The balance between the teeth demineralization and remineralization is mainly influenced by the amount of calcium (Ca2+) and phosphate (PO43−) ions that are available at their surface [1]. When this balance is disturbed, due to biofilm accumulation (e.g. during orthodontic treatment), initial caries lesions or so-called white spot lesions (WSL) can be developed which are usually more opaque than the surrounding sound tissue [2], [3], [4]. Due to the absence of living cells within its structure, the enamel cannot be regenerated [5,6] turning the WSL treatment a challenge [7]. Especially considering that 36 % of the WSL are stable after 7 years of appearance [2].

When the WSL demineralization process further develops, there is a high risk of enamel cavitation [8]. Hence, the WSL resolution is extremely relevant for clinicians and their patients. Among the non-invasive strategies for the treatment of WSL remineralization, considered a net mineral gain within the lesion, has been extensively explored [5,9]. The saliva mineralization can be potentiated by providing extrinsic sources of Ca2+ and PO43−, as these ions could facilitate in-depth subsurface remineralization by a higher diffusion gradient. A remineralized WSL has both a better appearance, as well as the resistance to endure further acid challenges [1,10].

Within the WSL remineralizing strategies, the use of fluoride products is a widely recommended treatment [8]. But one that is still considered limited as its effectiveness counts with moderate or low levels of certainty [2,5,8,11]. While, the addition of artificial nano-hydroxyapatite (nano-HA), composed mainly by calcium and phosphate, into dental products (e.g. toothpastes, creams, rinses) has been employed as an analogous biological material [12], [13], [14]. This bioactive and biocompatible material could reestablish the enamel's ionic constitution, within the destroyed hydroxyapatite crystals, through the Ca2+ and PO43− deposition and/or its direct incorporation in the inward areas of the enamel in the longer-term remineralization process [5,10,15,16]. However, when applied in a self-administered mode the nano-HA may encounter the same compliance dependence as products like fluoride [2].

The complete remineralization and masking of the WSL has been considered limited with the use of fluoride products and the use of new combined strategies that complement the fluoride remineralizing effectiveness has been recommended [2,10,17]. Among these, nano-HA + fluoride has been considered a good treatment alternative. Its activity superiority is based on the fact that the fluoride remineralization mechanism, of catalyzing the incorporation of Ca2+ and PO43− within the enamel crystal lattice, is usually restrained to the availability of these ions within the saliva. So, it would be expected that the association of fluoride with other calcium/phosphate-based products turn out to be a more effective treatment alternative for preventing enamel demineralization and increasing its remineralization [3,18,19]. This indicates that fluoride can be useful to potentiate other treatment strategies [6].

Considering the previous information, a recent systematic review and meta-analysis assessed in vivo and in situ evidence regarding the prevention and remineralization potential of nano-HA-containing products on WSL [20] finding that the monotherapy with this product was inferior to prevent WSL and comparable to remineralize them when compared to NaF. However, with a limited level of evidence due to the quality of the studies. The current evidence points to the superiority of the association of nano-HA and fluoride for remineralizing purposes and that there exists a gap of knowledge regarding this possible association advantage. Thus, this systematic review aimed to appraise the clinical evidence (in vivo and in situ) that assessed the effect of dental products containing nano-HA and fluoride on the remineralization of initial caries lesions (WSL) in permanent human teeth (in vivo) or animal-derived teeth (in situ).