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Evidence-Based Strategies for Boosting Remineralization

As dental caries remains a serious public health problem, implementing minimally invasive approaches to addressing caries risk and preventing tooth decay is prudent.

Dental caries is a chronic, multifactorial, pathological disease of tooth structure that negatively affects populations across the world. The Global Burden of Disease, a collaboration of more than 1,800 researchers from 127 countries, reported that 35% of the world population experiences dental decay.1 The United States Centers for Disease Control and Prevention reports that 45.8% of youth ages 2 to 19 experienced caries from 2018 to 2019, and 91% of adults ages 20 to 64 and 96% of adults age 65 and older had tooth decay during 2011 to 2012.2–4

Dental caries can result in impaired quality of life due to pain, anxiety, acute and chronic infections, and eating and sleep disruption. Decayed teeth may impact a person’s ability to interact with others (resulting in social isolation and reduced income) on one end of the spectrum, and on the other end, decay can cause sepsis, resulting in death.5


Demineralization of enamel occurs when salivary pH drops below 5.5. Factors that directly affect the acidity of salivary pH include:

  • Food characteristics—certain foods adhere to teeth longer than others providing substrate for bacteria for longer amounts of time
  • Individual factors—acidogenic bacteria/plaque microbial composition, saliva characteristics, and tooth structure differences
  • Behavioral factors—frequency of fermentable carbohydrate consumption, oral hygiene, and professional dental care
  • Genetic influences

Socioeconomic factors are also related to caries progression. People with lower socioeconomic status experience the highest prevalence and pathogenicity of dental caries.2 Of these factors, none is more deleterious than fermentable carbohydrate consumption including:

  • Sucrose
  • Fructose
  • Glucose
  • Cooked starch

Dental caries does not develop in the absence of sugar, a fact that has been robustly researched and discussed in the literature. Interventions and recommendations based on caries risk assessment, a large part of which involves identifying and controlling consumption of sugary foods, have long been recognized as an effective caries prevention approach, reducing caries in high risk populations by as much as 38%.6 However, in the US, appropriate use of caries risk assessment techniques/procedures and modern caries identification techniques is not widespread.7–9


The strength of enamel, the most mineralized tissue in the body, is conferred by hydroxyapatite crystals, which are composed of calcium and phosphate ions. The remainder of enamel’s structure is made up of water and proteins called enamelins. Once salivary pH drops below 5.5, calcium and phosphate are dissolved from the tooth surface (demineralization), creating a weaker structure. Enamel is unable to undergo cellular regeneration—it cannot repair itself. Therefore, remineralization of enamel is wholly dependent on re-incorporation of the lost calcium and phosphate back into the crystallite structure. Remineralization agents have been broadly classified by researchers.10 However, the efficacy of some of these agents has yet to be proven in clinical studies. Therefore, this review will focus only on materials whose efficacy in remineralizing enamel has been proven in high-quality clinical trials.


The presence of fluoride during the remineralization process creates a new structure called fluorohydroxyapatite, which is stronger and more resistant to decay than hydroxyapatite. This characteristic of fluoride is what makes it such an effective anticaries/remineralization agent and why it remains the standard therapy for remineralization.

While community water fluoridation is regarded as the “most cost-effective method of delivering fluoride to all members of the community regardless of age, educational attainment, or income level,”11 its most pronounced benefit is on primary teeth.4 Research has consistently shown that fluoride’s greatest benefit is delivered topically (via toothpastes, mouthrinses, varnishes, gels, etc) and not systemically (during tooth formation). In addition to using a fluoride toothpaste twice daily, the American Dental Association’s (ADA) clinical practice guidelines recommend the following for primary teeth:12

  • 38% silver diamine fluoride (SDF) solution (biannual application) instead of 5% sodium fluoride (NaF) varnish (applied weekly for 3 weeks) to arrest advanced cavitated carious lesions on any coronal surface
  • Sealants plus 5% NaF varnish (application every 3 months to 6 months) to arrest or reverse noncavitated carious lesions on occlusal surfaces
  • 1.23% acidulated phosphate fluoride (APF) gel every 3 months to 6 months or 5% NaF varnish every 3 months to 6 months to arrest or reverse noncavitated carious lesions on facial or lingual surfaces of primary and permanent teeth

For permanent teeth, the ADA’s clinical practice guidelines recommend:

  • Sealants plus 5% NaF varnish (application every 3 months to 6 months) to arrest or reverse noncavitated carious lesions on occlusal surfaces
  • 5,000 ppm fluoride (1.1% NaF) toothpaste or gel (at least once a day) over 5% NaF varnish (applied every 3 months to 6 months) to arrest or reverse noncavitated and cavitated carious lesions on root surfaces of permanent teeth
  • To arrest or reverse noncavitated carious lesions on occlusal surfaces of permanent teeth, prioritize the use of sealants plus:
  • * 5% NaF varnish (application every 3 months to 6 months)


  • * Sealants alone over 5% NaF varnish alone (application every 3 months to 6 months)
  • * 1.23% APF gel (application every 3 months to 6 months)


  • * 0.2% NaF mouthrinse (once per week)

While fluoride gels and mouthrinses are effective in preventing demineralization, their remineralization efficacy is limited.13 These evidence-based recommendations are easy to incorporate into clinical practice and the ADA has created chairside guides available at:


Salivary pH is a critical component of the demineralization process. Aciduric and acidogenic bacteria (bacteria that generate and thrive in acidic environments) force salivary pH to drop. It is not possible to remove all of the bacteria from the oral cavity, so controlling bacterial proliferation as a means of lowering salivary pH is an effective way to facilitate remineralization.14 Strong evidence supports the effect of sodium bicarbonate, arginine, and xylitol in increasing salivary pH.14


Arginine is a semi-essential amino acid found is saliva that effectively increases salivary pH. Arginine is metabolized by nonpathogenic bacteria and one of the biproducts, ammonia, neutralizes/ buffers acidity in the oral cavity. First discovered in the late 1970s, the research on arginine is extensive, and a recent systematic review revealed that arginine-containing compounds provide greater benefits in arresting and reversing caries lesions compared with conventional fluoride toothpaste alone.15


Xylitol is a naturally occurring sugar-alcohol present in fruits such as plums, strawberries, and raspberries, and vegetables such as cauliflower, pumpkin, and spinach. However, it is produced either by chemical hydrogenation of xylose or by biotechnological processes from xylan-rich plant resources for use in dental products such as gum, rinses, varnishes, and toothpaste. Xylitol works in two ways:

  1. Reduces bacteria’s ability to attach to the tooth surface
  2. Disrupts bacterial metabolism that leads to cell death.

The most effective use of xylitol is in chewing gum, which increases salivary flow in addition to its effect on acidogenic bacteria.16


More than 700 different bacterial species aggregate in the oral cavity and form communities (biofilm), creating a complex ecosystem which, in health, exists symbiotically with the host. The bacteria in the biofilm are always metabolically active, releasing biproducts (particularly lactic acid), causing fluctuations in salivary pH.

Streptococcus mutans are the most cariogenic organisms because of their ability to produce large quantities of glucans and acid, their abundance in the oral cavity, and their ability to firmly adhere to the tooth surface.17,18 Other acidogenic and aciduric bacteria, including members of the mitis-, anginosus-, and salivarius-groups of streptococci; Enterococcus faecalis; Actinomyces naeslundii; Actinomyces viscosus; lactobacilli (important for further caries development, especially in the dentin); and S. sobrinus are also able to cause dental caries, but not as effectively as S. mutans.

In the past decade, there has been a surge in research involving the use probiotics as remineralization agents. Probiotics are living microorganisms that are safe for human consumption and provide health benefits when ingested in sufficient quantities.19 The study of probiotics in dentistry grew out of their proven association with gut health and wide use in the prevention or treatment of gastrointestinal infections and diseases.

In the oral cavity, probiotic intake resulted in significant increases in salivary pH, a process which is seen by many as crucial to remineralization.14,19 Probiotics may be taken directly with food (cheese, yogurt, fermented milk, fruit juice, or chewing gum) or as pharmaceutical preparations in the form of tablets, etc. A recent systematic review of randomized clinical trials confirmed probiotics’ ability to halt caries progression, although further research is recommended before including probiotics as a standard caries management therapy.20


Calcium and phosphate are essential for remineralization. Casein phosphopeptide amorphous calcium phosphate (CPP-APP), a nanocomplex of milk protein (casein phosphopeptide) and amorphous calcium phosphate, has been shown to be an effective remineralization agent.21,22 CPP-APP stabilizes calcium and phosphate ions on the tooth surface (allowing for bioavailability) and is available in gel, cream, or mousse forms, and as chewing gum.22 Fluoride can also be added to this mixture, creating CPP-APPF. While, in theory, the addition of fluoride increases the remineralization potential of this compound, studies have not shown it to be more effective than CPP-ACP in remineralizing carious lesions.13 In situ and in vitro studies using calcium sodium phosphosilicate, sodium trimetaphosphate, and B-tricalcium phosphate have shown promise in the prevention and treatment of caries, but there are not enough well-done clinical studies that demonstrate their remineralization effect.


Although the reduction of fermentable carbohydrate intake and the incorporation of fluoride in toothpaste and community water systems have been the mainstay of dental caries prevention, recent data confirm that dental caries remains a serious worldwide public health problem. The ADA has long encouraged the implementation of minimally invasive approaches to treat incipient and white spot lesions. To support clinicians in their practice, clinical practice guidelines for the treatment of these lesions have been developed and are easily accessible. These guidelines include fluoride and nonfluoride caries preventive agents, available in different formulations, for professional and at-home use. While these agents have been reviewed, there are differences in products and dental hygienists must consult manufacturer instructions in order to properly use these agents in clinical practice.


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  2. Fleming E, Afful J. Prevalence of total and untreated dental caries among youth: United States, 2015–2016. NCHS Data Brief. 2018;307:1–8.
  3. Dye BA, Thornton-Evans G, Li X, Iafolla TJ. Dental caries and tooth loss in adults in the United States, 2011–2012. NCHS Data Brief. 2015;191:1-8.
  4. Slade GD, Grider WB, Maas WR, Sanders AE. Water fluoridation and dental caries in US children and adolescents. J Dent Res. 2018;97:1122–1128.
  5. FDI World Dental Federation. Key Facts About Oral Health. Available at:​oral-health/​ask-the-dentist/​facts-figures-and-stats. Accessed March 18, 2020.
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  8. Riley JL 3rd, Qvist V, Fellows JL, et al. Dentists’ use of caries risk assessment in children: findings from the Dental Practice-Based Research Network. Gen Dent. 2010;58:230–234.
  9. Riley JL 3rd, Gordan VV, Rouisse KM, McClelland J, Gilbert GH; Dental Practice-Based Research Network Collaborative Group. Differences in male and female dentists’ practice patterns regarding diagnosis and treatment of dental caries: findings from The Dental Practice-Based Research Network. J Am Dent Assoc. 2011;142:429–440.
  10. Arifa MK, Ephraim R, Rajamani T. Recent advances in dental hard tissue remineralization: a review of literature. Int J Clin Pediatr Dent. 2019;12:139.
  11. United States Department of Health and Human Services. Statement on the Evidence Supporting the Safety and Efficacy of Community Water Fluoridation. Atlanta: Centers for Disease Control and Prevention; 2018.
  12. Slayton RL, Urquhart O, Araujo MWB, et al. Evidence-based clinical practice guideline on nonrestorative treatments for carious lesions: a report from the American Dental Association. J Am Dent Assoc. 2018;837:819–849.
  13. González-Cabezas C, Fernández CE. Recent advances in remineralization therapies for caries lesions. Adv Dent Res. 2018;29:55–59.
  14. McComas M. Achieving pH neutralization. Dimensions of Dental Hygiene. 2019;17:25–30.
  15. Li J, Huang Z, Mei L, Li G, Li H. Anti-caries effect of arginine-containing formulations in vivo: a systematic review and meta-analysis. Caries Res. 2015;49:606–617.
  16. Riley P, Moore D, Ahmed F, Mohammad SO, Worthington HV. Xylitolcontaining products for preventing dental caries in children and adults. Cochrane Database Syst Rev. 2015;26:CD010743.
  17. Metwalli KH, Khan SA, Krom BP, Jabra-Rizk MA. Streptococcus mutans, Candida albicans, and the human mouth: a sticky situation. PLoS Pathog. 2013;9:e1003616.
  18. Conrads G, de Soet JJ, Song L, et al. Comparing the cariogenic species Streptococcus sobrinus and S. mutans on whole genome level. J Oral Microbiol. 2014;6:26189.
  19. Lin TH, Lin CH, Pan TM. The implication of probiotics in the prevention of dental caries. Appl Microbiol Biotechnol. 2018;102:577–586.
  20. Nagarjuna P, Sekharareddy CV, Sudhir KM, Kumar KRVS, Srinivasulu G. Probiotics in prevention of dental caries: a systematic review. IOSR Journal of Dental and Medical Sciences. 2016;15:89–101.
  21. Imani MM, Safaei M, Afnaniesfandabad A, et al. Efficacy of CPP-ACP and CPP-ACPF for prevention and remineralization of white spot lesions in orthodontic patients: a systematic review of randomized controlled clinical trials. Acta Inform Med. 2019;27:199.
  22. Yengopal V, Mickenautsch S. Caries preventive effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP): a meta-analysis. Acta Odontol Scan. 2009;67:321–332.

From Dimensions of Dental Hygiene. April 2021;19(4):2225.

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