A Systematic Review on the Implication of Minerals in the Onset, Severity and Treatment of Periodontal Disease

molecules Re iew A Sys ema ic Re iew on he Implica ion o Mine als in he Onse , Se e i y and T ea men o Pe iodon al Disease Al onso Va ela-López 1, F ancesca Giampie i 2, Ped o Bullón 3, Mau izio Ba ino 2 and José L. Quiles 1,* 1 Depa men o Physiology, Ins i u e o Nu i ion and Food Technology “Jose Ma aix”, Uni e si y o G anada, Biomedical Resea ch Cen e , A da. Conocimien o s.n., 18100 A milla, G anada, Spain; al a ela@ug .es 2Dipa imen o di Scienze Cliniche Specialis iche ed Odon os oma ologiche (DISCO)-Sez. Biochimica, Facol à di Medicina, Uni e si à Poli ecnica delle Ma che, 60131 Ancona, I aly; .giampie i@uni pm.i (F.G.); [email p o ec ed] (M.B.) 3Depa men o S omalogy, Den al School, Uni e si y o Se illa, C/A icena s.n., 41009 Se illa, Andalusia, Spain; [email p o ec ed] *Co espondence: jlquiles@ug .es; Tel.: +34-958-241-000 (ex . 20316) Academic Edi o : De ek J. McPhee Recei ed: 21 July 2016; Accep ed: 31 Augus 2016; Published: 7 Sep embe 2016 Abs ac : Pe iodon al disease is an in lamma o y disease wi h high p e alence in adul s ha leads o des uc ion o he ee h-suppo ing issues. Pe iodon al he apy has been adi ionally di ec ed a educ ion o he bac e ial load o a le el ha encou ages heal h-p omo ing bac e ia and main enance o o al-hygiene. The ole o nu i ion in di e en ch onic in lamma o y diseases has been he subjec o an inc easing body o esea ch in he las decades. In his sense, he e has been an impo an inc ease in he olume o esea ch on ole o nu i ion in pe iodon i is since he die has known e ec s on he immune sys em and in lamma o y cascades. Mine als play a key ole in all hese p ocesses due o he mul iple pa hways whe e hey pa icipa e. To cla i y he ole o he di e en mine als in he es ablishmen , p og ession and/o ea men o his pa hology, a sys emically e iew o published li e a u e ci ed in PubMed un il May 2016 was conduc ed, which included esea ch on he ela ionship o hese elemen s wi h he onse and p og ession o pe iodon al disease. Among all he mine als, calcium die a y in ake seems impo an o main ain al eola bone. Likewise, die a y p opo ions o mine als ha may in luence i s me abolism also can be ele an . Las ly, some obse a ions sugges ha all hose mine als wi h oles in immune and/o an ioxidan sys ems should be conside ed in u u e esea ch. Keywo ds: mine al; calcium; pe iodon i is; o al heal h; die ; nu i ion 1. In oduc ion Pe iodon al disease is an in lamma o y disease ha leads o des uc ion o he ee h-suppo ing issues (i.e., he pe iodon ium). The e m mainly includes gingi i is, ch onic pe iodon i is and agg essi e pe iodon i is [ 1 ]. Pe iodon i is is a ubiqui ous disease wi h high p e alence in adul s. In pa icula , he WHO sponso ed Global Bu den o Diseases s udy indica es ha 11.2% o adul s wo ldwide expe ience se e e pe iodon al disease. This disease is conside ed he esul o he in e ac ion be ween pa hogenic bac e ia and he hos ’s immune esponse [ 2 , 3 ]. Den al plaque bio ilm ha is o med by bac e ia and oxins is he p ima y e iology [ 4 , 5 ]. Pe iodon al disease is ini ia ed by he accumula ion o a pa hogenic bio ilm a and below he gingi al ma gin [ 6 ]. In u n, bac e ial p oduc o componen s s imula e polymo phonuclea and o he esiden cells which may damage connec i e issue su ounding he ee h i hei s imula ion is excessi e [ 4 , 5 , 7 ]. As consequence, a Molecules 2016,21, 1183; doi:10.3390/molecules21091183 www.mdpi.com/jou nal/molecules Molecules 2016,21, 1183 2 o 21 p og essi e b eakdown o he pe iodon al ligamen and al eola bone accompanied by pe iodon al pocke o ma ion, gingi al ecession o bo h occu [ 8 ]. I is conside ed ha bo h local and sys emic ac o s a ec he se e i y and p og ession o pe iodon al disease. The e a e ce ain g oups o “dysbio ic” mic oo ganisms (“pa hogenic species”) conside ed as causa i e agen s [ 9 ] whose amoun would inc ease agains mic oo ganisms ha co-exis symbio ically wi h a p opo iona e hos esponse ha is in u n associa ed wi h esolu ion o des uc i e in lamma o y cascades. These usually a e some G am-nega i e bac e ia species ha d i e excess in lamma ion in pe iodon i is suscep ible subjec s ha would ha e a “hype -in lamma o y” esponse [ 6 ]. Thus, i is hough ha hos esponse and immune sys em a e he ac ual de e minan s o his disease, a leas in many cases [9]. Pe iodon al he apy has been adi ionally been di ec ed a educ ion o he bac e ial load o a le el ha encou ages heal h-p omo ing bac e ia and main enance o o al-hygiene [ 6 , 10 ]. Howe e , because o sys emic ac o s also seem o a ec pe iodon al disease, o he esea ch opics ha e appea ed in las decades. The ole o nu i ion in di e en ch onic in lamma o y diseases has been he subjec o an inc easing body o esea ch in he las decades. In his sense, he e has been an impo an su ge in he amoun o esea ch on he ole o nu i ion in pe iodon i is since he die has known e ec s on he immune sys em and in lamma o y cascades. Unde s anding he ole and implica ion o di e en nu ien s in his disease should allow iden i ying nu i ional isk ac o s and modula o s o pe iodon al in lamma ion o a ge ed p e en ion and ea men app oaches in pa ien s wi h speci ic nu i ional deple ion. This is pa icula ly in e es ing o people wi h ac o s ha comp ise he abili y o abso b o me abolize key die a y nu ien s due o di e en causes, including gene ics [11]. Nu ien s can be ca ego ized as ei he mac onu ien s (needed in ela i ely la ge amoun s and in mos o cases o p o ide ene gy) o mic onu ien s. These las a e die a y compounds ha do no p o ide ene gy bu a e equi ed by li ing o ganisms and a e essen ial o op imal heal h, p ope g ow h, and me abolism. I has been sugges ed ha pe iodon i is is associa ed wi h de iciencies in se um mic onu ien le els ha usually inc ease he isk o disease [ 12 ]. These basically include i amins and mine als [ 12 ]. Mine als make up abou 4% o he body weigh and hey a e mainly loca ed in he skele on, enzymes, ho mones and i amins. They usually ac as co ac o s in enzymes and hei p esence in balanced concen a ions in di e en body compa men s is needed o mul iple physiological p ocesses (hea hy hm, muscle con ac ion, ne e conduc ion, and acid-base balance homeos asis). Mo eo e hey also ha e s uc u al unc ions ha a e pa icula ly impo an o bones and ee h. Mine als can be classi ied as ei he majo mine als (>100 mg/day) o ace elemen s (<100 mg/day). The majo mine als a e sodium, po assium, calcium, magnesium, phospho us and sul u . The ace mine als a e: i on, zinc, iodine, selenium, luo ide, coppe , cobal , ch omium, manganese and molybdenum [1,13]. Nume ous e iews abou he associa ion be ween pe iodon i is and di e en componen s o he die ha e been published [ 1 , 6 , 9 – 12 , 14 – 18 ], bu only a ew o hem used a sys ema ic app oach [ 9 , 11 , 12 , 19 ]. Mo eo e , hey we e es ic ed o ce ain popula ion g oups [ 11 ], s udy ypes [ 9 , 11 , 12 ] o did no include animals [ 1 , 6 , 9 , 11 , 12 , 14 , 15 ]. This pape sys emically e iews he li e a u e a ailable in he PubMed da abase he incep ion o he da abase un il May 2016 on he e ec s o di e en mine al in akes o nu i ional s a us wi h he onse , se e i y and ea men o pe iodon al disease bo h in humans and animals, a ending wi h special in e es o die a y in e en ions and he implica ions o each one o he mechanisms in ol ed in hese pa hologies. 2. Resul s The sea ch e ms used p o ided a o al o 5478 i ems. A e abs ac sc eening his numbe was educed o 70 po en ial a icles o be included. Finally, a comp ehensi e ull- ex eading was pe o med and 44 mo e we e disca ded (Figu e 1). O e all, he e we e da a o nine o he di e en mine als: calcium, magnesium, phospho us, i on, po assium, coppe , zinc, selenium and manganese, which a e p esen ed in hei espec i e subsec ions. Some o he included s udies in es iga ed po en ial Molecules 2016,21, 1183 3 o 21 associa ions o e ec s o wo o mo e di e en mine als and consequen ly, hey we e epea ed in di e en subsec ions. Molecules2016, 21, 1183 3 o 21 po en ial associa ions o e ec s o wo o mo e di e en mine als and consequen ly, hey we e epea ed in di e en subsec ions. Figu e 1. Flow diag am and sea ch s a egy. 2.1. Calcium Wi h he me hodology used, 15 publica ions abou he ole o calcium in pe iodon al disease we e selec ed, speci ically 12 obse a ional s udies in humans [20–29] and i e expe imen al s udies in animals [30–34]. Die a y in ake es ima es we e ob ained in nine o hem [20–26,28,29]. Mos o hem we e c oss-sec ional s udies, bu he e a e also a case-con ol [28] and a coho s udy [29] (Table 1). In addi ion, h ee o hem also included se um calcium le els [20,22]. Likewise, he e we e a c oss- sec ional s udy [35] and a case-con ol s udy [27] whe e se um calcium le el was he sole a iable ela ed o his nu ien analyzed. Anyway, i is impo an o poin ou ha se um calcium le els a e a ec ed by nu i ional de iciencies only in se e e cases, because o homeos asis p ocesses ha con ol i . Howe e , possible associa ions be ween calcemia and pe iodon al heal h could help us o unde s and he impo ance o his mine al. Mo eo e he use o calcium-an agonis d ugs [36] was also e alua ed in a desc ip i e in es iga ion. In addi ion o hese s udies, o he wo discussed calcium o magnesium a io in blood [36,37], bu hey will be co e ed below oge he wi h o he in es iga ions abou magnesium. Rega ding c oss-sec ional s udies, a ious clinical ou comes ha e been used o e alua e pe iodon al disease o pe iodon i is se e i y. In one o he c oss-sec ional s udies ha u ilized da a om 11,787 subjec s who pa icipa ed in he Na ional and Heal h Nu i ion Examina ion Su ey (NHANES) III, Nishida e al. [20] ound an in e se associa ion among die a y in akes and p e alence o pe iodon al disease in younge subjec s (20–39 yea s) wi h odds a ios (ORs) o 1.84 (95%CI: 1.36–2.48, p < 0.001) o men, and 1.99 (95%CI: 1.34–2.97. p < 0.01) o women; and in medium-age men (40–59 yea s) wi h an OR o 1.90 (95%CI: 1.41–2.55, p < 0.001). Howe e , i was obse ed ha low o al se um le els (adjus ed by calcium in ake) we e ela ed o pe iodon al disease only in younge emales wi h an OR o 6.11 (95%CI: 2.36–15.84, p < 0.001). In e es ingly, his g oup o subjec s was he only one ha e ealed a dose- esponse ela ionship wi h a 54% highe isk o pe iodon al disease o he lowes in ake (2–499 mg) and 27% o he mode a e in ake g oup (500–799 mg) a e adjus men o gingi al bleeding and obacco consump ion [20]. O he c oss-sec ional s udy was ca ied ou in 3287 adul pa icipan s in he 2007–2008 Danish Heal h Examina ion Su ey (DANHES) who olun ee ed o Figu e 1. Flow diag am and sea ch s a egy. 2.1. Calcium Wi h he me hodology used, 15 publica ions abou he ole o calcium in pe iodon al disease we e selec ed, speci ically 12 obse a ional s udies in humans [ 20 – 29 ] and i e expe imen al s udies in animals [ 30 – 34 ]. Die a y in ake es ima es we e ob ained in nine o hem [ 20 – 26 , 28 , 29 ]. Mos o hem we e c oss-sec ional s udies, bu he e a e also a case-con ol [ 28 ] and a coho s udy [ 29 ] (Table 1). In addi ion, h ee o hem also included se um calcium le els [ 20 , 22 ]. Likewise, he e we e a c oss-sec ional s udy [ 35 ] and a case-con ol s udy [ 27 ] whe e se um calcium le el was he sole a iable ela ed o his nu ien analyzed. Anyway, i is impo an o poin ou ha se um calcium le els a e a ec ed by nu i ional de iciencies only in se e e cases, because o homeos asis p ocesses ha con ol i . Howe e , possible associa ions be ween calcemia and pe iodon al heal h could help us o unde s and he impo ance o his mine al. Mo eo e he use o calcium-an agonis d ugs [ 36 ] was also e alua ed in a desc ip i e in es iga ion. In addi ion o hese s udies, o he wo discussed calcium o magnesium a io in blood [ 36 , 37 ], bu hey will be co e ed below oge he wi h o he in es iga ions abou magnesium. Rega ding c oss-sec ional s udies, a ious clinical ou comes ha e been used o e alua e pe iodon al disease o pe iodon i is se e i y. In one o he c oss-sec ional s udies ha u ilized da a om 11,787 subjec s who pa icipa ed in he Na ional and Heal h Nu i ion Examina ion Su ey (NHANES) III, Nishida e al. [ 20 ] ound an in e se associa ion among die a y in akes and p e alence o pe iodon al disease in younge subjec s (20–39 yea s) wi h odds a ios (ORs) o 1.84 (95%CI: 1.36–2.48, p< 0.001) o men, and 1.99 (95%CI: 1.34–2.97. p< 0.01) o women; and in medium-age men (40–59 yea s) wi h an OR o 1.90 (95%CI: 1.41–2.55, p< 0.001). Howe e , i was obse ed ha low o al se um le els (adjus ed by calcium in ake) we e ela ed o pe iodon al disease only in younge emales wi h an OR o 6.11 (95%CI: 2.36–15.84, p< 0.001). In e es ingly, his g oup o subjec s was he only one ha e ealed a dose- esponse ela ionship wi h a 54% highe isk o pe iodon al disease o he lowes in ake (2–499 mg) and 27% o he mode a e in ake g oup (500–799 mg) a e adjus men o gingi al bleeding and obacco consump ion [ 20 ]. O he c oss-sec ional s udy was ca ied ou in 3287 adul pa icipan s in he 2007–2008 Danish Heal h Examina ion Su ey (DANHES) who olun ee ed o Molecules 2016,21, 1183 4 o 21 pa icipa e in an o al heal h examina ion. P e iously, as pa o he DANHES, subjec s had illed an In e ne -based ood equency ques ionnai e (FFQ) o e a yea ha was used o es ima e die a y in akes o calcium along wi h o he nu ien s. O al examina ion was used o iden i y subjec s wi h ch onic se e e pe iodon i is [ 21 ] de ined acco ding o he Cen e s o Disease Con ol and P e en ion (CDC) and Ame ican Academy o Pe iodon ology c i e ia (AAP) [ 38 ]. In akes o calcium wi hin ecommenda ions (1000 mg/day o women aged unde 50 yea s old and men unde 70 yea s old; o 1200 mg/day women aged 50 yea s old o mo e and men aged 70 yea s old o mo e) was in e sely associa ed wi h lowe likelihood o se e e pe iodon i is (OR = 0.76, 95%CI: 0.58, 0.99, p= 0.041) a e adjus men o ypical co a ia es (age, gende , educa ion, smoking, suc ose in ake, alcohol consump ion, numbe o ee h, daily b ushing, egula isi s o he den is and ch onic illness). In he same sense, F eeland e al. [22] showed a co ela ion coe icien o −0.24 be ween calcium in ake and Russell’s pe iodon al index (RPI) in a sample o 80 subjec s om a den al clinic, al hough he au ho s conside ed a signi icance le el o 0.075. Fu he , die a y in ake did no show any signi ican associa ion. Finally, o he c oss-sec ional s udy was ocused on p egnan women (n= 1162) as a isk g oup. Fo his die a y in ake da a we e collec ed du ing p egnancy by a die his o y ques ionnai e and pos -pa um o al examina ions we e pe o med. Mul iple eg ession analysis adjus ed o ypical co a ia es (age, egion o esidence, smoking s a us, oo hb ushing equency, use o an in e den al b ush, household income, and educa ion) indica ed ha subjec s in he highes qua ile o calcium in ake was associa ed wi h a lowe p e alence o pe iodon al disease han hose in he lowes , wi h a OR o 0.53 (95%CI: 0.30–0.94, p= 0.07 o end) [23]. In u n, o he es o desc ip i e pape s, no signi ican ela ionship wi h pa ame e s ela ed o pe iodon al disease was obse ed. In a s udy pe o med among Japanese non-smoke s [ 24 ], no ela ionship be ween calcium in ake and pe cen age o si es wi h bleeding was ound on p obing (BOP) o Communi y Pe iodon al Index (CPI), al hough co ela ions we e obse ed a a bi a ia e le el. Simila ly, no di e ences we e ound in se um le els we e measu ed in a case-con ol s udy compa ing ch onic and agg essi e pe iodon i is pa ien s de ined acco ding o he In e na ional Wo kshop o he Classi ica ion o Pe iodon al Diseases and Condi ions in 1999 (IWCPDC) c i e ia [ 39 ] wi h heal h indi iduals om a heal h cen e in China. Finally, in a s udy wi h adul indi iduals om he S udy o Heal h in Pome ania (SHIP) su ey (Ge many) who used blocking calcium-channels d ugs, highe pe iodon al pocke p obing dep h (PPD), bu no clinical a achmen loss (CAL), BOP, numbe o ee h o plaque was ound [36]. On he o he hand, he e was a c oss-sec ional su ey ocused on he in ake o dai y p oduc s wi h special in e es paid o milk, cheese and e men ed oods. Among hese, a s udy was conduc ed only in olde adul s, bu calcium in akes we e es ima ed oo [ 25 ]. In his, in akes o o al dai y calcium (incidence a e a io [IRR] = 0.97, 95%CI: 0.96–0.99, p= 0.021), calcium om milk (IRR = 0.97, 95%CI: 0.95–0.99, p= 0.025) and om e men ed oods (IRR = 0.96 95%CI: 0.92–0.99, p= 0.03), bu non-dai y calcium we e in e sely associa ed wi h he se e i y o pe iodon i is (de e mined h ough Communi y Pe iodon al T ea men Needed Index (CPITN) sco e) a e adjus men o se e al isk ac o s. Two mul i a ia e analyses indica ed di e ences in calcium in ake in he case-con ol ha compa ed gingi i is-a ec ed and non-a ec ed emale adolescen s whe eas in ano he i was subs i u ed by ibo la in as we ha e said abo e, bu i was due o he ac bo h we e in e co ela ed wi h milk consump ion [28]. Simila di e ences exis ed among coho s udies. In one o he coho s udies ha included 2113 medium-age (30–60 yea s) pa icipan s in Danish Moni o ing T ends and De e minan s in Ca dio ascula Disease (MONICA) s udy (Denma k), i was no ed nega i e associa ions o calcium in ake wi h numbe o oo h a baseline and subsequen oo h loss. I die a y ecommenda ions we e aken in o accoun , calcium in ake bellow ecommenda ions was associa ed wi h inc eased isk o subsequen oo h loss a e 6 yea s, only in men (IRR = 1.70, 95%CI: 1.15–2.48, p< 0.05) [ 26 ]. On he o he hand, i was epo ed ha high calcemia alues seem o p e en p og ession o pe iodon al disease a e 6 yea s in 70 yea s old subjec s om Niiga a ci y [29]. Molecules 2016,21, 1183 5 o 21 Table 1. Obse a ional s udies on mine als’ associa ions wi h pe iodon al disease. S udy Type Sample Sex, Age, N Die a y In ake Assessmen Nu i ional S a us Assessmen Pe iodon al S a us Associa ion Assessmen Main Resul s/Conclusions Re . CS NHANES III pa icipan s (USA) Bo h, ≥20 yea s, N = 11787 Die a y in ake o Ca (<500, 500–799, & ≥800 mg/day) by 24-h ecall Se um le els 1o o al Ca Pe iodon al disease (CAL > 1.5 mm) Adj OR (mul iple logis ic eg ession) In e se associa ion wi h in ake & se um le els bu only in ce ain age g oups & gende [ 20 ] CS 2007–2008 DANHES pa icipan s (Denma k) Bo h, ≥18 yea s, N = 3287 Die a y in ake o Ca (con inous, & < & ≥RDA) by FFQ -Se e e ch onic pe iodon i is 2mean CAL Adj OR (mul iple logis ic eg ession) Adj β (mul iple linea eg ession) Nega i e associa ion wi h mean CAL o in akes ≥RDA [ 21 ] CS Den al clinic pa ien s (USA) Bo h, N/A, N = 80 Die a y in akes o Ca, P, Fe, Zn & K by 24-h ecall (N = 56) Se um le els o Ca, Mg, P (Fe, Cu, Zn & K) RPI Linea co ela ion coe icien o in ake Adj β o se um le els (mul iple linea eg ession) In e se associa ion wi h Cu se um le els [ 22 ] CS P egnan women (Japan) Female, 31.5 ±4 yea s, N = 1162 Die a y in ake o Ca (qua iles) by DHQ -Pe iodon al disease (PPD ≥4 mm in ≥1 oo h) Adj OR (mul iple logis ic eg ession) In e se associa ion (highes q s. lowes q ) [ 23 ] CS Non-smoke adul s wi h ≥20 ee h (Japan) Bo h, ≥18 yea s, N = 497 Die a y in ake o Ca by 24-h ecall - CPI & %BOP Adj β (mul iple linea eg ession)No associa ions [ 24 ] CS SHIP pa icipan s (Ge many) Bo h, 20–80 yea s, N = 4290 Ca-an agonis s egula use & Mg-con aining d ugs in ake Se um Mg/Ca (qua iles) % PPD ≥4 mm, %CAL > 4 mm, numbe o ee h Adj OR (mul iple logis ic eg ession) In e se associa ion o se um Mg/Ca wi h %PPD > 4 mm & %CAL > 4 mm, only in subjec s aged ≥40 yea s (lowes qua il s. highes qua il). People aking Mg-con aining d ugs showed less CAL [ 36 ] S 135 subjec s om 3 d ollow-up o COHSS (Denma k) Bo h, >65 yea s, N = 135 Die a y in akes o dai y ood & Ca (100 g inc emen s) by DHI - Pe iodon i is (numbe o ee h wi h addi ional CAL ≥3 mm) Adj IRR (mul iple logis ic eg ession) In e se associa ion wi h in akes o o al dai y Ca, om milk & e men ed oods [ 25 ] CS non-smoke s & non-alcoholic women om CARDIAC s udy (Tanzania) Female, 46–58 yea s, N = 81 Die a y in ake o Mg (N/A) & 24-h u ina y exc e ions o K - numbe o ee h, & CPITN Simple co ela ion coe icien s Nega i e associa ion o K u ina y le els wi h CPITN [ 38 ] CS NHANES non-p egnan pa icipan s (Japan) Bo h, ≥20 yea s, N = 3043 Die a y in ake o Cu by 24-h ecall - CPI = 3–4 Adj OR (mul iple logis ic eg ession)No associa ion [ 39 ] CS KNHANES pa icipan s (Sou h ko ea) Bo h, ≥19 yea s, N = 1679 -Whole blood le els o Mn (qua iles) CPI ≥3Adj OR (mul iple logis ic eg ession)In e se asocia ion [ 40 ] Molecules 2016,21, 1183 6 o 21 Table 1. Con . S udy Type Sample Sex, Age, N Die a y In ake Assessmen Nu i ional S a us Assessmen Pe iodon al S a us Associa ion Assessmen Main Resul s/Conclusions Re . CC Female non-smoke adolescen s (I aly) Female, 17–19 yea s, N = 54 Die a y in ake o Ca, P & K (<2/3 RDA) by 3-days eco d - Gingi i is-a ec ed (≥1 si e wi h BOP) s. non-a ec ed Di e ences be ween g oups Nega i e associa ion o Ca in ake wi h gingi i is isk [ 28 ] CC Subjec s om a Heal h Cen e (China) Bo h, 16–64 yea s, N = 178 -Plasma le el o Ca & P (qua iles) Agg essi e pe iodon i is s. ch onic pe iodon i is—a ec ed 3 s. heal hy (S a ) Di e encies among g oups (ANCOVA) Pa in s had lowe le els o P [ 27 ] CC Non-smoke s ou pa ien s (India) Bo h, 30–60 yea s, N = 60 -Se um le els o Cu & Zn DM2 & pe iodon al disease-a ec ed s. only pe iodon al disease-a ec ed (30% si es wi h CAL ≥5 mm & BOP) s. heal hy Di e ences among g oups Subjec s wi h pe ioedon i is showed highe Zn le els espec o han hose wi h DM2 [ 41 ] CC Non-smoke s indi iduals wi h ≥20 ee h (India) Bo h, 30–60 yea s, N = 150 - Se um le els o Se DM2 & ch onic pe iodon i is-a ec ed 4, only ch onic pe iodon i is-a ec ed 4 s. heal hy Di e ences be ween g oups Subjec s wi h pe iodon i is (wi h o wi hou DM2) showed he lowes Se le els [ 42 ] C (5 yea s) MONICA s udy pa icipan s (Denma k) Bo h, 30–60 yea s, N = 2113 Die a y in akes o Ca ( o al, E-adjus ed as well as < & ≥RDA) by 7-days eco d - Too h loss Adj IRR (mul iple logis ic eg ession) In e se associa ion only in men [ 26 ] C (6 yea s) Niiga a ci y ci izens (Japan) Bo h, 70 yea s, N = 266 - Se um le els o Ca P og ession o pe iodon al diseae (numbe o ee h wi h addi ional CAL ≥3 mm) Adj β (mul iple linea eg ession)Nega i e associa ion [ 29 ] C (6 yea s) Niiga a ci y inhabi an s (Japan) Bo h, 73 yea s, N = 309 -Se um Ca/Mg (qua iles) Pe iodon al disease e en s (CAL ≥3 mm/yea a any ee h) Adj OR (mul iple logis ic eg ession) Nega i e associa ion o Ca/Mg a io wi h pe iodon al disease e en s only among smoke s [ 37 ] 1 Se um le els we e adjus ed by daily in ake o calcium in subsequen analyses, 2≥ 2 in e -p oximal si es wi h CAL ≥ 6 mm in di e en ee h & ≥ 1 in e -p oximal si e wi h PPD ≥ 5 mm. 3 acco ding o IWCPDC c i e ia [ 43 ]. 4 acco ding o AAP/CDC c i e ia o se e e gene alized ch onic pe iodon i is. Abb e ia ions: %: pe cen age o si es, β : linea eg ession coe icien , AAP: Ame ican Associa ion o Pe iodon ology, Adj: adjus ed, ABL: al eola bone loss, AL: a achmen loss, ANCOVA: Analysis o co a iance, BMD: bone mass densi y, BOP: bleeding on p obing, C: coho s udy, Ca: calcium, CAL: clinical a achmen loss, CARDIAC: Ca dio ascula Diseases and Alimen a y Compa ison, CC: case-con ol s udy, CDC: Cen e o Diseases con ol and P e en ion, COHSS: Copenhagen O al Heal h Senio S udy, CPI: Communi y Pe iodon al Index, CPITN: Communi y Pe iodon al Index T ea men Needed, CS: c oss-sec ional s udy, Cu: Coppe , DHI: die his o y in e iew, DHQ: die his o y ques ionnai e, DM2: ype 2 diabe es melli us, Fe: i on, FFQ: ood equency ques ionnai e , GI: Gingi al Index, h: hou s, IRR : incidence a e a io, IWCPDC: In e na ional Wo kshop o he Classi ica ion o Pe iodon al Diseases and Condi ions in 1999 [ 39 ], K: po assium, KNHANES: 4 h Ko ean Na ional Heal h and Nu i ion Examina ion Su ey, m: mon hs, Mg: magnesium, Mn: Manganese, MONICA: Moni o ing T ends and De e minan s in Ca dio ascula Disease, N: sample size, N/A: no a ailable, NHANES: Na ional heal h and Nu i ion Examina ion Su ey, NHANES III: Thi d Na ional Heal h and Nu i ion Examina ion Su ey, OR: odds a io, P: phospho us, PI: Plaque Index, PPD: pe iodon al p obing dep h, RDA: ecommended daily amoun , RPI: Russel ´ s Pe iodon al Index, Se: selenium, SHIP: S udy o Heal h in Pome ania; SOF: S udy o Os eopo o ic F ac u es, USA: Uni ed S a es o Ame ica, s: e sus, Zn: Zinc. Molecules 2016,21, 1183 7 o 21 Animal esea ch was ep esen ed by h ee a icles (Table 2), wo pe o med in a s (Ra us no egicus) [ 30 , 31 ] and one in mice (Mus musculus) [ 34 ]. Mos o hem analyzed he e ec o die a y calcium de iciencies on al eola bone [ 30 , 31 ], namely h ee conside ing in e ac ions wi h p egnancy and lac a ion [30,31]. Fo his aim, in one o hem, emale a s we e housed wi h male a s ed die -con aining calcium 0.9%, 0.3%, o 0.02% and a e 25 days we e subdi ided in o p egnan and non-p egnan animals. Addi ionally, pups we e main aining wi h hei mo he o lac a ion [ 31 ]. BMD and al eola bone dec eased acco ding o die a y calcium le els in bo h, adul s (p< 0.0001) and pups (22.5% less in 0.02% calcium and 12.7% in 0.3% calcium espec o 0.9% calcium die , p< 0.01), bu he magni ude was g ea e in he p egnan g oup han in non-p egnan when hey we e ed die s con aining calcium 0.02% and 0.3% (p< 0.05) [31]. Table 2. Expe imen al s udies on mine als e ec s on pe iodon al disease. Subjec s/Animals, Age, Sample Size (N) Expe imen al Design (Du a ion) Main Resul s/Conclusions Re . P egnan & non-p egnan Wis a a s, 10 weeks, N = 62 Die s con aining 0.9%, 0.3%, o 0.02% Ca (6 weeks). In p egnan a s, i includes ges a ion & lac a ion pe iods (3 weeks each) BMD o al eola bone dec eased wi h Ca in ake, bu his dec ease was g ea e in p egnan a s. Mo he ’s in ake also a ec ed o Pups‘ BMD [31] P egnan (lac a ing) & non-p egnan (non-lac a ing) Wis a a s, 10 weeks, N = 62 Die s con aining 0.9%, 0.3%, o 0.02% Ca (46 days) wi h expe imen al pe iodon i is induced by an elas ic ing (las 2 weeks). P egnan a s s a ed lac a ion on d 25 BMD & ACH dec eased in pe iodon i is side acco ding o he Ca in ake, bu his was g ea e in he lac a ing g oup [30] Male BALB/c mice inocula ed wi h Aac , 18 weeks, N = 40 Regula o CaCO3- ich die (30 o 60 days) Ca- ich die ed animals showed lowe os eoclas s, ABL & le els o TNF-αin pe iodon al issues [34] Sy ian hams e s, N/A, N = 10 Die wi h 5% Ca3(PO4)2o a mix u e o Na2HPO4& KH2PO4 (90 days o 150 days) Ca3(PO4)2- ich die inhibi ed ABL [44] Male SpDw a s, 3 mon hs, N = 24 Ca/P imbalanced die o induced dHPT o s anda d die (5 mon hs), ollowing by LPS- o saline-injec ions (nex 2 weeks) Ra s wi h dHPT & pe iodon i is e ealed he highes amoun s o in lamma o y cells & essels as well as o ABL & AL, ollowed by a s wi h only pe iodon i is & wi h only dHPT. [45] SpDw a s, Adul s, N = 24 Ca/P imbalanced die o induced dHPT o s anda d die (5 mon hs), ollowing by LPS- o saline-injec ions (nex 2 weeks) IL-1β& TNF-αwe e highes in a s wi h dHPT & pe iodon is, ollowed by hose wi h only LPS- ea ed. They we e posi i ely co ela ed o PTH le els in a s wi h only dHPT [46] Child en (India), 8.50 ±0.7 yea s, N = 68 O ally-adminis ed elemen al Zn supplemen s o placebo sy up DB (10 weeks) Zn supplemen s imp o ed PI, bu no GI [47] SpDw a s, a weaning, N = 14 Zn-de icien o no mal die (4 weeks) Ra s ed Zn-de icien die showed highe PI & GI. No di e ences we e obse ed o PPD sco e [48] male Wis a a s, a weaning (24 days), N = 14 Zn-de icien o Zn-con aining die (4 weeks) Aph hous ulce on he loo o he mou h was obse ed in Zn-de icien a s, which showed highe GI. No di e ences we e obse ed o PPD sco e [49] Abb e ia ions: ABL: al eola bone loss, ACH: al eola bone c es heigh , Aac : Ag ega ibac e ac inomyce encomi ans, AL: a achmen loss, BMD: bone mass densi y, Ca: calcium, DB: double blind, dHPT: die a y induced hype pa a hy oidism, GI: Gingi al Index, IL: In e leukin, IV: in i o s udy, K: po assium, LPS: lipopolysaccha ide; Na: sodium, P: phospho us, PI: Plaque Index, PPD: pe iodon al p obing dep h, PTH: Pa a hy oid Ho mone, SpDw: Spa gue-Dawley, SW: Swiss-Webs e , TNF- α : Tumo nec osis ac o alpha, USA: Uni ed S a es o Ame ica, Zn: Zinc. The expe imen al design in he o he s udy was simila , excep ha pe iodon i is was expe imen ally induced by an elas ic ing in he igh side o mandible on day 32. Simila ly, BMD Molecules 2016,21, 1183 8 o 21 on diseased si es dec eased acco ding o he amoun o calcium in he die a e he lac a ion pe iod (p< 0.05) and he magni ude o his dec ease was signi ican ly g ea e in lac a ing animals han in non-lac a ing animals, bu in his case only hose ed a die con aining 0.3% calcium (p< 0.05). Simila esul s we e seen on he con ol side in animals ed die s con aining 0.3% and 0.02% calcium (p< 0.05); howe e , he magni ude o his dec ease was much g ea e in he lac a ing g oup [ 30 ]. In addi ion, he au ho s supplied his ologic examina ion da a e ealing mo e de ails abou ABL. The magni ude o die a y calcium-dependen dec eases in in e den al bone mass and he heigh o he al eola bone c es (ABC) seemed o be g ea e in he lac a ing g oup. In mo e de ail, heigh o he in e den al ABC in he 0.3% calcium g oup, he dis ance be ween he ABC and cemen um-enamel jun ion (CEJ) o he i s and second mola s in lac a ing animals was signi ican ly g ea e han in non-lac a ing animals, bu in he con ol side he e we e di e ences among bo h g oups (p< 0.01). On he o he hand, al hough a simila dec ease was seen in he 0.02% calcium g oup, he di e ence be ween he lac a ing and non-lac a ing g oups was no s a is ically signi ican [ 30 ]. Animals we e subjec o a se e e calcium de iciency o 20 days, ollowed by a eco e y pe iod o 20 days. Simila dec ease in bone was obse ed in all si es du ing p og ession o calcium de iciency wi h a simila inc ease du ing eco e y. Maximum bone loss inc eased o mo e han 50%. ABL was cha ac e ized by a educ ion in abecula bone wi hou loss o al eola c es heigh (ACH) [ 33 ]. In he emaining s udy, he e ec s o calcium- ich die (by CaCO 3 addi ion) agains a egula die we e es ed on mice inocula ed wi h Agg ega ibac e ac inomyce encomi ans. A e 60 days, he numbe o os eoclas s was educed in mice ed on die ich in caclium, which led o diminished in ec ion-induced al eola bone loss. In addi ion, calcium- ea ed mice also p esen ed dec eased le els o umo nec osis ac o - α (TNF-α) in pe iodon al issues (p< 0.05) [34]. 2.2. Magnesium Fou s udies, all epo ing human obse a ional su eys [ 22 , 36 – 38 ], we e selec ed in ela ion o magnesium (Table 1). Magnesium was mainly measu ed in blood, al hough die a y in ake was also es ima ed in one o hem [ 40 ]. Mo eo e , in wo o he selec ed a icles, se um calcium/ magnesium a io was conside ed due o a po en ial in e ac ion be ween hese wo mine als’ e ec s. Acco ding o absolu e se um le els, F eeland e al. [ 22 ] ound no associa ion wi h RPI. On he o he hand, in ano he c oss-sec ional su ey ha conside ed people aged be ween 20 and 80 yea s old, a high se um calcium/magnesium a io was associa ed wi h educed PPD ( = − 36.1, p< 0.001), less CAL ( = − 42.8, p= 0.00) and a highe numbe o emaining ee h ( = 7.5, p= 0.019) [ 36 ]. Fu he mo e, he same s udy e alua ed he e ec o Mg-con aining d ug consump ion in a subse o 180 indi iduals aged 40 yea s old and olde . People aking magnesium-con aining d ugs showed less CAL (2.7 ± 1.6 s. 3.5 ± 1.6, p< 0.01) and PPD (2.4 ± 0.6 s. 2.8 ± 0.9, p< 0.01) compa ed wi h hei ma ched coun e pa s (in a 1:2 ma ched-pai analysis o age, sex, smoking, and educa ional le el). Magnesium in ake was es ima ed in an in es iga ion on hype ension isk ac o s and pe iodon i is ela ionship in (non-smoke s and alcohol non-d inke s) women aged 46–58 yea s om Tanzania, bu no co ela ions wi h he se e i y o pe iodon i is de e mined h ough CPITN sco e o numbe o ee h was obse ed [ 41 ]. No de ails abou in ake da a collec ion we e o e ed in he epo , so i s eliabili y is ques ionable. Finally, he e was only a coho s udy ha epo ed an in e se dose- esponse ela ionship be ween calcium/magnesium a io and pe iodon al disease e en s in elde ly pe sons om he s udy in Niiga a (Japan) ci izens bu only when smoke s we e conside ed, wi h ORs o 6.28 (95%CI: 1.45–27.28, p= 0.014) and 5.96 (95%CI: 1.30–27.34, p= 0.022), in i s and second qua iles espec han he ou h, espec i ely [37]. 2.3. Phospho us Th ee s udies ha e been selec ed in humans conce ning phospho us [ 22 , 27 , 28 ], a c oss-sec ional s udy [ 22 ] and wo case-con ol s udies [ 27 , 28 ], which we e al eady men ioned o he p e ious nu ien s (Table 1). The c oss-sec ional s udy was he pe o med by F eeland e al. [ 22 ] who did no ind co ela ions wi h le els in se um o die . Conce ning case-con ol s udies, one was ocused only Molecules 2016,21, 1183 9 o 21 on gingi i is in emale adolescen s om Rome [ 28 ] and di e en nu ien de iciencies ( wo hi ds o ecommended in ake), bu no associa ion was ound wi h de icien phospho us in akes. In he emaining s udy ha di e en ia ed be ween agg essi e and ch onic pe iodon i is pa ien s in a hospi al om China, se um phospho us le els we e lowe in bo h pa ien g oups compa ed o heal hy subjec s (1.06–0.18 and 1.10–0.15 mmol/L, espec i ely s. 1.26–0.17, p< 0.05) [27]. As o expe imen al s udies in animals, h ee we e ound [ 41 – 43 ]. One o he epo s was based on nu i ional in e en ions in Sy ian hams e (Mesoc ice us au a us) using die s supplemen ed wi h di e en phospha e sal s, so pu a i e e ec s on indings ha o he mine als migh ha e been in ol ed should be conside ed. In hese animals, a die wi h 5% Ca 3 (PO 4 ) 2 led o inhibi ion o ABL index (43.3 s. 45.9 in emales, 45.8 s. 50.9 in males). A simila e ec was obse ed o a die wi h a concen a ion o 1% (38.9 s. 47.2 in emales; 40.9 s. 50.3 in males), while wi h a die con aining a Na 3 HPO 4 and KH 2 PO 4 mix u e; he inhibi ion did no each he le el o signi icance [ 44 ]. I is e y impo an o no e he impo ance o he balance be ween calcium and phospho us, om he poin o iew o die a y in ake. The wo emaining pape s included a a model o hype pa a hy oidism in combina ion wi h expe imen ally induced pe iodon i is. Ra s we e ed a high calcium o phospho us a io (1:7) o 5 mon hs un il hype pa a hy oidism symp oms appea ed, and hen, hal o hem ecei ed E. coli lypopolysaccha ide (LPS) injec ions o one week o induce pe iodon i is. Ra s wi h only die a y induced hype pa a hy oidism (dHPT) demons a ed in lamma o y and degene a i e al e a ions in pe iodon ium wi hou pocke o ma ion, bu pe iodon i is was e iden in g oups ha ecei ed endo oxin injec ions. Addi ionally, dHPT and pe iodon i is-induced a s e ealed he highes amoun s o gingi al in lamma o y cell and essel coun s, ollowed by he only pe iodon i is-induced a s and only dHPT g oup. The di e ences be ween g oups we e simila o CAL, bone losses, and os eoclas numbe [ 42 ]. In he o he epo , he same au ho s compa ed ABL and gingi al le els o in e leukin (IL)-1 β and TNF- α be ween g oups when a s we e sac i iced. Hype pa a hy oidism inc eased ABL associa ed o pe iodon i is (0.99 ± 0.07 s. 0.70 ± 0.008 mm, p< 0.001), as well as gingi al le els o IL-1 β and TNF- α (92.25 ± 6.26 s. 68.25 ± 5.23 pg/mL o IL-1 β ,p< 0.01; and 80.73 ± 4.52 s. 62.85 ± 5.85 pg/mL o TNF- α ,p< 0.05). Se um le els o p oin lamma o y cy okines was also measu ed be o e pe iodon i is induc ion and hey we e highe in a s wi h dHPT (15.75 ± 0.49 s. 10.12 ± 0.92 pg/m, o IL-1 β and 176.75 ± 23.06 s. 13.02 ± 1.38 pg/mL o TNF- α , p< 0.001). Addi ionally hey we e posi i ely co ela ed wi h he pa a hy oid ho mone (PTH) le els in he expe imen al g oup ( = 0.93, p< 0.001 o IL-1 β ; and = 0.94, p< 0.001 o TNF- α le els). A gingi al le el, di e ences we e s ill p esen a e wo weeks, among a s wi hou pe iodon i is (49.57 ± 4.50 s. 26.05 ± 2.52 pg/mL o IL-1 β ,p< 0.01; and 34.39 ± 3.19 s. 18.44 ± 1.87 pg/mL o TNF- α ,p< 0.05), al hough he co ela ion wi h PTH le els p esen ed 2-weeks be o e, was ound jus in non-injec ed a s ( = 0.93, p< 0.001 o IL-1 β ; and = 0.79, p< 0.01 o TNF- α ). A ending o hese esul s, hype pa a hy oidism induced by a high phospho us die may be esponsible o he p oin lama o y s a e ha combined wi h LPS e ec inc eased bone eso p ion [46]. 2.4. I on Only one s udy was selec ed o cla i y he ela ionship be ween die a y i on and pe iodon al disease [ 22 ]. Die a y in akes o i on in humans only we e assessed in one c oss-sec ional s udy [ 22 ], bu associa ions wi h RPI we e no ound. On he o he hand, he selec ed s udy included in o ma ion ha would a oid es ima ing i on nu i ional s a us bu no ela ionship wi h RPI was ound, as occu ed wi h die a y in akes. Despi e o hese esul s, side emia alues alone has usually no been conside ed a good ma ke o i on le els in he body. 2.5. Coppe In humans, wo c oss-sec ional s udies [ 22 , 39 ] and a case-con ol s udy we e selec ed [ 41 ] (Table 1). One o he c oss-sec ional s udies chosen was he one pe o med by F eeland e al. [ 22 ] whe e he au ho s obse ed a di ec and linea ly ela ionship be ween se um coppe le el and RPI in single Molecules 2016,21, 1183 16 o 21 Index”[Mesh] OR “Gingi al Hemo hage”[Mesh] OR “pe iodon al disease” OR pe iodon i is OR “al eola bone loss” OR “al eola bone eso p ion” OR “ oo h a achmen ” OR “ oo h mobili y” OR “gingi i is” OR “clinical a achmen le el” OR “pe iodon al a achmen le el” OR “a achmen loss” OR “pe iodon al pocke ” OR “pocke dep h” OR “p obing dep h” OR “bleeding on p obing” OR “gingi al bleeding” OR “Gingi al Hemo hage” OR “gingi al index” OR “bleeding index” OR “pe iodon al index”. In addi ion o his, a second opic ela ed o nu i ion o die was c ea ed, whe e he sea ch e ms we e he ollowing: “Food”[Mesh] OR “Die ”[Mesh] OR “Ea ing”[Mesh] OR “Nu i ion Su eys”[Mesh] OR “Nu i ion Assessmen ”[Mesh] OR “Nu i ion The apy”[Mesh] OR “Nu i ion P ocesses”[Mesh] OR “Nu i ional S a us”[Mesh] OR nu i ion* OR nu i ion OR nu ien * OR nu ien OR ood OR die a y OR die * OR in ake OR in akes OR Consump ion* OR Consump ion OR Inges ion OR Ea ing. 4.3. Sea ch S a egy The sea ch s a egy aimed o ind online published s udies in he English language om incep ion o he da abase un il May 2016. A comp ehensi e li e a u e sea ch was un independen ly by wo pe sons. Fi s , pape s we e sc eened by i le and abs ac . Sc eening p ocedu es we e adjus ed o highe sensi i i y (wi h es ic i e sea ch i ems omi ed). Secondly, ull ex -pape s we e e ie ed and selec ed based on he eligibili y c i e ia, and duplica ed s udies we e excluded. Ti les wi hou an abs ac o which he i le sugges ed ha hey we e ela ed o he objec i es o his e iew we e selec ed o sc een he ull ex . Re iew au ho s’ disag eemen s o inconsis encies conce ning inclusion o publica ions o ex ac ion o da a we e discussed o e en ually achie e mu ual consensus. 4.4. Da a Collec ion P ocess, Da a I ems and Summa y Measu es The quan i a i e da a ex ac ed om pape s included speci ic de ails abou he in e en ions, popula ions, s udy me hods, and ou comes o signi icance o he e iew ques ion and speci ic objec i es. Da a om eligible s udies we e independen ly e alua ed. When hey we e a ailable, mean, di e ences among g oups, and i s s anda d de ia ions we e included in esul s desc ip ion. In he same sense, i was also collec ed associa ion measu emen s (i.e., co ela ion o eg ession coe icien s, IRRs, ORs, and hei co esponding 95%CI), as well as signi icance le els o p- alues conside ed, bu only i signi ican associa ions and/o di e ences we e ound. 4.5. Quali y Assessmen and Risk o Bias Subsequen ly, selec ed publica ions we e ully- ead o de e mine hei quali y, mainly h ough he assessmen o isk o bias. The me hodological quali y o a publica ion was de e mined in acco dance wi h se e al c i e ia depending on he s udy design. In he case o obse a ional s udies, he use o andomiza ion (only in clinical ials), ma ching o es ic ion a he design le el was aken in o accoun , whe eas he use o mul i a ia e analysis, s a i ica ion o equency ma ching was app aised a a da a analysis le el. Conce ning bias, ou ypes ha e been p oposed: selec ion, de ec ion, a i ion and epo ing [ 71 ]; al hough o he au ho s ha e simpli ied his classi ica ion in o wo ca ego ies: selec ion and in o ma ion [ 72 ]. Anyway, c i ical issues o p e en ing hem depend on s udy design. In c oss-sec ional s udies, h ee issues we e mainly e alua ed: sample andomiza ion; eliabili y and objec i i y o a iable assessmen , as well as de ini ion o g oup i compa isons we e made. In case-con ol s udies, objec i i y and eliabili y o e alua ions o subjec s ha in his case including ca ego ies de ini ions and exposu es e alua ion me hod oo we e also aken in o accoun . Las ly, in coho s udies, exposu e and s a us de ini ion, ea men du a ion and eliabili y and objec i i y o ou come assessmen we e conside ed. Likewise, di e ences in in ensi y o medical su eillance, loss o ollow-up, missing da a ea men , and di e ences ela ed o he ou come o exposu e o isk ac o s be ween hose who d op ou and hose who s ay in he s udy we e also e alua ed. Inclusion c i e ia and/o sou ces o da a o indi iduals backg ound we e conside ed o he es ablishing o he sample ex e nal alidi y and se o popula ion ep esen ed. Addi ionally, g ouping c i e ia in da a Molecules 2016,21, 1183 17 o 21 analysis we e aken in o accoun when hey we e p esen ed, especially i hey we e selec ed pos hoc om al e na i e op ions. On he o he hand, in e en ion ials we e assessed acco ding o Coch ane guidelines, which ake in o accoun i e ype o bias: selec ion, pe o mance, de ec ion, a i ion and epo ing bias [ 73 ]. Based in i s ecommenda ions, he ollowing domains we e e alua ed: sequence gene a ion ( andomiza ion), alloca ion concealmen , blinding o pa icipan s, ope a o s and/o examine s, incomple e ou come da a and selec i e epo ing. In unc ion o his assessmen esul s, deg ee o isk (high, low o unclea ) was es ablished o each ype o bias, as well as i s possible magni ude and di ec ion. The isk o bias and i s possible e ec s we e summa ized o each ou come wi hin each s udy. Finally, i was summa ized o he e iew as a whole, whe e i was possible. 5. Conclusions The he e ogenei y o da a and s udies, as well as he lack o esea ch on he ques ion o his e iew o ce ain mine als, in gene al, lead o he conclusion ha he e is limi ed e idence o con i m a possible e ec o die a y in akes o mos mine als on he isk o se e i y o pe iodon al disease. Fo his eason mo e obse a ional su eys wi h g ea sample sizes om ep esen a i e g oups o di e en mine als a e needed. Addi ionally, consensus in pe iodon i is diagnosis is needed o imp o e ou o e all unde s anding o his subjec . In any case, ensu ing ha heal hy subjec s o pa ien s do no su e om a speci ic nu i ional de iciency is ecommendable. Among all he mine als, calcium die a y in ake seems impo an o main ain al eola bone a leas wi h in akes unde ecommenda ions in ce ain g oups o isk o popula ions. Likewise, main aining adequa e p opo ions in he die wi h espec o calcium o mine als ha may in luence bone and calcium me abolism (i.e., magnesium and phospho us) also can be ele an . Mo eo e , some obse a ions sugges ha all hose mine als wi h oles in immune sys ems (magnesium, zinc o coppe ) and/o an ioxidan sys ems (magnesium, zinc, coppe , manganese o selenium) should be conside ed in u u e esea ch. Al hough he e is no e idence o indica e ha indisc imina ely inc easing he amoun s inges ed o he indica ed mine als will educe o help ea pe iodon al disease, i seems easonable o sugges a mine al supplemen when pa ien s show inadequa e nu i ional s a us. Acknowledgmen s: Al onso Va ela-López is ecipien o a “Con a o Puen e” om he Uni e si y o G anada. Au ho s acknowledge o he Uni e si y o G anada and he Au onomous Go e nmen o Andalusia o pa ial suppo o he esea ch eam. F ancesca Giampie i was suppo ed by a Fondazione Umbe o Ve onesi Fellowship. Con lic s o In e es : The au ho s decla e no con lic o in e es . Re e ences 1. Schi e le, R.E. Pe iodon al disease and nu i ion: Sepa a ing he e idence om cu en ads. Pe iodon ol. 2000 2009,50, 78–89. [C ossRe ] [PubMed] 2. 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