In a recent article published in Frontiers in Public Health, researchers performed a randomized, double-blinded clinical trial of 18 months in adults enrolled at the Universities of Medical Sciences, Poznan and Bialystok, Poland (two-centered) as test subjects and controls.
The study aimed to compare the caries-preventing effect of a fluoride-free, hydroxyapatite, (Ca5(PO4)3(OH), toothpaste (in test subjects) and toothpaste with sodium fluoride (in positive controls).
Study: Caries-preventing effect of a hydroxyapatite-toothpaste in adults: a 18-month double-blinded randomized clinical trial. Image Credit: Ground Picture/Shutterstock.com
Hydroxyapatite is an ingredient in dental and medicinal products, such as toothpaste, mouthwashes, etc. Clinical studies have shown that this calcium phosphate mineral effectively improves periodontal health and relieves dentin hypersensitivity.
Hydroxyapatite acts in the oral cavity via two mechanisms. First, it inhibits demineralization and remineralization of demineralized tooth surfaces. In vitro and in situ studies have also shown its caries-preventing effects.
The distinguishing factor is that hydroxyapatite has a pH buffering effect and shows protective calcium- and phosphate-releasing properties in cariogenic biofilms.
For several decades, fluoride has been used in oral care products to prevent dental caries, even though it is well-recognized that excessive fluoride exposure can cause fluorosis and other adverse side effects.
Thus, fluoride concentration in toothpaste is limited, especially for children under six years. However, reduced toothpaste amounts can lead to reduced cleaning efficacy.
Two studies have shown the non-inferiority of hydroxyapatite toothpaste to fluoride-containing toothpaste but only in adolescents and children, not adults.
Paszynska et al. showed its non-inferiority against 500 ppm amine fluoride in children, and Schlagenhauf et al. proved its non-inferiority against 1,400 ppm fluoride in adolescents receiving orthodontic treatment.
About the study
Unlike Paszynska et al. and Schlagenhauf et al., who used commercial toothpaste, researchers used toothpaste formulations differing only in two ingredients, i.e., hydroxyapatite and fluoride (1,450 ppm).
In this way, they could directly compare these two kinds of toothpaste for daily oral care in adults (both men and women) aged 18 to 45.
The study participants had a minimum of 10 caries-free molars and premolars, indicated by a Decayed Missing Filled Surfaces (DMFS) index equal to zero, and they willingly used an electric-powered toothbrush, changing the brushing heads every two months.
The primary study endpoint was the percentage of subjects showing no surge in DFMS between study visits 1 and 4, set 18 months apart, analyzed for the per-protocol (PP) population comprising 171 individuals.
Then, they repeated these for the intention-to-treat (ITT) population comprising all 189 subjects who performed at least one follow-up visit (V2, V3, or V4). The study also had two secondary endpoints, the percentage of subjects showing no change in mineral density and changes in all teeth with bacterial plaque.
The team used DIAGNOcam, a modern device for transillumination of dental tissues, to analyze mineral density changes and followed the Plaque Control Record (PCR) criteria to evaluate bacterial plaque-induced changes in all teeth.
The team labeled neutral plastic toothpaste tubes (all of the same shape) with a random number. Thus, they blinded the test subjects and the investigators to toothpaste composition. Furthermore, they asked all the study participants to brush their teeth twice a day, i.e., in the morning and the evening, after meals, for at least three minutes.
During the study screening, the team collected baseline (day 0) data in a chronological sequence, PCR, DMFS, and DIAGNOcam. Based on PCR findings, they performed professional tooth cleaning, but only on V1 and V4, and allowed no fluoride application after the cleaning.
A trained nurse or dentist allocated toothpaste to test subjects and controls, with proper instructions regarding using the assigned electric toothbrush and toothpaste.
The team reassessed the PCR and DMFS at the first follow-up examination on study day 182 (six months). They repeated the procedures performed on V2, i.e., study day 364 (12 months). During the final visit, i.e., study day 546 (18 months), researchers repeated PCR, DMFS, and DIAGNOcam assessments.
Notably, the team performed safety assessments in all subjects at every visit, in which they examined the oral cavity and perioral area and recorded adverse and serious adverse events (AEs and SAEs).
The study monitor reviewed the case report forms submitted by the investigator and his staff and verified their completeness, data plausibility, consistency, protocol adherence, etc.
In non-inferiority testing performed using a confidence interval (CI) approach, the team set an inter-group non-inferiority margin Δ of 20%. In addition, they performed a logistic regression analysis for the primary and secondary endpoints as dependent variables and used toothpaste, gender, age, and center as covariates. Likewise, they used an analysis of covariance or ANCOVA) for PCR and a t-test for ΔPCR, i.e., PCR V4 – PCR V1 results to compare test and control toothpaste.
Post-randomization, of 194 enrolled subjects, 97 applied the hydroxyapatite toothpaste (test), and the other 97 applied the fluoride toothpaste (control). The mean DMFS index varied slightly across test toothpaste vs. control toothpaste groups and from baseline (V1) to the end of the study (V4).
In the PP population, the upper limit of the one- and two-sided 95% CI for the difference in the percentage of subjects showing no increase of DMFS was 6.84% and 8.24%, respectively, i.e., below the non-inferiority margin of Δ≤ 20%.
Similarly, in the ITT population, the upper limit of the one- and two-sided 95% CI for the difference in the percentage of subjects without an increase of DMFS was 5.68% and 7.27%, respectively. Both results were in concordance and established the non-inferiority of the test toothpaste to the control toothpaste.
Per the PP and ITT analyses, no increase in DMFS index, the primary parameter in the present study, was observed in 89.29% and 90.43% of subjects of the hydroxyapatite group and 87.36% and 88.42% of the fluoride group subjects.
In logistic regression analysis, the PP population results confirmed that the risk of an increase in DMFS did not vary between control and test groups; however, the odds ratio of increased DMFS was 4.7-fold higher in men than women.
The overall percentage of caries lesions NCL% increased slightly between V1 and V4. These findings are consistent with two previously published clinical trials showing fluoride-free hydroxyapatite toothpaste is non-inferior to fluoride toothpaste in caries prevention.
DIAGNOcam detects lesions underneath the tooth surface. Like the DMFS indices, DIAGNOcam results reinstated that the hydroxyapatite toothpaste is non-inferior to the fluoride toothpaste.
Accordingly, in the PP analysis, the authors noted no increase in the percentage of caries lesions in 60.71% and 57.47% of the subjects of the hydroxyapatite and fluoride groups. Also, none of the individuals withdrew from the study to develop new caries.
The Safety Analysis set comprised all 194 randomized subjects, and none reported the occurrence of any AEs or serious AEs.
To conclude, studies have established hydroxyapatite as efficient in caries prevention, reducing dentin hypersensitivity, improving periodontal health, biofilm control, and teeth whitening. In addition, it does not stain the tooth surface, is safe even if accidentally swallowed, and does not interfere with the oral microbiome.
The current study is the third clinical caries study comparing hydroxyapatite with 1,450 ppm fluoride concerning the primary endpoint DMFS index. Its results showed the non-inferiority of the fluoride-free hydroxyapatite toothpaste to the fluoride toothpaste, paving the way for its use in oral care products.