Mineralizing agents to manage early carious lesions. Part II: clinical application

The prevalence of dental caries worldwide has seen a steady decline in the past 50 years, largely due to the wide use of fluoride.¹ Typically, early carious lesions (white spot lesions) are present on tooth surfaces most commonly missed during oral hygiene, and where plaque accumulates easily – the proximal (Figure 1) and cervical margins (Figure 2). Fluoridated products are still considered the most efficient way to prevent and remineralize carious lesions. However, fluoride on its own does not remineralize carious lesions. It requires the presence of other mineral ions present within the oral cavity. With advances in the understanding of the mechanisms of carious lesion formation and progression and the chemistry of remineralization/mineral deposition, new therapies have been developed. Their remineralization chemistry has been investigated comprehensively in laboratory studies and discussed in Part 1 of this review. Some of these new technologies have been commercialized, with various clinical benefits claimed by the manufacturers.

The aim of this second article is to provide an overview of clinical evidence on currently available remineralization technologies, and the guidelines on related interventions in primary care practice.

Clinical evidence for remineralization

Tables 1–6 summarize the findings from some of the key clinical studies on current remineralization approaches.

Fluoride

The introduction of fluoride is considered an important cornerstone in the prevention of dental caries. Its remineralization effectiveness has been supported by numerous clinical studies. Fluoride is added as the main active ingredient in both consumer (toothpastes and mouthrinses) and professional products (varnishes, topical gels and restorative materials), as well as in foodstuffs such as salt and dairy products, especially when public water fluoridation is not feasible.¹ Retrospective analysis of clinical data from a 3-year trial suggests that the use of fluoride toothpaste can reverse early caries through remineralization² and this effect could be enhanced by additional application of fluoride mouthrinse after toothbrushing, or by fluoride varnish.^3,4,5 In a systematic review of topical fluoride application in the prevention of dental caries, Marinho et al found that the efficacy was positively associated with the intensity of fluoride application and concentration; therefore, the impact of fluoride is dose dependent.⁶

Considering the dose-response feature of fluoride, it seems rational to increase the concentration of fluoride in different modalities to maximize its clinical benefits for those patients at risk. In recent years, some high-F toothpastes, such as 5000ppm (Duraphat5000, Colgate-Palmolive, New York, USA) have been used to manage adults at high risk of caries. These products are only available via prescription by a medical or dental professional. Clinical studies have revealed that a high-fluoride toothpaste intervention can effectively improve remineralization.^7,8

Despite the significant clinical benefits, concerns regarding fluoride use should not be overlooked. Since the first report in 1993, dental fluorosis caused by fluoride application has been under the spotlight.¹ Contradicting clinical results were reported in the past regarding the prevalence of fluorosis after self-applied fluoride use.⁹ In a more recent Cochrane review, an increased risk of mild fluorosis was observed when toothpastes with 1000ppm fluoride were administrated to children aged 5–6 years, although this was mitigated by the beneficial caries prevention effect.¹⁰ Fluoride concentration in toothpaste has been limited to 1000–1450ppm by regulatory authorities in most consumer markets, with even lower concentrations recommended for children under 6 years old (European Academy of Paediatric Dentistry: 1000 and 500ppm for those aged 2–6 years and 6 months–2 years, respectively^11,12). The reason for the restriction of paediatric toothpaste formulation is to mitigate the systemic impact of ingested toothpaste, which occurs inevitably when children use toothpaste.

Another concern is that fluoride is most effective at the surface of the carious lesion leading to surface remineralization, while there is minimal remineralization within the body of the lesion.¹² Full remineralization is therefore difficult to achieve using topically applied fluoride, regardless of the product. The benefits of high fluoride application are limited up to a point and may cause lesion lamination.¹³ There is a growing market of acidulated phosphate fluoride (APF) products attempting to tackle this issue. These products are present in mouthrinse, gel or foam that have low pH (~3.0) to create pathways for fluoride and mineral ion ingress through the less porous enamel lesion surface, into the body of the carious lesion.¹⁴ Its remineralization effect on carious lesions is challenged by some in situ studies and randomized clinical controlled trials (RCTs) that found no additional benefits in addition to standard fluoride toothpaste,^15,16 while discolouration and etching of restorative materials, as well as dentine hypersensitivity owing to their acidity, may increase, especially when used frequently.¹³

Casein phosphopeptide–amorphous calcium phosphate (CPP-ACP)

CPP-ACP and its combination with fluoride, CPP-ACFP, are found in different forms and formulations: creams, mouthwashes and chewing gum. The aim of CPP-ACP use is to remineralize incipient enamel lesions at both the surface and subsurface level (an example of its clinical application is depicted in Figure 3). Its clinical efficacy has been evidenced by an increasing body of RCTs.¹⁷ Studies have suggested that CPP-ACP could deliver significantly better remineralization of WSLs in children and adolescents when compared to conventional fluoride products, including toothpaste, mouthwash or fluoridated hydroxyapatite.^{18,19,20,21,22,23,24,25,26} However, conflicting results have been reported, concluding that clinical remineralization efficacy of CPP-ACP was not superior, and may even be inferior to fluoride therapies.^27,28,29 Several RCTs indicated that CPP-ACP failed to show greater remineralizing benefits over placebo pastes.^30,31,32 There is also a great variety of findings presented in the literature, with some supporting the significant caries remineralizing and prevention effects of CPP-ACP, while others claim its long-term or synergistic effect with fluoride is limited.^33,34,35

The disparity and contradiction from clinical trials can be attributed to many factors, including lesion type, duration, the form of the applied agents and the evaluation methodologies. In Llena et al, pit and fissure lesions showed limited remineralization, probably due to insufficient penetration of CPP-ACP in these areas.¹⁸ It is also noted that in many studies, additional oral hygiene measures, such as the use of fluoride toothpaste or antimicrobial mouthwash, are included, which introduce more variables to a study and may mask the efficacy of the target intervention. Another limitation of the published clinical trials is the patient age. Many primarily focus on children and adolescents below the age of 18 years and only a few took adults or older adult patients into consideration.^29,36 Therefore, the clinical efficacy of CPP-ACP remains uncertain in the adult and older adult populations. In addition, subjects with different susceptibility to caries may also introduce a risk of bias to the trials. For example, remineralizing effects maybe limited on orthodontic patients because the appliances reduce the efficiency of oral hygiene, but more obvious on dental students who are better aware of oral hygiene.^33,37 More well-designed, long-term RCTs with broader patient and indication types are warranted.

Self-assembling peptides (SAP)

SAP P11-4 promotes enamel remineralization by diffusing into the subsurface zone and providing a matrix for oriented crystal growth. It has been commercially available in some countries since 2013 (Curodont Repair, Credentis AG, Windisch, Switzerland). There have been several small-scale clinical trials to investigate its clinical efficacy in remineralizing incipient occlusal,^38,39 buccal/labial,^40,41,42 proximal,⁴³ or post-orthodontic⁴⁴ WSLs. All studies observed significant regression of caries and improved appearance of the WSLs after the P11-4 intervention compared with placebos or fluoride varnishes, implying superior subsurface remineralization. Its combination with fluoride varnish, however, offered no obvious added effect.⁴¹ Neither adverse effects nor severe adverse effects were reported, except in Burton et al where possible P11-4-related adverse effects of hypersensitivity in two cases were found.⁴⁵

It is worth mentioning that most studies were single-blinded RCTs owing to modality reasons. In addition, Credentis AG (manufacturer of Curodont Repair) either funded or had employees listed as co-authors in most of these studies, which raises the question of potential research bias. The split-mouth nature of some studies may have crossover effects that influence the results.^40,41,44 The short duration of these studies, ranging from 6 to 12 months, limits the medium- and long-term potential of using SAP, and further clinical research is required.

One concern regarding SAP technology is that its clinical application requires several steps, including meticulous preparation of the materials, and tooth preparation by conditioning and etching.⁴² The fact that SAP remineralization is driven by saliva may also limit its efficacy in patients with poor saliva quality, or in those with poor compliance.⁴⁶ Nevertheless, the ability of SAP in guided enamel remineralization at the subsurface level defines progress in non-invasive caries therapy. More well-designed RCTs are necessary.

Calcium sodium phosphosilicate (bioactive glass)

Calcium sodium phosphosilicate, invented by Professor Hench in the late 1960s and in clinical use since 1985, was originally indicated for use in bone regeneration.⁴⁷ NovaMin is the trademark of a bioglass formulation designed for oral care purposes. Currently available dental products using NovaMin technology are produced by Haleon (formerly GlaxoSmithKline Consumer Healthcare) and include Sensodyne Protect & Repair Toothpaste (Haleon, Weybridge, UK). The most noted effect of NovaMin is its effect on dentine hypersensitivity.⁴⁸ Its clinical efficacy as a remineralizing agent remains questionable. RCTs on the remineralization potential of NovaMin are sparse, with one being conducted by Hoffman et al who investigated the use of NovaMin in prevention of WSLs and gingivitis during orthodontic treatment.⁴⁹ The results showed that the NovaMin-containing toothpaste was similar to fluoride toothpaste in remineralization. However, it cannot be extrapolated that NovaMin possesses a similar prevention efficacy against WSLs as fluoride, because, in addition to NovaMin, the tested toothpaste also incorporated 5000ppm sodium fluoride, which on its own, is also capable of remineralization. Recently, a new bioglass formulation, BioMinF, has emerged to aid remineralization. This incorporates fluoride into the glass matrix as a soluble additive. In vitro investigations suggest better it has better remineralization properties than NovaMin owing to accelerated, yet sustained, dissolution of glass, enhanced concentration of phosphate and a reduced wash-off of fluoride.^50,51 However, no clinical studies are yet published that prove its clinical benefits. In general, bioglass as a remineralization agent seemingly holds promise, but more RCTs are required before any definitive conclusion can be drawn.

Functionalized tricalcium phosphate (f-TCP)

f-TCP is an end product of β-TCP through mechanochemical ball-milling with organics, tailored to boost the activity of fluoride ions during remineralization. It has been patented by 3M (Minnesota, USA) and launched in some markets in various forms, including cream (Clinpro Tooth Crème, 950ppm fluoride), toothpaste (Clinpro 5000 Anti-Cavity Toothpaste, 5000ppm fluoride) and varnish (Clinpro White Varnish, 22,600ppm fluoride). Previous studies failed to show significant remineralization of the WSLs treated by f-TCP, which seem to imply a limited long-term remineralization potential.^52,53 More recent clinical trials, however, demonstrated significant improvement of WSLs after f-TCP applications, and efficacy was similar to or marginally better than that of other agents, such as CPP-ACP, nano-hydroxyapatite and SAP.42,54–57 Nonetheless, the transient nature of f-TCP might hinder it from being effective. In Kau et al, participants were instructed not to rinse, but to expectorate, so that active constituents from the f-TCP cream were not cleared out immediately. The disparity within the published clinical trials suggests that f-TCP needs more well-designed RCTs before clinical recommendation.

Other calcium phosphate remineralization agents

Amorphous calcium phosphate (ACP) is a technology developed in 1999 using unstabilized calcium phosphate to boost remineralization. It has been incorporated into toothpaste, gel and varnish products. Evidence of ACP on remineralizing caries is mostly limited to in situ and laboratory studies using in vitro or animal models.^58,59 The only double-blinded RCTs were conducted by Papas et al on patients with high caries risk who had received therapeutic radiation therapy for head and neck cancer.^60,61 Significantly reduced net yearly increment was described for root caries of participants in the ACP group (Enamelon, Premier Dental Products Co, PA, USA). However, its unstable nature could induce intra-oral precipitation of calcium phosphates, which might increase the risk of dental calculus, reducing bioavailable calcium and phosphate ions. Furthermore, fluorapatites are formed when fluoride ions are present, which may also reduce its bioavailability, hence potentially limiting intra-oral efficacy.

Synthetic hydroxyapatite (HA) has been used in toothpaste since the 1980s by Sangi Co Ltd (Saitama, Japan). Since then, other toothpastes have emerged that incorporate HA.⁶² In recent years, HA-related anti-caries products have been gaining research interest. Clinical evidence of the treatment of the WSLs by hydroxyapatite has been reported in some RCTs with timescales ranging from 6 weeks to 12 months, with results indicating that nano-HA had caries remineralizing capabilities similar to fluoride toothpastes or mouthwashes.^{63,64,65,66,67} More well-designed RCTs are a prerequisite before any clinical recommendations.

Clinical guidance

In the UK, there are two main guidelines that outline the prevention and management of dental caries in adults and children, the Delivering Better Oral Health Toolkit,⁶⁸ and the Prevention and Management of Dental Caries in Children 2018.⁶⁹ Both outline the use of different over-the-counter, prescription-only and professionally applied oral care products for the management of caries.

The Toolkit dedicates two chapters to the management of dental caries (Chapter 4)⁷⁰ and the use of fluorides (Chapter 9),⁷¹ with an overview/summary of their recommendations for prevention of dental caries in children and adults found in Chapter 2.⁷² In the summary guidance tables, fluoride use is mentioned at length, while there is no mention of other non-fluoride agents. Table 7 outlines specific recommendations of fluoride use for different populations according to their age and risk of caries. In Chapter 4, a brief mention is made of topical remineralizing agents that are suggested to be effective in remineralizing early enamel lesions in high-risk patients, these typically consisting of casein phosphopeptide (CPP-ACP).

The SDCEP guidelines were published in 2018.⁶⁹ They specifically mention fluoride, but no other non-fluoride agent. All children receive standard prevention appropriate to their age, and those with increased risk of caries receive enhanced prevention until their risk reduces. These recommendations are summarized in Table 8.

It is important to note that in both sets of guidelines, there is no mention of non-fluoride-based products for the main clinical remineralization strategies owing to there being a limited high-level evidence base. However, this does not mean that these products are automatically without merit in targeted populations.

Conclusions

Delivering better oral health, specifically caries, should be focused on primary and secondary prevention delivered using the minimum intervention oral care (MIOC) framework.^73,74,75,76 As part of this, there is the need for development of new remineralization technologies and products. Although fluoride products remain the most effective in remineralizing enamel caries, their benefit may have plateaued, and certain negative perceptions, such as risk to health and dental fluorosis, may hinder their further clinical application. Among other technologies, CPP-ACP is a promising therapy, despite some contradictory findings from clinical studies. SAP may be the next generation for remineralization with its ability in structuring guided enamel remineralization. Calcium sodium phosphosilicate, f-TCP, ACP and synthetic HA demonstrate some remineralization capability; however, the level of clinical evidence is limited. Although these non-fluoride technologies hold promise, more well-designed RCTs are required to clarify their actual clinical benefits over traditional gold-standard fluoride, especially in higher-risk, vulnerable patient groups where these adjunctive therapies would have most benefit. The two main UK-based guidelines outline extensively, and in detail, the fluoride preparations that can be used for the management of dental caries based on the level of risk of caries development; neither provide guidance on the use of non-fluoride preparations in the management of caries.