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 .
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