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The most prevalent disease in children not requiring hospitalization is dental caries,1 which is a common and preventable problem for people of all ages. For children, untreated cavities can cause pain, dysfunction, absences from school, and difficulty concentrating, greatly impacting their quality of life.2 Caries is a transmissible, vector-driven infectious disease in which cariogenic bacteria are transferred from a host, usually the mother, to the child.3
Noninvasive treatment of incipient, noncavitated dental caries lesions, also known as white spot lesions, was conceptually introduced in the 1980s with fluoride applications as the primary pharmacological agent.4,5Topical fluoride applications of low concentration/high frequency at home, or high concentration/low frequency in the dental office, work to provide a reservoir of calcium fluoride in the saliva, which may help render the enamel more acid resistant to future insults.6 As fluoride taken systematically in excessive doses has been associated with adverse effects, such as fluorosis, controlled topical exposure of the carbonated hydroxyapatite (enamel) has been proposed to be more efficacious.7 The use of fluoride (stannous fluoride or sodium fluoride) delivered by various vehicles is recommended for children older than 1 year of age in age-appropriate doses.4,5,8-11
Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) in a proprietary form has been applied as a mousse and a varnish and used in an adult toothpaste to encourage remineralization and decrease sensitivity in teeth.12-14 A formulation containing CPP-ACPF and xylitol specifically for children younger than 12 years of age is available,15 which incorporates the latest advances in remineralization technology utilizing CPP-ACPF to reduce caries by reversing demineralization16 in teeth and is formulated to reduce the formation of plaque and biofilms.17-19
REMINERALIZATION EFFECT OF CPP-ACP
Amorphous calcium phosphate (ACP), first described by Aaron S. Posner in the mid-1960s, is the initial solid phase that precipitates from a highly supersaturated calcium phosphate solution and converts to a stable crystalline phase. In the oral cavity, unstabilized ACP rapidly crystallizes and may increase calculus deposits.20 Reynolds et al at the University of Melbourne studied anticaries agents and identified that the milk protein casein, when aggregated with calcium phosphate, forms casein phosphopeptide (CPP).21 The nanocomplexes of CPP form within a pH range of 5.0 to 9.0.21 The levels of calcium and phosphate bound by CPP increase as the pH level rises, and the calcium and phosphate become bioavailable to remineralize the enamel hydroxyapatite crystal.22,23 The remineralizing effect is caused by the stabilization of calcium ions and phosphate ions in the solution. Binding ACP to multiple amine residues present in CPP enables the formation of CPP-ACP nanoclusters, which increases the total surface area and improves its interaction with the biofilm and enamel. The clusters behave like salivary proteins such as statherin and compounds such as calcium phosphopeptides and phospho-
proteins by regulating the behavior of calcium and phosphate, stabilizing and preventing nucleation and spontaneous precipitation of calcium ions.22,24When dental products containing CPP-ACP are used, ion saturation in saliva and biofilm are produced, and calcium and phosphate ions are available as ACP for subsequent precipitation, which promotes the dental remineralization process.25,26
The tooth enamel, carbonated hydroxyapatite, is a poorly formed, weak mineral that can demineralize at a pH of 5.5 to 6.0, depending upon prior exposure to fluoride. The enamel of pediatric primary teeth has a higher organic content (collagen) and less inorganic content (carbonated hydroxyapatite) than adult teeth and is less resistant to acid destruction. Frequent applications of topical fluoride in the dental operatory (high concentration/low frequency) and on a daily basis from toothpaste and fluoridated tap water (low concentration/high frequency) provide a reservoir of fluoride that is reincorporated into the matrix during remineralization. In teeth, the newly formed fluorohydroxyapatite is more acid resistant and has a lower wetting potential than the untreated enamel.8
The traditional use of sodium fluoride develops a harder outer surface of the tooth, blocking the fluoride from being incorporated in the deeper layers of the demineralized enamel. CPP-ACP has been found to allow deeper penetration because of its bonding to the biofilm.27
Demineralization of the tooth following ingestion of acidic foods or beverages or through the action of cariogenic bacteria may also progress to white spot lesions. Original clinical studies on the use of CPP-ACP in patients during and after orthodontic treatment showed equivocal results in reducing white spot lesions.28 The benefits of CPP-ACPF have been shown in studies for remineralization of white spot lesions following acid demineralization during orthodontic treatment in teens.16
BIOFILMS, CARIES FORMATION, AND CPP-ACP
Significant in the oral cavity, biofilms consist of clusters of microbes in close proximity, bonded by glucans to the tooth surface. They maintain their own acidic circulation system, generally unaffected by the pH of the saliva (which is approximately 6.8) and maintained by a phosphate buffer system. The acidic pH within the dental biofilm results in increased levels of acid-tolerant microorganisms, promoting the development of caries and their progression.29-31 Mechanical debridement, mech-
anical tooth brushing, and chemical removal of this biofilm are necessary steps to maintain the health of the oral tissues, prevent caries, and reduce periodontal and gingival disease.32CPP-ACP has been shown to cause a decrease in biofilm retentivity.4,5,8-10
Fluoride provides a secondary function at high concentrations by blocking the enolase (phosphopyruvate hydratase) system in Streptococcus mutans, potentially preventing biofilm formation and adherence to teeth, despite an increase in fluoride-resistant bacteria.33 Fluoride as an antibacterial agent, when compared in different formulations of varnish, has been shown to be most effective in casein phosphopeptide-amorphous calcium phosphate with fluoride (CPP-ACPF),25,34 and
additional antibacterial benefit may come from a xylitol sweetener.19,25
Fluoride-resistant S mutans have also been a concern; however, recent research shows that as these bacteria develop, they have decreased metabolism of carbohydrates and a less structured and retentive biofilm.31 CPP-ACP in mousse form reduces biofilm formation of the cariogenic bacterium S mutans without a bactericidal
effect, which has therapeutic benefits, especially in orthodontic and pediatric patients.17 Casein pyrophosphate bonds to the biofilm and allows the release of fluoride into the system. In a recent study comparing the efficacy of CPP-ACP and fluoride in children over a 6-month period, the highest reduction in S mutans-positivity was seen in children treated with CPP-ACP.35
FLUORIDE DENTRIFRICES AND CPP-ACPF FOR USE IN CHILDREN
For more than four decades, fluoride-containing dentifrices have been key in reducing caries in children.36 Toothpastes for children may contain the same concentration of fluoride (1,000 ppm) as adult toothpastes but are generally free of additive agents such as bleaches, harsh abrasives for whitening, and desensitizers. Toothpastes marketed for children may also have a reduced fluoride concentration (500 ppm), or none at all, and are labeled as such. Some include artificial sweeteners such as saccharine or natural sweeteners such as fructose or xylitol, a sugar alcohol that has been shown to have a bactericidal effect, thereby reducing microbe count and biofilm production and adhesion.18,19
The exposure to and ingestion of fluoride is controlled by the amount of dentifrice applied and frequency of use. Fluoride availability for remineralization is determined by frequency, time, and concentration of exposures. The American Dental Association-recommended amount of toothpaste with a 1,000 ppm formulation for children is a smear of toothpaste (the size of a grain of rice) from the time the first tooth erupts until age 3 years.10 Children aged 3 years and older should use a pea-sized amount of toothpaste. These amounts help limit
the exposure of children to fluoride from ingested dentifrice to levels below those suggested by the National Academies of Sciences, Engineering and Medicine Health and Medicine Division (HMD) of 0.05 mg/kg/day.37,38The amount of toothpaste swallowed is directly associated with the age of the child, with younger children swallowing a proportionally larger amount than older children. All toothbrushing in children should be supervised by an adult to prevent excessive ingestion of toothpastes containing fluoride.39
Currently available remineralizing dental cream or dentifrice products that contain CPP-ACP or CPP-ACPF include Topacal C-5 (Enamel Improving Cream, NSI Dental Pty Ltd), Enamelon® (Premier), which contains stannous fluoride,11 and MI Paste® ONE (GC America), which contains sodium fluoride,40among others. CPP-ACPF is available as a mousse formulation, a varnish, and a dentifrice. The mousse formulation of CPP-ACP and CPP-ACPF is applied to demineralized teeth following routine oral hygiene procedures of brushing and flossing. CPP-ACPF varnish can be applied at regular intervals by a health professional to patients of all risk cate-
gories, including patients who are at high risk for caries or those who exhibit areas of demineralization and white spot lesions. The dental cream Topacal, which contains CPP-ACP, has been shown to promote regression of white spot lesions,34 while the dentifrice MI Paste®Plus (GC America) has been found to prevent demineralization and the development of new white spot lesions.41 CPP-ACPF formulated as a mousse or a varnish has been used successfully and safely in children.42The quarterly application of CPP-ACPF varnish has been shown to reduce caries activity and white spot lesions significantly in preschool children, and teeth treated with CPP-ACPF show superior enamel resistance and decreased active demineralization compared with those treated with traditional sodium fluoride varnishes.42
A tooth mousse containing CPP-ACPF has been found to reduce biofilm formation.17With the dentifrice MI Paste ONE (GC America), which contains CPP-ACPF, xylitol, and potassium nitrate, biofilm removal is achieved through the use of silica,40,43 which in this formulation has a low Relative Dentin Abrasivity (RDA) index.37,44 This product is not indicated for use in patients younger than 12 years of age, because it contains potassium nitrate, a dentin-desensitizing agent. However, a formulation of this CPP-ACPF dentifrice without the desensitizing agent (MI Paste® ONE Kids, GC America) has been developed for children between the ages of 2 and 12 years, with the goal of decreasing white decalcification and improving enamel resistance to acid destruction, and thus preventing caries. Research data are not yet available supporting this specific formulation.
ALLERGENICITY AND SENSITIVITY WITH CPP-ACPF DENTAL PRODUCTS
It has been thought that sodium lauryl sulfate (SLS), a surfactant and detergent commonly used in toothpastes, can cause dermal sensitization, but these claims are unsubstantiated.45 SLS can, however, diminish the cariostatic effect of fluoride when present with sodium monofluorophosphate during topical application, as it has been found that increasing amounts of lauryl sulfate decreased the amount of alkali-soluble fluoride deposited on the enamel.46 The CPP-ACPF dentifrice for children (MI Paste ONE Kids) utilizes sodium lauroyl sarcosinate,15 a foaming and cleansing agent derived from the naturally occurring amino acid sarcosine. Sodium lauroyl sarcosinate is nontoxic and has no mutagenic, irritating, or sensitizing effects.47
Milk proteins, casein and whey, can cause an allergic response in susceptible people, which can include swelling of the airway and perioral structures, respiratory distress, and an anaphylactoid reaction. This is not to be confused with lactose intolerance, which can occur because of the body's inability to metabolize lactose into glucose and galactose with the enzyme lactase, leading to gastric distress and bloating. Therefore, products containing these milk proteins are safe for use in lactose-intolerant patients, although if these proteins are ingested, they may induce similar symptoms. In the case of an allergic reaction, the patient should cease using the product, rinse the mouth, and seek out immediate emergency medical care.
CONCLUSION
The use of a fluoride-containing dentifrice is key to reducing caries rates in children. Application of casein phosphopeptide-amorphous calcium phosphate with fluoride (CPP-ACPF) following brushing to reduce biofilms has been shown to promote remineralization and to be beneficial in reducing white spot lesions. CPP-ACPF formulated as a mousse or a varnish, applied to teeth after toothbrushing, has been successfully and safely used in children. A dentifrice that incorporates CPP-ACPF specifically formulated for children younger than 12 years of age is available for supervised home use, which enables biofilm removal through toothbrushing to be combined with CPP-ACPF application and may prove beneficial in the prevention and remineralization of dental caries.
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