04-04-08 Anti-Caries Mechanisms of Fluoride

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• Role of structural-bound vs topical fluoride• The effect of fluoride on demineralization• The effect of fluoride on remineralization

Objectives:

DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY4 April 2008

Outline

Caries resistance concept vs Current philosophy

Why it was believed that structurally-bound F wasimportant?

How fluoride inhibits demineralization

What are the conflicting evidences?

How fluoride enhances remineralization

Systemic F for the maximum benefit(less soluble enamel )

Risk of developing (mild) fluorosis

Historical perspective

Caries-reducing effect of fluoride is from its presence during activecaries development to alter the dynamics of de- and remineralization

Current philosophy

Fluoride presented during tooth formation provided 'caries resistance'

Why do we want to know how fluoride prevents dental caries?

Basis to develop effective ways of using fluoride

Posteruptive effect

Topical fluoride application

Historical perspective vs current philosophy

It was thought that fluoride had to be present duringtooth formation to provide 'caries resistance' to theteeth. Current philosophy believes that the caries-

reducing effect of fluoride is primarily achieved by its presence during active caries development by alteringthe dynamics of mineral dissolution andreprecipitation.

The question of how fluoride prevents dental caries issignificant because that is the basis for developingeffective ways to use fluoride.

Along with the former ‘caries resistant’ concept, systemic fluoride was necessary for the maximum benefitto have enamel with less acid solubility. But the ingested fluoride comes with a risk of developing (mild)fluorosis. The current concept, which emphasizes the 'topical' or posteruptive effect of fluoride haschanged the principle of how fluoride should be used.

Systemic incorporation of fluoride into enamel during development

‘More perfect’ enamel crystals Less acid soluble

Structurally-bound fluoride i s life-long protection.

The more fluoride incorporated, the better the cariostatic effect.

Fluoride present during tooth formation provided 'caries resistance'

Systemic F for the maximum benefit (less soluble enamel )

Risk of developing (mild) fluorosis

Consequence

Caries Resistance ConceptCaries Resistance Concept

Treatment strategy according to this concept:

Caries resistant concept

When fluoride is incorporated into the enamelcrystals, the crystals (fluroapatite or fluoridated-hydroxyapatite) are ‘more perfect’ and less acidsoluble. Therefore it was thought that fluoride had to

present during tooth formation to make teeth moreresistant to caries attack.

Structurally-bound fluoride was believed to give life-long protection. The more fluoride incorporated, the

better the cariostatic effect. Treatment strategyaccording to this concept is to give systemic fluoride(e.g., vitamin) when the child is young and teeth areforming. The consequence of this treatment strategyis potential of developing mild fluorosis, which is‘worth’ if dental caries is prevented.

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Water fluoridation (10 years) reduced DMF

Fluoride incorporated in tooth structure increases caries-resistance

Teeth formed in flu oridated area

Increased F content in sur face enamel

F in water supplies

Lower caries prevalence

Fluoridatedarea

Non-fluoridatedarea

2.5 ppm

But….2000 vs 3000 ppm F is toosmall for 50% reduction in DMF!

Why was fluoride believed to make teeth more resistant to caries attack?

Comm Dent Oral Epid 1985;13:65-7.

No correlation between DMFT and enamel fluoride concentration

This concept of fluoride incorporated in the tooth structure increasing caries-resistance sounds true. And itseems to work, because water fluoridation substantially reduced the number of cavities in children. Teethformed in fluoridated area had an increased F content in surface enamel. However, the increased F contentin surface enamel, 2000 ppm in non-fluoridated area vs 3000 ppm in fluoridated area, cannot responsiblefor the 50% reduction in DMF. In addition, an epidemiology study did not find any correlation betweenDMF and enamel fluoride concentration.

Shark enamel (almost pure fluorapatite; 30,000 ppm F ) developedcaries lesions in an in situ model (4 wks), although less severe

0

300

600

900

1200

1500

1800

Human Shark Hum an +Rinse

Shark + Rinse

M i n e r a

l l o s s

Human Shark Human+ rinse

Human enamel + 0.2% NaF rinse (daily, 4 wks) ~ Shark enamel

F in tooth structur e is not crucialF in tooth structure is not crucial

Ögaard B et al.Scand J Dent Res1991;99:372-377

FAP has only a moderate caries protective potential, ~ daily F-rinse.

1

Human enamel:CaF2-like globules

Shark enamel:Nothing observed

does not provide enoughCa? (Ca is firmly bound)

CaF2-like material:caries inhibition effect

of topical fluoride

Ögaard B et al. Scand J Dent Res 1991;99:372-377 & 1988;96:209-211.

Shark enamel +

0.2% NaF rinse

was not as good

as human enamel

+ 0.2% NaF rinse0

300

600

900

1200

1500

1800

Hum an Shar k Hum an +Rinse

Shark + Rinse

M i n e r a

l l o s s

Human Shark SharkHuman+ Rinse + Rinse

Fluoride in tooth structure is not crucial in caries prevention

F in the tooth structure is not that important to inhibit dental caries. Shark enamel, which is almost pure

fluorapatite (30,000 ppmF) representing the structurally bound fluoride, developed caries lesions in an insitu model, although less severe than human enamel. Researchers placed shark or human enamel in aremovable appliance worn in the mouth to undergo the caries process. The results showed that after 4weeks on normal diet (non-disturbed plaque accumulation), both human and shark enamel developed carieslesions, although less severe in shark. When subjects rinsed with 0.2% NaF daily, which represented the

topical effect of fluoride, the caries lesion was inhibited to a similar level as shark enamel. This studyshowed that fluroapatite has only a moderate caries protective potential, which can be obtained by daily F-rinse. In other words, topical fluoride is as effective as pure fluorapatite.

Surprisingly, when the group with shark enamel had the same NaF mouthrinse, the demin was notinhibited. Why? Scanning electron microscopy showed that CaF 2-like material did not form on sharkenamel after treated with NaF solution, but it was found on human enamel. CaF 2 cannot form on sharkenamel because shark enamel cannot provide enough Ca, which is firmly bound in the crystals. This part ofthe study indicated that CaF 2-like material plays a role in the caries inhibition effect of topical fluoride.

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Calcium fluoride-like material

Tooth surface + high level F CaF 2

Oralenvironment

Phosphate 'shell' reduces solubility

Fluoride reservoir; releases F in acidic environment

phosphate

pH 4-5

F-

ten Cate. Eur J Oral Sci 1997;105:461-5.

pH 4-5 more soluble release F

Rapidly dissolv

Forms on tooth surface exposed to high level of fluoride

exSlightly soluble in water, dissolves in strong mineral acids and KOH

Retain on enamel > 2 weeks

high level F : >300 ppm at pH 7.2 or >100 ppm at pH 5

Calcium fluoride-like material

Calcium fluoride-like material is formed on the surfacewhen teeth are exposed to high concentrations offluoride (>300 ppm at pH 7.2 or >100 ppm at pH 5).CaF 2 is slightly soluble in water and buffers, anddissolves in strong mineral acids and KOH.

CaF 2 was unwanted in the past for preventive strategy because it was thought to be rapidly lost from the oralcavity. Later it was found that CaF 2 is retained on

tooth enamel for more than 2 weeks.

When CaF 2 is formed in the oral environment, phosphate ions may adsorb to the surface, forming a 'shell'and reducing the solubility. The solubility is pH dependent, more soluble at pH 4-5. Therefore, CaF 2 serves as a fluoride reservoir which releases F in acidic environment.

No difference in caries status in young adults (18-22 years old) whoreceived fluoridated water only until about 5-8 years old (13 years

discontinued) vs those who never received fluoridated water.

Kobayashi et al, Comm Dent Oral Epid 1992

DMFT

Fluoridatedwater

8.92 +4.79

Nonfluoridatedwater

10.73 + 5.48 NS

Fluoride in the tooth structure cannot give a life-long prot ection.

Clinical evidence: F in tooth struct ure is not crucialClinical evidence: F in tooth struct ure is not cruci al

Okinawa study

Kobayashi et al, Comm Dent Oral Epid 1992

DMFT

DMFS

Fluoridatedwater

8.92 + 4.79

15.02 + 9.14

Nonfluoridatedwater

10.73 + 5.48

20.36 + 13.43

NS

P < 0.05

Discussion: (group of 6-8)

From this Okinawa study, although DMFT between 2 groups were notdifferent which is the main conclusion of the study, DMFS were significantlydifferent. How can you explain the result?

Clinical evidences: Fluoride in tooth structure is not crucial in caries prevention

Okinawa study: There was no difference in caries status (DMFT) in young adults who receivedfluoridated water only until about 5-8 years old and those who never received fluoridated water. Thesubjects were 18-22 years old at the time of the study, which was 13 years after discontinuation of waterfluoridation. This study shows that fluoride in the tooth structure cannot give a life-long protection.

0

2

4

6

8

10

0 1 2 3 4 5Year

D M F S

ControlFluoride

Children that had water fluoridation started at age 12 (teeth already formed;no extra structural F) showed significant reduction in caries prevalence.

Harwicket al. Br Dent J 1982

Δ = 20 %

Δ = 26 %

Δ = 28 %

Clinical evidence: F in tooth struct ure is not crucialClinical evidence: F in tooth struct ure is not crucial

Low level topical F is more important than F in the tooth stru cture.

Study by Harwick et al: Children that moved into aarea with water fluoridation, or the fluoridation startedwhen their teeth had already formed showed significantreduction in caries prevalence. In this study, waterfluoridation started when this group of children were atage 12 (teeth fully formed, no structural fluoride). Thenumber of carious surfaces developed afterwards wasless compared to those lived in area without fluoridatedwater. The differences between the groups increasedevery year, became 28% less after 4 years in the group

moved to area with water fluoridation at 12 years old.

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The caries reduction is a result of the topical effect alone, no additional fluoride in the tooth structure because the teeth were fully formed. Therefore, low level topical fluoride is more important thanstructurally-bound fluoride.

The caries-reducing effect of fluoride is primarily achieved by its presenceduring active caries development at the plaque/enamel interface where itdirectly alters the dynamics of mineral dissolution and reprecipitation, andto some extent, affects plaque bacteria.

Maximize benefit (throughout life) with minimal adverse effects

Caries Controlled ConceptCaries Controlled Concept

Treatment (preventive) strategy according to this con cept:

Primary mode of action of fluoride is post-eruptive topical effect.

Topical fluoride; low level, frequent exposure, life-long

Caries controlled concept

The caries-reducing effect of fluoride is primarilyachieved by its presence during active cariesdevelopment at the plaque/enamel interface where itdirectly alters the dynamics of mineral dissolution andreprecipitation, and to some extent, affects plaque

bacteria. The primary caries-preventive mode of actionof fluoride is post-eruptive topical mechanism.According to this concept, the best strategy to controlcaries is topical fluoride at low concentration, life-long,and frequent exposure. This concept delivers the

maximum benefit of fluoride throughout life withminimal adverse effects.

3. Enhancing remineralization

Major mechanisms of fluoride on caries process:

1. Affect bacterial metabolism

Require high concentration of fluoride

2. Inhibit demineralization

Fluoride present at the crystal surfaces during acid challenge

Form a layer of fluorapatite-like material on the crystal surfaces

Featherstone JDB. The science and practice of caries prevention. JADA 2000;131:887-899

The major mechanisms of fluoride on the caries process

are:

1. The effect on bacterial metabolism, which requires highconcentration of fluoride

2. Inhibiting demineralization when fluoride is present atthe crystal surfaces during acid challenge.

3. Enhancing remineralization and forming a layer offluorapatite-like material on the crystal surfaces.

Fluoride in the solution inhi bits demineralizationFluoride in the solution inhibi ts demineralization

3 wt %

Featherstone JDB et al. J Dent Res 1990;69:620-5

Dissolution of 3 wt% carbonatedapatite in presence of fluoride

Initial dissolutionrate of CAP

Initial dissolutionrate of HAP

1 ppmF in the acid bufferreduced the dissolution rate ~1/3 (to the same level as HAP)

No measurable reduction insolubility of 3% CAP (~ enamel)

with 1000 ppmF incorporated

3 ppm F reduces ~ 40% (log)1 ppmFin acid buffer

3 ppmFin acid buffer

F in the aqueous phase

Adsorbed to the crystal surface

Protect against acid dissolution

F inhibits demineralization

This study measured the dissolution of 3 wt%carbonated apatite (similar to tooth enamel) in the

presence of fluoride in the acid solution. Low level ofF (e.g., 1 ppm) in an acid solution reduced thedissolution rate of carbonated HAP to the same level as

pure hydroxyapatite. 3 ppm F in the acid reduced 40%of the dissolution rate (logarithmic relationship). WhenF is present in the aqueous solution, it is adsorbedstrongly to the surface of the crystals and acts as a

potent protection mechanism against acid dissolution.

In contrary, when 1000 ppm F was incorporated into the carbonated apatite, no measurable reduction in thesolubility is observed. This study showed that fluoride ions in the fluid phase are much more effective ininhibiting demineralization than fluoride incorporated into the crystals at levels found in enamel.

4



Fluoride (even lowconcentration)reduces rate of

mineral dissolution

p H ~ c a r i e s f o r m

a t i o n

M i n e r a

l l o s s

( C a

l c i u m

)

F l u o r i d e , 1 - 1 0 p p m

Enamel samples subjected to solutions varying in pH and F conc.

ten Cate JM, van Loveren C. Fluroide Mechanisms. Dent Clin N Am 1999;43:713-742.

Fluoride in the solution inhibi ts demineralizationFluoride in the solution inhibits d emineralization

Enamelcrystal

(Carbonated

apatite)

Partiallydissolved

crystal

Aci d

FAP-like‘veneer’

Ca, P, F Rem in

Demin

Adapted from Featherstone JDBJADA 2000;131:887-99.

This FAP-like coating precipitated in the crystal surface, not F incorporatedduring tooth formation, is the major contribution to reduce enamel solubility

Partially demineralized crystals = nucleators

Fluoride ions adsorb to the crystal surface

Attract Ca, P new mineral formation

The newly formed FAP-like ‘veneer’

Exclude carbonate

Composition between HAP and FAP

Low solubility

Crystal surfaces become less soluble

Fluoride enhancesFluoride enhances remineralizationremineralization

A series of experiments investigated fluoride insolution (between 0-10 ppm) in the pH range thatcaries occurs (pH 4-5). Enamel specimens weresubjected to solutions varying in pH and Fconcentration. The amount of mineral lost duringdemineralization is a function of pH and fluoride.Fluoride (even low concentration) is an importantdeterminant of the rate of mineral dissolution.

F enhances remineralization

When enamel dissolves in acid, the partiallydemineralized crystals act as nucleators for crystal

growth. Fluoride enhances remineralization byadsorbing to the crystal surface, and attractingcalcium ions, followed by phosphate ions, leading tonew mineral formation. The newly formed 'veneer'excludes carbonate and has a composition betweenHAP and FAP. The new 'veneer' crystals have lowsolubility similar to that of acid-resistant mineralfluorapatite. Hence the crystal surfaces becomemuch less soluble.

This FAP-like coating precipitated in the crystal surface is the major contribution to reduce enamelsolubility, not structurally-bound F incorporated during tooth formation.

Arrested enamel lesion had higher

resistance to acid challenge

than the adjacent area

Koulourides T, Cameron BJ Oral Pathol 1980;9:255-269

Arres tedenamelcaries

Arrest edenamelcaries

2 n d D e m

i n

2 n d D e m in

Lesion surface

Higher F content

RemineralizedRemineralized area has higher acid r esistancearea has higher acid resis tance

Remineralized area has higher acid resistance. Itwas observed that arrested enamel lesions hadhigher acid resistance than the adjacent soundenamel. Acquired acid resistance is the

phenomenon of decalcified dental tissueremineralizes and obtains fluoride, thus inheriting

protection to further demineralization. In thisexperiment, reserachers put teeth with naturalarrested lesions in acid. The adjacent soundenamel developed a new lesion, but the area ofarrested caries was fine. The lesion area,especially at the surface, has higher fluoridecontent than the adjacent sound enamel.

5



Sound

White spot(arrested)

White spot(active)

Cavity

Culemborg(no water F; 0.1 ppm)

Tiel(Fluoridation; 1 ppm)

Age 9 Age 15

241

59

123

13

263

64

64

45

318

54

34

0

271

81

49

5

Total

1862354

2518212611261

12

47

22

2441710

452214271480

0

212

(n=436) (n=406)Backer Dirks O.J Dent Res1966;43:503 Age 9 Age 15 Total

Fluoride has greater effect on l esion progression than initiatioFluoride has greater effect on lesion p rogression th an initiatio nn

Fluoride has greater effect on lesion progression than lesion initiation: This study done in two Dutch towns,one had water fluoridation, the other did not. Culemborg, without fluoridated water, showed that 45 teeth(from total of 436 teeth) progressed into the cavities when the children were followed from age 8 to 15. InTiel, with fluoridated water, only 5 from 406 teeth (1.25%) progressed to cavities, compared to 45 teeth(~10%) in Culemborg. In both cities, more than 10% of the sound teeth had developed white spot lesions.But the number of lesions progressed to active white spot were smaller in Tiel where the water was

fluoridated. The lesion appearance was different. In Culemborg, the lesions had white, chalky surfaces,while the lesions in Tiel tended to have shiny, glossy surfaces.

Principal mechanisms of fl uoride actions rely on

F in saliva

F in the plaque fluid and tooth interface

F in the fluid among the mineral crystals in the lesion

Primary action of fluoride

Topical; after tooth eruption

Benefits continue throughout life(as long as F is available)

Summary:

Principal mechanisms of fluoride actions rely on the presence of fluoride in saliva, in the plaque at thetooth surface, and in the fluid among the crystals inthe subsurface lesion. Primary action of fluorideoccurs topically after tooth eruption and the benefitscontinue throughout life as long as F is delivered tothe microenvironment of the teeth.

6



F incorporated into the mineral duringtooth development has only minor effect

Delivery methods that bring F to the tooth surface,saliva, plaque fluid

The frequency of fluoride exposure

To optimize clinical effects of fluor ide:

The clinical effect of fluoride can be optimized byusing delivery methods that bring F to the toothsurface or into the plaque, rather than incorporatingF into the mineral during tooth development. Thefrequency of fluoride exposure to the tooth surfaceis important. These delivery methods are topicalsources that continually provide low levels of F in

beverages and foods, dental products, and drinkingwater.

Beverages and foods

Toothpastes

Mouthrinse

Drinking water


Give some examples of topical source that can provide lowlevel of F continuously.

Recommended references

1. Ten Cate JM, van Loveren C. Fluoride Mechanisms. Dent Clin North Am

1999;43(4):713-742.2. Featherstone JD. The science and practice of caries prevention. J Am Dent

Assoc 2000;131:887-899.

3. Ten Cate JM. Current concepts on the theories of the mechanism ofaction of fluoride. Acta Odontol Scand 1995:57:325-329.

4. Fejerskov O. Changing paradigms in concepts on dental caries:Consequences for oral health care. Caries Res 2004;38:182-191.

5. ADA Reports. Position of the American Dietetic Association: The impact offluoride on health. 2005;105:1620-1628.


If structurally bound fluoride is no longer believed to be the major mode ofanticaries mechanism of fluoride, why the ADA still recommend children livein non-fluoridated area to have supplement fluoride tablets?

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04-04-08 Anti-Caries Mechanisms of Fluoride