Evidence-Based Remineralization Therapies

Dental caries is a prevalent disease and significant public health issue.^1–5 Modern dentistry aims to manage lesions in earlier stages with noninvasive techniques that include remineralization.^1,2 The process of tooth remineralization is essential to prevent the progression of caries and arrest incipient lesions. This is a cost-effective approach to regenerate damaged tooth structure.² As oral health professionals, all dental team members should seek to remain current on the remineralization agents available for clinical recommendation and practice adoption.

The structure of dental enamel is characterized by a constant balance between demineralization and remineralization.² Nevertheless, an interruption in this process can lead to the development of demineralized lesions.¹ Demineralization is the reversible process of losing mineral ions from hydroxyapatite crystals of tooth structure, including enamel, dentin or cementum.² The demineralized hydroxyapatite crystal can be mineralized if exposed to an oral environment that supports remineralization.²

This is achieved when the oral plaque and mixed saliva are oversaturated with ions, including calcium, phosphate, sodium, magnesium, chloride, fluoride and hydroxide, that help remineralize  dental enamel.³ A remineralized tooth surface is far more resistant to subsequent acid attacks.^4–6 It is imperative to halt or reverse demineralization to prevent the risk of caries and need for invasive dental procedures.^4,7 Therefore, it is essential to discuss remineralization therapies with patients exhibiting signs of demineralization. Although numerous remineralization practices have been described in the literature, the focus of this article is to discuss evidence-based research and agents for preventive oral care.^2,6,8–10

SALIVA’S ESSENTIAL ROLE

Saliva is an essential biological factor which acts as an antibacterial agent that cleanses the teeth and neutralizes oral acids.⁶ Within normal physiological conditions of neutral pH, a noncariogenic environment, and healthy salivary flow, saliva is a constant source of calcium and phosphate ions.^2,6 These ions are required for remineralization;^2,11 in addition, the bioavailability of calcium and phosphate ions ensures diffusion into an area of mineral deficiency, such as a white spot lesion.²

The ability of saliva to neutralize the oral pH and remineralize tooth enamel is contingent upon the capacity of three buffering systems.⁶ The first is the carbonic/bicarbonate from parotid gland saliva as the primary regulator of pH; the second is the phosphate buffer found mainly in non-stimulated saliva; and the third is the protein system.⁶ However, natural remineralization from saliva alone is insufficient for two reasons: It is a slow process, and the low concentration of calcium and phosphate ions is only adequate to remineralize the surface of the lesion, not the entire lesion. The subsurface of the white spot lesion remains demineralized during this natural remineralization process.^12,13 Thus, clinicians are advised to add extrinsic sources of stabilized calcium and phosphate ions to patients’ daily oral health regimen to amplify the natural remineralization potential of saliva and produce faster and deeper subsurface remineralization.^12,13

CURRENT REMINERALIZING AGENTS

Current remineralization agents — such as fluoride, silver diamine fluoride (SDF), calcium/phosphate-based products, and xylitol — are available over-the-counter or through dental prescription.

Fluoride — The role of fluoride in preventing and arresting caries is supported by multiple systematic reviews.^14,15 Fluoride ions have multiple functions in the oral cavity.^4,16 This agent interferes with the activity of acid-causing bacteria and promotes remineralization. When bacterial acids break down the enamel, calcium and phosphate ions are released from the tooth surface. Fluoride ions bring these minerals back to the tooth surface and facilitate the growth of new fluorapatite.^14–16

Fluoride in saliva and plaque is key to preventing tooth demineralization and enhancing remineralization.^2,10 The fluoride’s bioavailability depends on the fluoride content in dental plaque, fluoride formulation, saliva secretion, and salivary content.^10,17 Naumova et al¹⁰ demonstrated a rise in salivary fluoride concentration immediately after brushing with a dentifrice containing either sodium fluoride or amine fluoride. The surge in salivary fluoride was immediate and lasted for a minimum of 30 minutes, whereas the plaque fluoride concentration increased 30 minutes after brushing.¹⁰ Clinically, fluoride in dental plaque is as essential as salivary fluoride because the plaque’s acidogenic bacteria are the leading cause of caries.¹⁰ In lower concentrations, fluoride is bacteriostatic, while it is bactericidal in higher concentrations. A meta-analysis by Walsh et al¹⁷ found that compared to non-fluoridated dentifrice, toothpaste with a minimum of 1000 to 1250 ppm fluoride ions has an anticaries effect. The study by Naumova et al¹⁰ did not find any significant difference in bioavailability between sodium fluoride and amine fluoride in saliva or plaque.

To remineralize enamel with fluoride, calcium and phosphate ions are required to facilitate the process.^2,6 For every two fluoride ions, 10 calcium ions and six phosphate ions are necessary to form one unit cell of fluorapatite.² During healthy physiological conditions, fluoride and saliva are often enough to remineralize incipient lesions. However, in a highly cariogenic or xerostomic oral environment, the presence of inadequate calcium and phosphate ions can impair remineralization.^2,12,13,16 The efficacy of fluoride in remineralizing the tooth structure can be improved with additional strategies, such as calcium-based boosters.^2,13 The addition of extrinsic sources of stabilized calcium and phosphate ions to a patient’s daily oral health regimen (via gel, toothpaste and/or mouthrinse) can amplify the natural remineralization potential of saliva and produce faster and deeper subsurface remineralization.^12,13

Silver diamine fluoride — Featuring high concentrations of fluoride and silver, SDF is a translucent liquid commonly utilized for professional topical fluoride application. This product is mainly available in a 38% concentration formula, which contains 44,800 ppm of fluoride.¹⁸ Combining silver’s antibacterial and antimicrobial properties with fluoride and ammonia creates an effective preventive agent.¹⁹ A systematic review with meta-analysis by Oliveira et al²⁰ found that applications of 1% chlorhexidine, 5% sodium fluoride, and 38% SDF demonstrated preventive and remineralization impacts on caries-susceptible root surfaces. In addition, it inhibited cariogenic bacteria and prevented collagen degradation in dentin. The authors further stated that application of 38% SDF annually to older adults with exposed root surfaces is an efficient, economical and effective way to halt tooth demineralization and caries progression.²⁰

When comparing chlorhexidine varnish to SDF, applying 1% chlorhexidine varnish at quarterly intervals had a significantly higher preventive effect at 12 months over a yearly application of SDF, but there was no difference between the two products at 24 months. The application of 1% chlorhexidine varnish or 5% fluoride varnish quarterly and the annual application of 38% SDF have similar effects in the long term.²⁰ While the annual application of SDF makes it more cost-effective, the associated tooth staining may impact patient’s compliance and satisfaction.^19,20 A newer product which requires the application of potassium iodide to the tooth surface following SDF delivery has some supporting evidence that it reduces staining.²¹

Casein phosphopeptide amorphous calcium phosphate — Calcium phosphate-based remineralization technologies are promising adjuncts in the management of incipient caries lesions.² Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) is a bioactive material derived from the milk protein casein that increases calcium and phosphate bioavailability. In basic terms, CPP stabilizes ACP.²² In dental plaque, clusters of ACP are formed through the combination of CPP with calcium phosphate.^2,16 This milk protein acts as a reservoir to precipitate these minerals onto the tooth surface.^9,16,23 This results in a supersaturated enamel that resists demineralization and improves remineralization.¹⁶ Additionally, CPP-ACP inhibits bacterial adhesion to the tooth surface, thus slowing plaque formation.¹² Furthermore, through the production of ammonia, the breakdown of the CPP buffers the oral environment by raising the oral pH.¹²

Research shows that CPP can be detected at low levels in those who consume dairy products.²² Also, the use of mouthrinses and chewing gum containing CPP-ACP significantly increases the availability of calcium and phosphate in plaque. In the chewing gum studies, this increase lasted for several hours after use. The use of CPP-ACP products increases calcium and phosphate levels in plaque biofilm and enhances remineralization compared to unstabilized ACP or calcium added to products independently.²²

Dental products containing CPP-ACP in addition to fluoride are effective remineralizing agents.^2,16 A recent systematic review and meta-analysis by Ma et al⁹ assessed whether CPP-ACP effectively remineralizes white spot lesions compared to non-CPP-ACP pastes, fluoride toothpaste, or a placebo. Results showed that CPP-ACP products produced a better remineralization effect on white spot lesions compared to non-CPP-ACP-containing products; therefore, the authors recommended the use of CPP-ACP products for patients with white spot lesions.

Similarly, Shen et al²⁴ compared various calcium phosphate and fluoride-containing varnishes to a placebo in preventing enamel demineralization. Results indicated the fluoride-containing varnishes significantly inhibited demineralization in comparison to the placebo varnish. The varnish that included CPP-ACP and fluoride was deemed superior to the fluoride varnish in preventing enamel demineralization, as it released the highest concentrations of calcium, phosphate and fluoride ions.

Remineralization can similarly be achieved by raising salivary calcium/phosphate (Ca/P) levels to a ratio of 1.6.⁸ The Ca/P ratio in dental plaque is approximately 0.3, which is low;^6,8 therefore, the use of calcium-containing products may promote remineralization.^6,8 Research shows that consumption of cheese and yogurt without added sugar significantly improved calcium and phosphorus concentration in plaque biofilm, and is therefore a viable option to enhance remineralization.²⁵

Xylitol — This is a five-carbon natural sugar alcohol with a dietary sweetening property similar to sucrose.²⁶ Research suggests xylitol is safe, noncariogenic, and has a dose/frequency-dependent effect on the cariogenic bacteria mutans streptococci in dental plaque.^26–28 Habitual consumption of xylitol is defined as the daily intake of 5 to 7 grams of xylitol three times per day; the recommended consumption dose for caries prevention is 6 to 10 grams/day.²⁶ Systematic reviews have concluded the habitual consumption of sucrose-free xylitol/polyol-combination chewing gum or lozenges is effective in preventing coronal caries.²⁷ Additionally, research studies cite that xylitol significantly reduced caries when used in combination with fluoridated toothpaste.^27–29 In their systematic review, Mickenautsch and Yengopal²⁹ thus recommended the addition of xylitol to existing fluoride treatments to prevent caries.

Tri-calcium phosphate — Produced with a “pulverizing process of fused beta-tricalcium phosphate and sodium lauryl sulfate or fumaric acid,” tricalcium phosphate (TCP) is a compound that accelerates enamel fluoride uptake.^24,30,31 When TCP contacts a saliva-moistened tooth surface, it is believed the protective barrier breaks down, which results in the availability of calcium, phosphate and fluoride ions.^24,30 In vitro and in situ studies show that TCP products improve remineralization and enhance anticaries action; however, their clinical efficacy remains unknown.^5,24,32,33 Research indicates that TCP improves the fluoride uptake of enamel treated with fluoridated toothpaste and increases the mineralization of dentin in bovine teeth.^24,32,34 Alamoudi et al³³ found that combining TCP with fluoride varnish significantly inhibited demineralization on primary teeth in vitro. In enamel subsurface lesions, Hamba et al⁵ observed increased remineralization in samples exposed to fluoridated toothpaste containing TCP.

FUTURE REMINERALIZING THERAPIES

Titanium tetrafluoride (TiF₄) is a fluoridated compound that the literature suggests reduces demineralization through the creation of an acid-stable surface layer on the tooth.^24,35,36 It provides mechanical protection and enhances fluoride uptake due to the fluoride binding to the metal ions.²⁴ When a varnish containing TiF₄ is applied to the tooth, it is believed the titanium ions react with apatite to create “an acid resistant, glaze-like layer that is rich in hydrated titanium phosphate and titanium dioxide.”³⁶ This layer inhibits microorganism adhesion and viability, and also hinders subsequent plaque growth. Comar et al³⁶ further reported that varnish containing TiF₄ generates a higher calcium and fluoride deposition than sodium fluoride varnish on both healthy and demineralized enamel surfaces. This is possible due to its viscosity, which increases the contact time with enamel, therefore improving the reaction of titanium with the tooth’s apatite.^36,37 Varnish containing TiF₄ also has a low pH and can augment enamel fluoride uptake compared to sodium fluoride varnish.³⁶

Polat and Ilday²³ found that TiF₄ combined with an Er:YAG laser produced an even greater remineralization effect. They assessed various remineralization agents, including TCP, CPP-ACP, TiF₄ and bioactive glass individually and in combination with an Er:YAG laser. This study evaluated the effects of each on microhardness values of 150 extracted third molars and found statistically significant differences among each group.²³ Except for the CPP-ACP/Er:YAG laser combination, each individual agent combined with the Er:YAG laser produced microhardness values that were significantly higher than any agent alone. The TiF₄/Er:YAG laser combination showed better resistance to demineralization and demonstrated the most effective remineralization.²³ A systematic review by Wahengbam et al³⁸ reported that TiF₄ is a viable option for remineralization because of its formation of an acid-resistant coating; this is in addition to its higher uptake, greater penetration, and longer retention of fluoride. Despite various studies supporting the beneficial properties of TiF₄, the performance of this agent is still unclear and its chemistry is not completely understood.³⁸

CONCLUSION

The ongoing processes of demineralization and remineralization are a constant factor in the oral cavity, and the minerals available in saliva and plaque determine which action takes precedence. Thus, it is vital to maintain an oral environment that inhibits demineralization and promotes remineralization. In addition to dietary counseling, oral hygiene instruction, and recommendation and application of preventive agents, dental team members must be aware of the current remineralization therapies available to prevent or arrest caries. Incorporating evidence-based remineralization strategies is an important step in reducing caries risk and avoiding invasive restorative treatment.

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From Decisions in Dentistry. April 2023;9(4):40-43.