**4. Discussion**

To the best of our knowledge, this is the first scoping review to investigate the putative role of dietary supplements in affecting bone structural and mechanical properties involved in dental implant osseointegration, as well as in improving clinical outcomes, such as the maintenance of peri-implant tissue health and implant success rate.

The Federal Food, Drug, and Cosmetic Act defines a dietary supplement as a product that is intended to supplement the diet, which bears or contains one or more ingredients including a vitamin, mineral, herb, and amino acid, or a concentrate, metabolite, constituent, extract, or combinations of these [50]. The term "nutraceutical" was coined by Stephen De Felice to define "food (or parts of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease", by the fusion of the words "nutrition" and "pharmaceutical", commonly used in marketing with no regulatory legal definition [51]. Ten years later, nutraceuticals are defined as dietary supplements that include a concentrated form of a presumed bioactive substance, originally derived from a food, but present in a non-food matrix, and used to maintain or improve health status in dosages exceeding those obtainable from conventional foods [52].

It should be stressed, however, that there is no consensus with regard to "nutraceutical" definition or similar terms. Aronson recently considered that the term "nutraceuticals" is too vague and should be abandoned, even if he did not propose any robust alternatives [53].

According to the recent data of the United States (US) Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey (NHANES), more than 25% of the US population had an insufficient intake of vitamins A, C, D, and E, as well as calcium, magnesium, and potassium in their diet; thus, the modern diet of Western countries does not seem to have an adequate intake of micronutrients. It was reported that micronutrient deficiencies affect around two billion people worldwide [54]. However, a consensus about the use of these substances, particularly concerning the adequate amount and safety, is not ye<sup>t</sup> reached, even if they are supposed to have multiple physiological beneficial effects.

Several micronutrients are hypothesized to have an influence on skeletal system, particularly on jaw bone and alveolar bone [9] and on dental implant osseointegration. However, according to our findings, very few elements (i.e., vitamin D, magnesium, resveratrol, and vitamin C) were the matter of previous investigations on their role in dental implant osseointegration. Available data sugges<sup>t</sup> that severe vitamin D deficiency or even the presence of established osteoporosis led to a higher implant failure rate [29,31] or to a worse BIC [34,35]. In osteoporotic rats, vitamin D depletion led to a significant decrease in BIC in the cortical area. Moreover, rats that received vitamin D showed a similar BIC to the control group [34]. Animal studies on vitamin D and osseointegration confirmed that the early stages of bone healing could be significantly influenced by vitamin D status [35–40]. In humans, Mangano et al. [29,31] reported a clear trend toward an increased incidence of early implant failures within the group with lower serum 25(OH)D levels. In particular, the authors reported 11.1% EDIF in patients with serum 25(OH)D < 10 ng/mL (severe vitamin D deficiency), 4.4% for those with 25(OH)D between 10 and 30 ng/mL, and 2.9% in patients with normal vitamin D status.

Moreover, Wagner et al. [30] showed that osteoporosis has a significant negative influence on marginal bone loss around implants and that vitamin D supplementation counteracts the marginal bone loss, with overall results of beneficial e ffects on the peri-implant bone formation.

Vitamin D deficiency commonly occurs in the general population. This hormone has a crucial function in skeletal mineralization, but also plays an important role in immunity and inflammatory response, increasing anti-inflammatory cytokines and decreasing pro-inflammatory ones [55].

Bashutski et al. [56] showed that, in vitamin D-deficient individuals, minimal benefits could be obtained from periodontal surgery along with an impaired post-surgical healing. Vitamin D could have other e ffects on osseointegration that are more related to soft tissue healing and marginal seals around implants, together with an e ffect on resistance against bacterial infections of the peri-implant sulcus. Also, topical applications of vitamin D were used for implant coating, showing some beneficial e ffects in animals, such as a reduction in crestal bone loss and an increase of BIC [57]. However, several critical issues persist regarding the use of vitamin D in enhancing osseointegration, particularly concerning its mechanism(s) of action, the influence of di fferent serum 25(OH)D levels, and the recommended dosages required to significantly improve dental implant success rate.

Also, vitamin C deficiency may have a role in tissue healing and stability around dental implants. This micronutrient plays an important role in the biosynthesis of collagen, which is an important component of connective tissue of the gingiva, peri-implant mucosa, and alveolar bone [58]. These e ffects were confirmed by Li et al. [47], who found that vitamin C supplementation improved postoperative wound healing following dental implant surgery. Moreover, protective e ffects of this intervention on bone health could be expected, as vitamin C could hinder the e ffects of oxidative stress in promoting bone resorption and consequently reducing bone strength [59], although this hypothesis is not ye<sup>t</sup> confirmed. However, the role of vitamin C supplementation in the general population, as well as in patients receiving dental implants, might be significantly a ffected by lifestyle, including smoking habits and diet, two factors that a ffect wound healing times. Furthermore, plasma ascorbic acid concentrations are not reported in clinical practice [60].

With regard to resveratrol, Casarin et al. [43] investigated its role on bone healing of calvarial defects in rats through messenger RNA (mRNA) quantification of bone morphogenetic protein (BMP)-2, BMP-7, osteopontin (OPN), bone sialoprotein (BSP), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL). Gene expression analysis showed a higher expression of *BMP-2* (*p* = 0.011), *BMP-7* (*p* = 0.049), and *OPN* (*p* = 0.002) genes in the resveratrol-fed group than in the control group.

Ribeiro et al. [42] reported encouraging data about biomechanical retention and peri-implant bone formation in resveratrol-fed rats exposed to cigarette smoking inhalation, supporting a positive role of this substance in controlling di fferent osteogenic mechanisms. Their gene expression analysis demonstrated that lower RANKL/OPG levels were detected in rats receiving resveratrol, as well as in non-smoking animals, when compared to animals exposed to smoking and receiving placebo. Both studies on resveratrol confirmed the substantial improvement in implant stability, by modulating the expression of genes involved in bone regulatory processes. However, the main limitation of findings supporting resveratrol, as well as magnesium, is the availability of animal studies only.

However, considering the results of our research, several micronutrients are non-authorized or even not considered by the "EU Register on nutrition and health claims" on the basis of current scientific evidence.

Major nutrients involved in skeletal health include calcium, phosphorus, vitamin D, magnesium, and potassium, but other micronutrients and trace elements such as boron, selenium, iron, zinc, and copper also impact bone metabolism. Information on the influence of such "minor" elements coming from studies on nutrient depletion and studies on osseointegration is still lacking.
