephrology and Amsterdam Cardiovascular Sciences,AmsterdamUniversity Medical Centers,Amsterdam,NetherlandsCalciumsupplementsarebroadlyprescribedtotreatosteoporosiseitherasmonotherapyor together with vitamin D to enhance calcium absorption.It is still unclear whethercalcium supplementation significantly contributes to the reduction of bone fragility andfracture risk.Data suggest that supplementing post-menopausal women with highdoses of calcium has a detrimental impact on cardiovascular morbidity and mortality.Chronic kidney disease(CKD)patients are prone to vascular calcification in part dueto impaired phosphate excretion.Calcium-based phosphate binders further increaserisk of vascular calcification progression.In both bone and vascular tissue,vitaminK-dependent processes play an important role in calcium homeostasis and it is temptingto speculate that vitamin K supplementation might protect from the potentially untowardeffects of calcium supplementation.This review provides an update on current literatureon calcium supplementation among post-menopausal women and CKD patients anddiscusses underlying molecular mechanisms of vascular calcification.We proposetherapeutic strategies with vitamin K2 treatment to prevent or hold progression ofvascular calcification as a consequence of excessive calcium intake.Keywords:calcium paradox,vitamin K,vascular calcification,calcium supplements,bone lossINTRODUCTIONCalcium is an abundant element in nature and is a major component of sedimentary rockthat covers 75 to 80%of the Earths surface.Calcium is also widely abundant in the humanbody,primarily in bone,and teeth.Calcium salts are occasionally found outside bone in avariety of tissues;this is broadly termed as extra-skeletal calcification.In these extra-skeletal sites,calcium exists in multiple forms,including amorphous calcium phosphate,hydroxyapatite,andmagnesium whitlockite.A remarkable observation is that under several pathological conditions,as will be discussed,calcium mineral content of bone declines,while it is increasing onthese extra-osseous sites.This has been termed the“calcium paradox”and was introduced todescribe the paradoxical correlation between lower bone calcium content with parallel increasedvascular calcium content(1).The calcium paradox refers to epidemiological data reporting thatpostmenopausal women experience bone loss,yet simultaneously screen positive for vascularcalcification.This phenomenon is common in osteoporotic women and patients suffering fromchronic kidney disease(CKD).Prevalence and morbidity of both cardiovascular disease andosteoporosis are increasing in the global population.Such observations have been noted in severalstudies,where a correlation of low bone mineral density(BMD)was associated with increasedcardiovascular mortality(26).Wasilewski et al.Calcium Supplements and Vascular CalcificationThe use of calcium supplements has been widely adviseddue to their assumed ability to support bone health and BMD(7,8).Calcium is an essential element for bone growth duringchildhood(9),as well as in preserving bone mineral densityduring adolescence(10).However,a systematic review andmeta-analysis of the effects of calcium supplementation alongwith vitamin D treatment showed that this treatment was notassociated with a lower incidence of fracture risk in adults,questioning whether calcium supplementation contributes tothe maintenance of healthy bone(11).In turn,recent datasuggest that calcium supplements increase prevalence ofmyocardial infarction(12),and may increase risk of coronaryartery calcification(CAC)(13).Moreover,higher doses ofcalcium from supplements than calcium obtained from dietaryintake might promote cardiovascular calcification(14).Thus,despite the relative benefit of calcium supplementation forbone,calcium supplements became controversial because ofa possibly increased cardiovascular risk.Substantially differentfrom calcium from dietary sources,calcium form supplementsinduce an acute rise in serum calcium levels that highly oscillatesin blood for up to 6h(15,16).The plasma calcium concentrationis tightly regulated by vitamin D,parathyroid hormone(PTH),and calcitonin(17,18).VitaminK-dependentproteins(VKDP)alsoplayanimportant role regulating mineralization both in bone andthe vasculature.Osteocalcin(OC)is produced exclusivelyby osteoblasts and supports the binding of calcium to thebone mineral matrix,whereas matrix Gla-protein(MGP)issynthesized by vascular smooth muscle cells and chondrocytesto prevent ectopic calcification.While hepatically producedcoagulation factors are the prototypical VKDP,the extra-hepaticVKDP also unequivocally need vitamin K as cofactor to becomebiologically active.Related to that,vitamin K2 has been shownto prevent bone loss and strength and prevents stiffening ofarteries(19,20).Western diet does not provide sufficient vitaminK to activate all OC and MGP that is produced(21,22).Alsoin CKD patients,vitamin K deficiency is prevalent,so K2supplementation has been suggested as treatment option toattenuate vascular calcification(23,24).In this review we provide the latest insights of the calciumparadox and the potential of using vitamin K to support bothbone and vascular health.BONE METABOLISMCalcification generally is a physiological process,necessaryto build bone and dentin.Bone provides structural support,strength,necessary for locomotion,and protection from theenvironment.The balance in bone formation and boneresorption is crucial for optimal bone health.A disturbed balanceof this process results in bone loss and is termed osteoporosis.Duringchildhoodboneisformedandbonepeakmassisachievedduring young adulthood,after which bone mass graduallydeclines.Bone loss is the consequence of bone resorptionoutbalancing bone formation(25).This is accompanied bybone architectural changes including trabecular bone becomingthinner,less abundant,and osteoclastic perforation of corticalbone(26).Bone FormationThe skeleton is systematically renewed in the process of boneremodeling to maintain strength and rigidity.Bone remodelingcan be considered to be part of calcium homeostasis systemand enables the skeleton to adapt to changes.Bones adapt theirstructure depending on their function,mechanical strain andneed for stability during development.It is mediated on thesurface of cortical and trabecular bone,and at anatomicallydifferent sites named basic multicellular subunits(27).Two pathways of bone formation exist,together termedosteogenesis.The first is known as endochondral ossification andinvolvesadifferentiationofmesenchymalcellsintochondrocytesor osteoblasts(28,29).As chondrocytes mature,they expand insize and become hypertrophic and eventually undergo apoptosis,secreting vesicles that initiate mineralization of extracellularmatrix(30).As they die,with vascular evasion and matrixremodeling(osteoclast mediated),the calcified cartilage issubsequently replaced by bone.Nestin-positive mesenchymalprogenitorsassociatedwiththeinvadingvasculaturedifferentiateinto bone-forming osteoblasts and deposit a type I collagen-based bone matrix on the degraded cartilage template(31),(32).The second process of bone formation is intramembranousossification.First,mesenchymal cells directly differentiate intoosteoblasts,which are bone-forming cells.Next,type I collagenmatrix is deposited by these cells,that can bind calciumsalts,which form hydroxyapatite crystals.This mineralizationof the matrix underlies the strength and compactness ofthe bone.With time,osteoblasts eventually become trappedin calcified extracellular matrix and transdifferentiate intoosteocytes.Osteoblasts are the only bone cell type releasingthe vitamin K-dependent protein OC(discussed below).As thenewlyformedboneislaid,itsdepositionmustbetightlyregulatedto maintain homeostasis.This balance is achieved by bone-resorbing cells,entering the blood vessels of bone,which aretermed osteoclasts and are of macrophage origin.Each osteoclastis able to secrete hydrogen ions,thereby acidifying the bonesurface dissolving mineralized matrix,followed by interactionsthat enhance the action of osteoblasts(3335).Upon resorption,bone-matrix embedded osteocalcin is released contributing to itscirculating levels(36).Bone LossBone loss is most typical in women after reaching theage of 50 years following menopause.The pattern of sexhormonal secretion drastically changes after the menopause,resulting in disbalance in bone turnover markers,makingpostmenopausalwomensusceptibletoosteoporosisandfractures.Remarkably cardiovascular diseases are also moreprevalent in postmenopausal women.Therefore,it is importantto understand the molecular mechanisms by which hormonalchanges leads to both osteoporosis and cardiovascular disease(37,38).The post-menopausal period is accompanied bysubstantial reduction of estrogen levels leading to boneresorption,yet simultaneously reducing calcium absorptionFrontiers in Cardiovascular Medicine|www.frontiersin.org2February 2019|Volume 6|Article 6Wasilewski et al.Calcium Supplements and Vascular Calcification(39).It is not the aim of this review to elaborate on the effectof estrogen on the vasculature reviewed elsewhere(39).Instead,we will focus on specific pathways involved in calciummetabolism.PTH is released upon hypocalcemia,indirectly stimulatingrelease of calcium from bone.In CKD,autonomous productionof PTH may occur.Additionally,PTH promotes reabsorptionof ultra-filtered calcium in distal tubules and activates vitaminD thereby increasing circulating calcium levels by raisinggastrointestinal uptake of calcium(17,18).Calcium-sensingreceptors(CaR)present on the surface of parathyroid glandsenable sensing of circulating calcium concentration(40),contributing to calcium modulation.Vitamin D is a fat-soluble vitamin that can be obtainedfrom diet,sun exposure,or supplements,and is metabolizedby a series of enzymatic reactions in the body producingits active 1,25-dihydroxyvitamin D form(41,42).Vitamin D(in inactive form)is often prescribed in combination withcalcium supplements.Active 1,25-dihydroxyvitamin D enhancesabsorption of intestinal calcium and phosphate thus contributingto the regulating of mineral balance(43,44).In the absence ofvitamin D,only 1015%of intestinal calcium is absorbed,whichcan be increased to 3040%in the presence of active vitaminD(45,46).Vitamin D was found to stimulate production ofvitamin K-dependent proteins,like osteocalcin(47).Osteocalcinis a protein involved in bone mineralization reviewed elsewhere(48).Remarkably,inclusionofvitaminKincalciumandvitaminD supplements improved BMD and ucOC when compared withvitamin D and calcium alone(49).CKDpatientsoftenexperiencedeficiencyof1,25-dihydroxyvitaminDasaconsequenceoflostkidneymass and the effects of fibroblast growth factor 23(50),resulting in declined activity of 1-alpha hydroxylase(5153).Reduced serum levels of 1,25-dihydroxyvitamin D lead tohypocalcemia on top of positive phosphate balance,bothstimulating PTH release and eventually leading to secondaryhyperparathyroidism.VASCULAR CALCIFICATIONVascular calcification is a pathological process,and has beenfirmly established as a risk factor for cardiovascular eventsand mortality(54,55).Vascular calcification is a process ofextraosseous mineral deposition in blood vessels,including largearteries such as aorta,carotid arteries,iliac arteries,and cardiacvalves.Bonemineralizationandvascularcalcificationsharemanysimilarities,including expression of bone-related proteins inthe vasculature and secretion of extracellular vesicles(EVs)both preceding the phase of calcification(56,57).Vascularcalcification can occur either in the tunica media or tunicaintima of the vessel wall.Medial calcification is also knownas Mckenbergs sclerosis and involves vascular smooth musclecell(SMC)calcification in the absence of previous local lipidaccumulation,and inflammation.Medial calcification is relatedto CKD,diabetes mellitus,and aging,and results in increasedarterial stiffness and risk of cardiovascular events(58,59).Incontrast,intimal calcification is associated with atheroscleroticplaque formation and the amount of calcification is consideredto be a measure of atherosclerotic burden(1).For many years vascular calcification was considered asa clinically irrelevant process reliant of passive depositionofcalciumcrystals,merelyreflectingapassivefeatureof disease and aging.Recent evidence however suggestsotherwise,and vascular calcification appears to be a highlyregulatedprocess.SMCsreleasecalcificationinhibitors,thus efficiently preventing spontaneous calcification in spiteof supersaturation of extracellular calcium and phosphatelevels(60).Vascular Smooth Muscle Cell PhenotypicSwitchingSMCs are the main cellular component of the tunica mediain arterial vessels providing structural support and regulatingvascular tone and elasticity to alterations in pressure conditions.In physiology SMCs possess a contractile phenotype andexpress contractile-specific markers,including alpha-smoothmuscle actin,calponin,and SM22alpha,enabling them toperform contraction of the vessel wall reviewed elsewhere(61,62).SMC function is associated with a high level ofphenotypic plasticity in order to perform a variety of functionsincluding production of extracellular matrix and repair(61,63).Several factors have been implicated in regulating SMCphenotype,including mineral imbalance(calcium,magnesium,and phosphate-induced loss of calcification inhibitors andpresence of calcification promotors)(64).Downregulationof contractile markers is a hallmark for SMC phenotypicswitching(65).Ithasbeenshownthatphosphatecaninduce an osteochondrogenic phenotypic switching of SMC,aswillbeoutlinedinmoredetailbelow(61,6669),whereas elevated calcium levels shift th