**3. Results**

From the micronutrients listed in the "EU Register of nutrition and health claims made on foods", the TEP selected the following 18 nutraceuticals that may have influence on bone and teeth: calcium, fluorides, magnesium, potassium, resveratrol, vitamin C (ascorbic acid), vitamin D, vitamin E (alpha-tocopherol), vitamin K2 (menaquinone-7, MK7), zinc, vitamin A, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacinamide), vitamin B5 (pantothenic acid), vitamin B6, vitamin B7 (biotin), and vitamin B12 (Table 1). However, according to the "EU Register of nutrition and health claims made on foods", fluoride is non-authorized for supporting bone mineralization, and potassium is non-authorized for maintaining tooth mineralization, whereas vitamin B2, vitamin E, vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B7, and vitamin B12 are non-authorized for both functions. Moreover, potassium and zinc are not considered to influence tooth metabolism, while vitamin K2, resveratrol, and vitamin B5 are not recommended for bone and tooth metabolism according to the "EU Register of nutrition and health claims made on foods". Among these substances, we found studies concerning nutraceuticals and dental implants or osseointegration only for vitamin D, magnesium, resveratrol, vitamin C, a mixture of calcium, magnesium, zinc, and vitamin D, and synthetic bone mineral (a supplement containing calcium, phosphate, magnesium, zinc, fluoride, and carbonate).


**Table 1.** Effects of selected micronutrients on bone and tooth health.


**Table 1.** *Cont*.

In particular, we included 11 studies concerning vitamin D, of which five were clinical studies (three retrospective studies, one case series, and one case report), and six were preclinical studies on animals: two preclinical studies on animals concerning magnesium, two preclinical studies on animals for resveratrol, one preclinical study on animals concerning the supplementation with a combination of calcium, magnesium, zinc and vitamin D, two preclinical studies on animals concerning synthetic bone mineral (composed by dicalcium phosphate dihydrate and magnesium and zinc chlorides), and one clinical study concerning vitamin C supplementation (Figure 1, Table 2).

**Figure 1.** Flow diagram of sources selection process.




**Table 2.** *Cont*.


**Table 2.** *Cont*.


## **Table2.** *Cont*.

## *3.1. Vitamin D*

## 3.1.1. Animal Studies

In our scoping review, we included six preclinical studies on animal models, more precisely, on rats.

Liu et al., in 2014 [34], found that vitamin D supplementation in rats affected by chronic kidney disease (CKD) improved bone-to-implant contact (BIC) compared to CKD rats that did not receive vitamin D, making this finding comparable to that of rats without CKD. Also, the bone volume in the

circumferential zone within 100 mm of the implant surface increased after vitamin D administration. At two weeks, the push-in test showed significantly better results for the vitamin D-treated group compared to untreated CKD mice.

Zhou et al., in 2012 [35], demonstrated that vitamin D supplementation in osteoporotic rats, eight weeks after implantation, improved bone volume, osseointegration, mean trabecular number, mean trabecular thickness, and trabecular connective density, while it decreased trabecular separation, as well as increased bone area density, BIC, and the maximal push-out force.

Wu et al., in 2012 [36], inserted titanium implants in diabetic rats and evaluated the e ffects of di fferent kinds of diabetes therapies. The combined therapy with insulin and vitamin D showed the best e ffects on osseointegration, bone volume, mean trabecular thickness, mean trabecular number, connective density, mean trabecular separation, push out force, shear strength, BIC, and bone area ratio. Treatments with vitamin D or insulin only showed better results compared to untreated diabetic rats, but worse than the combined therapy. All the parameters listed above, in the combined treatment group, resulted similar to those of the control healthy group.

Akhavan et al., in 2012 [37], evaluated the e ffects of vitamin D supplementation on BIC in diabetic rats compared to a placebo group. At three weeks, the vitamin D group showed higher values of BIC compared to the placebo group, and also at six weeks, even if in a non-statistically significant way, leading the authors to conclude that vitamin D seems to not have an e ffect on the osseointegration of implants in diabetic rats.

Dvorak et al., in 2012 [38], showed that, in osteoporotic rats, a vitamin D depletion led to a significant decrease in BIC in the cortical area. In rats that received a vitamin D-free diet, followed by vitamin D repletion, no significant di fference could be found compared to the control group that received a standard vitamin D diet.

Kelly et al., in 2008 [39], found that vitamin D deficiency, 14 days after implantation, led to a lower push-in test and a decreased BIC compared to a normal vitamin D status.

## 3.1.2. Clinical Studies

The clinical studies on vitamin D that we included in this scoping review were three retrospective studies, one case series, and one case report.

From the retrospective studies of Mangano et al. of 2016 [31] and 2018 [29], it emerged that, in patients with vitamin D deficiency, there were a higher percentage of early dental implant failures (failures that occurred before prosthesis positioning, EDIF). However, although there was a clear trend toward an increased incidence of EDIF with lower serum 25(OH)D, no statistically significant di fference was found among the three groups with di fferent vitamin D status.

In the retrospective study of Wagner et al. of 2017 [30], osteoporosis was shown to have a significant negative influence on marginal bone loss around implants, but vitamin D significantly affected the marginal bone loss at the mesial and distal implant aspect, showing beneficial e ffects on the peri-implant bone formation.

Fretwurst et al., in 2016 [32], reported two cases of implant failures occurring within 15 days of surgery in patients with vitamin D deficiency; in one patient, there were even two consecutive implant failures. In both patients, after vitamin D supplementation, implants were placed successfully. The authors also noticed that failures were sometimes associated with pain and discomfort in vitamin D-deficient patients.

Also, Bryce and Macbeth, in 2014 [33], reported a case of missed osseointegration in a patient affected by severe vitamin D deficiency.
