Long-term stable osseointegrated dental implants are the main objective of implantodonty. Although proven to be reliable in the long term, failures at an early stage of osseointegration have been described [1-2]. The search to identify mechanisms that lead to early implant failure is constantly evolving [2-3]. Recently in orthopedics, has been verified that there is an association of low vitamin level with the risk of developing a periprosthetic infection, in joint prostheses, and since then some dental studies regarding vitamin D deficiency and its implications have begun to emerge. Kelly and collaborators (2009) based on a hypothesis that vitamin D insufficiency affects the osseointegration of titanium implants conducted an experimental study in rats induced to vitamin D deficiency. The authors concluded that vitamin D insufficiency significantly impaired establishment of osseointegration of Ti6Al4V implant in vivo in rats [4-5]. Vitamin D is a fat-soluble hormone that is actively transformed through the liver and kidney [6]. It is synthesized endogenously in the skin from exposure to sunlight, as well as from food or supplements. All of this gives vitamin D a unique character among the other vitamins [7-9]. Vitamin D is vital for brain health, the cardiovascular and respiratory system, skin and the immune and endocrine systems [10-13]. It is well known that vitamin D deficiency can impair health due to poor immune response to oral microbial infections, increasing the risk of periodontitis [14]. In addition, vitamin D plays an important role in bone metabolism. In bone, vitamin D stimulates the activity of osteoclasts and osteoblasts, keeping bone metabolism in balance [15]. About 10% to 20% of the vitamin D required for the proper functioning of the human body is obtained from exogenous sources through the intake of vitamin D-rich foods, with the remaining 80% to 90% produced endogenously [16]. It plays an essential role in maintaining normal levels of calcium and phosphorus in the blood and thus affects bone remodeling [17-18]. In addition, vitamin D also plays a role in reducing the effects of inflammation and helps to improve the body's natural immune reactions. There are few studies of a relationship between bone metabolism, vitamin D, and early implant failure in humans, although there are already some case reports that address this issue, there is a significant need for studies in the area.

The aim of this study was to evaluate through literature review the interference of vitamin D deficiency and dental osseointegration failure.

The most relevant studies originally published in the English language over the last ten years were analyzed using the PUBMED databases. The search strategy used the following keyword combinations: (“dental implants”) AND (“vitamin D”) AND ("implants failure") OR ("osseointegration"). Only articles directly related to the theme were included in the study, that is, articles that related dental implants with vitamin D. The inclusion and exclusion criteria are presented in (Table 1).

Table 1: Criteria for article eligibility.

When conducting the research in PUBMED, 14 articles were found, however 7 articles met the inclusion and exclusion criteria of this study. All the studies analyzed reported the success and / or failure of the dental implant associated with vitamin D supplementation. / or vitamin D deficiency. The selected studies are listed in Table 2 and described in the literature review chapter, item - 4.2 Vitamin D deficiency in Implantology.

Vitamin D metabolism

The main chemical forms of vitamin D are ergocalciferol (vitamin D?) and cholecalciferol (vitamin D?), and the generic designation of vitamin D includes both vitamin D? and vitamin D? [19]. These differ in their origin, chemical composition as well as biological activity. Cholecalciferol is 2 to 3 times more active than ergocalciferol due to differences in its chemical structure and consequently in its metabolism [20]. Ergocalciferol is obtained from the ultraviolet irradiation of ergosterol, a plant steroid present in the fungal and invertebrate membrane, and can be found in mushrooms and yeast exposed to sunlight. It can only be used by the body through ingestion of vegetable foods [20]. Cholecalciferol is endogenously produced in the body from the sun's action on the skin through ultraviolet irradiation of the cholesterol precursor, dihydrocholesterol, or provitamin D. It naturally finds in the skin. This vitamin is synthesized in the skin and can also be obtained from ingestion of deep and cold water fatty fish such as salmon, tuna as well as from ingestion of fish oil or egg yolk. Vitamin D obtained from diet or through the skin is biologically inert, so both forms of vitamin D undergo a successive chain of reactions until metabolically active molecules are obtained [8]. The first step in the process of endogenous synthesis of vitamin D group molecules begins at the deep epidermal layer, namely in the spinous and basal strata, where 7 - dihydrocholesterol is stored, which is located in the bilipid layer of cell membranes [16]. O7 - Dihydrocholesterol, caused by heat and ultraviolet radiation from 290 to 315 nm, is isomerized in the skin into cholecalciferol, a pre-vitamin D? [9]. It is therefore a photolytic and non-enzymatic reaction. Pre-vitamin D? undergoes another non-enzymatic reaction, producing thermal isomerization in the skin, reaching a peak of vitamin D within 30 to 60 days after sun exposure. Cholecalciferol as well as ergocalciferol, once absorbed by the intestinal mucosa, reach the bloodstream attached to a carrier protein (DBP, vitamin D binding protein) and are then transported to the liver [16]. In the liver, cholecalciferol undergoes a first hydroxylation, mediated by 25-hydroxylase, thus obtaining 25-hydroxyvitamin D. Ergosterol evolved to 25-hydroxyergocalciferol. This hydroxylation develops in the hepatic microsomal system and is considered inversely proportional to the amount of skin pigmentation and directly proportional to the amount of sun exposure [16,9]. The 25-Hydroxyvitamin D is a partially water-soluble form which has a short half-life and circulates bound to the binding proteins. The hepatic content of 25-hydroxyvitamin D regulates hydroxylation, so its presence in the liver reflects its reserve, and is therefore considered a form of vitamin D of utmost importance. Liver hydroxylation is poorly regulated, and the blood level of 25-hydroxyvitamin D is proportional to the amount of vitamin D ingested and produced by the skin [8]. In the kidneys, 25-hydroxyvitamin D requires new hydroxylation. If the action of 24,25-hydroxylase is transformed into an inactive form, if hydroxylation is mediated by 1α-hydroxylase (CYP27B1), then 1,25-dihydroxyvitamin D or calcitriol forms the biologically active form of the vitamin D [8-9]. The 1,25-dihydroxyvitamin D circulates at concentrations lower than 25-hydroxyvitamin D, however, has a higher affinity for the receptor and is biologically more potent [8]. The 1α-hydroxylase is an enzyme of renal origin that is activated directly by parathyroid hormone (PTH) by decreasing serum phosphate levels or indirectly due to a decrease in plasma calcium ions concentration [8]. Due to this, The conversion of 25-dihydroxyvitamin D into its active form is influenced by the levels of calcium, phosphorus and parathyroid hormone (PTH) [21]. Several studies indicate that serum PTH levels are inversely proportional to those of 25-dihydroxyvitamin D. it has been found that stabilizing PTH levels and maintaining normal calcium availability requires a minimum serum 25-dihydroxyvitamin D concentration of 28 ng / mL. If this is not the case, bone health may be adversely affected [22].

Table 2: Selected articles.

Vitamin D in its active form, as well as PTH, stimulate bone resorption by osteoclasts, thereby increasing serum calcium concentrations [8]. Increased plasma levels of 1,25-dihydroxyvitamin D caused by hypocalcemia decrease activity. of 1α-hydroxylase [23]. At the small intestine level, 1,25-dihydroxyvitamin D stimulates intestinal absorption of calcium. In the absence of vitamin D, only 10-15% of dietary calcium and about 60% of phosphorus is absorbed. Vitamin D sufficiency increases calcium absorption by 30-40% and phosphorus by 80% . The 1,25-dihydroxyvitamin D stimulates its own destruction by increasing the expression of 24-hydroxylase (CYP24R) which metabolizes 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to inactive water-soluble forms. The 1,25-dihydroxyvitamin D exists in most tissues of the human body and regulates gene expression by activating more than 200 target genes [24]. Most of the biological actions of 1,25-dihydroxyvitamin D are exerted due to the presence of receptors. of vitamin D [8]. The biological effects of 1,25-dihydroxyvitamin D are mediated by its receptor - VDR, a transcription factor that belongs to the nuclear hormone receptor family. For non-VDR cells, red blood cells, mature striated muscle cells and some cells of the central nervous system may be mentioned [23].

Vitamin D Deficiency in Implantology

Recently, investigations have been done to verify the effect of vitamin D deficiency on dental implants osseointegration. Most of these studies appear to indicate a positive effect of vitamin D on osteointegration [25]. However, to date, not yet fully clear the relationship between bone metabolism, vitamin D and early dental implant failure as well as the positive effect of vitamin D supplementation on peri-implant bone healing [26]. The work of Zhou investigated the influence of vitamin D on the osseointegration process of titanium implants in osteoporosis-induced rats with and without vitamin D supplementation. The animals were randomly divided into 2 groups: control (10 rats) and vitamin D medication (10 rats). Vitamin D was administered by oral probe at 0.1 g / kg / d. Eight weeks later, the tibias with screws were harvested for CT, histological and biomechanical analysis Compared with the control group, the vitamin D group had an increase in bone volume percentage by 96.0%, osseointegration by 94.4%, mean trabecular number by 112.5%, mean trabecular thickness by 51.8%, trabecular connective density by 38.0% and decreased trabecular separation by 39.3% on tomographic analysis. 1,25 (OH) 2D3 increased bone area density by 1.2 times and bone-implant contact by 1.5 times on histomorphometry, and increased maximum push-out force by 2.0 times on the biomechanical test. . The authors concluded that vitamin D optimized implant osseointegration in osteoporotic rats [27]. investigated the relationship between a vitamin D receptor (VDR) polymorphism (rs731236, TaqI) and dental implant loss. We analyzed 217 patients who were divided into two groups: (i) control group (C), 137 subjects with at least one osseointegrated implant for 6 months or more and no implant loss, and (ii) study group (S), 80 individuals with at least one implant loss. After DNA collection and purification, the analysis of the VDRTaqI polymorphism was performed by polymerase chain reaction - restriction fragment length polymorphisms (PCR-RFLP). Results showed positive evidence of association with implant loss and the following variables: edentulism, implant position, primary stability and implant length. There was no association between VDRTaqI polymorphism genotypes or alleles and implant loss between groups [28]. Evaluated the effect of a vitamin D deficiency on implant osseointegration in male Sprague-Dawley rats. Samples were maintained under cessation of vitamin D intake and UV exposure. Serum levels of 1.25 (OH) 2D3,25OHD3, Ca and P were determined. Miniature cylindrical Ti6Al4V implants (2 mm long, 1 mm diameter) were made with either an acid modified surface (DAE) or a modified surface with discrete crystalline deposition (DCD) of hydroxyapatite nanoparticles. DAE and DCD implants were installed in the femur of vitamin D deficient rats and control rats. After 14 days of healing, femur implant samples were submitted to push-in implant testing and noncalcified histology. The surfaces of the implant specimens recovered after the push-in test were further evaluated by scanning electron microscopy (SEM). The push-in implant test revealed that the AED and DCD implants in the vitamin D-insufficient group (15.94 ± 8.20 N, n = 7; 15.63 ± 3.96 N, n = 7, respectively). ) were significantly lower than those in the control group (24.99 ± 7.92 N, n = 7, p <0.05; 37.48 ± 17.58 N, n = 7, p <0.01, respectively ). The transcortical bone-implant contact (BIC) was also significantly decreased in the vitamin D-insufficient group. Scanning electron microscopy (SEM) analyzes further suggested that the remaining calcified tissues adjacent to the implant surface after the push-in test appeared exceptionally fragmented. The researchers concluded that the effect of vitamin D insufficiency that significantly impaired the establishment of osseointegration of the Ti6Al4V implant in vivo [29]. Fretwurst et al (2016) illustrated in their work two case reports of vitamin D deficiency and early implant failure. Prior to implant placement, the first patient received autologous bone graft. Both patients received dental implants from different manufacturers in the mandible molar region. In the case of bone graft in the first patient, all implants were placed in a two-stage procedure. All implants had to be removed within 15 days of installation. Serum vitamin D levels were measured: both patients had vitamin D deficiency (serum vitamin D level <20 μg / l). Following vitamin D supplementation, implant rehabilitation was successful in both patients. Prospective and randomized clinical trials should be followed to assert the relationship between vitamin D deficiency, osteoimmunology and early implant failure [26]. Was performed a retrospective study, in 2016 with a selection of 822 patients, who investigated the relationship between blood vitamin D levels and the occurrence of early dental implant placement failures. Average serum vitamin D levels in the general population were 29.9 ng / mL. In patients with early dental implant failure the levels serum vitamin D levels were 25.5 ng / mL [25]. Statistical analyzes report a very low incidence of early failure in patients with blood levels of vitamin D above 30 ng / mL (2.2%). The incidence of early failure was almost double in patients with insignificant blood levels of vitamin D, from 10 to 30 ng / mL, and becomes even greater in patients with severe vitamin D deficiency (9.0%) [25]. In 2018, Mangano et al. with the purpose of evaluating the relationship between low vitamin D levels and early dental implant loss (PPID) performed a retrospective study using data from patients who underwent dental implants from a private clinic during the period from January 2003 to December 2017. For data analysis, a chi-square test was used to investigate the effect of patient-related variables (age, gender, smoking, history of periodontal disease, and serum vitamin D levels) on PPID. Originally, 885 patients treated with 1,740 dental implants were included in this study. There were 35 lost implants (3.9%). No correlation was found between PPID and patient gender (P = 0.998), age (P = 0.832), smoking (P = 0.473) or history of periodontal disease (P = 0.386) [30-31]. Three implant losses (11.1%) were reported in 27 patients with serum vitamin D levels <10 ng / mL, 20 ordered implants (4.4%) in 448 patients with levels between 10 and 30 ng / mL, and 12 lost implants (2.9%) in 410 patients with levels> 30 ng / mL. Although there was a clear tendency for an increased incidence of EDIF with reduced vitamin D levels, there was no statistically significant difference (P = 0.105) between these three groups. The authors concluded that despite the limitations of the study (retrospective design, low number of patients with enrolled severe vitamin D blood levels), this study failed to demonstrate a significant relationship between low serum vitamin D levels and increased risk of PPID. However, since a dramatic increase in PPID with reduced blood vitamin D levels has been reported, more properly designed clinical trials (prospective or randomized controlled trials in a larger sample of severely disabled patients) are needed to further investigate this topic [31].

Deficiency of Vitamin D

Factors of Risk/Causes: It is estimated that there are about one billion people in the world with vitamin D deficiency [32]. There are some risk groups for vitamin D development: pregnant women, children, the obese, the elderly, patients with type I skin, transplant patients and other are subject to immunosuppressive therapies and should therefore be monitored [31]. There are uncounted of factors that influence the skin production of vitamin D. A correctly applied sunscreen with protection factor 30 reduces the ability of the skin to produce vitamin D by 95% to 99%. Black individuals are 90% less efficient at producing. vitamin D compared to light-colored individuals. Air pollution with increased levels of ozone and nitrogen dioxide absorb ultraviolet radiation (UVB), and this is often a neglected risk factor for vitamin D deficient levels. Latitude and seasons also affect the prevalence of vitamin D insufficiency once this increases during winter months and decreases during summer [33]. Aging is also a risk factor for deficient vitamin D levels due to reduced skin ability to synthesize pro-vitamin D, less sun exposure, sometimes inadequate nutrition, lower gastrointestinal absorption and possible use of drugs that interfere with vitamin D absorption and metabolism [34].

Treatment of Vitamin D Deficiency

According to the Society of Endocrinology, vitamin D deficiency it is verified with 25-hydroxyvitamin D levels equal to or less than 20 ng / mL, insufficient vitamin D levels between 21 and 29 ng / mL, and sufficient vitamin D levels equal to or greater. at 30 ng / ml. Maintaining 25-hydroxyvitamin D levels between 40 and 60 ng / mL is optimal and up to 100 ng / mL is safe. Vitamin D poisoning is usually not found up to 150 ng / mL. The best method for determining vitamin D status is by measuring blood levels of 25-hydroxyvitamin D. Although the biologically active form of vitamin D is 1.25 dihydroxyvitamin D, it does not tell you about the actual state of the levels vitamin D, since normally in children and adults with vitamin D deficiency it is at normal or even high levels. Treatment of deficient Vitamin D levels can be achieved by exposure to sunlight or artificial UVB light, or by supplementation. Obese adults and children need two to five times more vitamin D to treat and prevent deficient levels of vitamin D. It is now known that to prevent vitamin D deficiency in the population, a daily amount should be taken between 1000 to 2000 IU of vitamin D. One or two exposures per week should provide optimal levels of 25-hydroxyvitamin D, this will be dependent on blood levels of 25-hydroxyvitamin D. Sun exposure of arms and legs for periods of 5 to 30 minutes between 10 am and 3 pm twice a week may be appropriate for prevent a vitamin D deficiency [35-36]. The treatment of choice for vitamin D deficiency is colecalciferol (Vitamin D?). Oral vitamin D supplementation is challenging when compared to treatment through exposure to UVB radiation. Because there is a risk of toxicity with oral supplementation, which is not the case with sun exposure.

Vitamin D demonstrates several effects on bone metabolism, it increases gene expression of non-collagenic proteins, increases extracellular matrix protein formation by osteoblasts and stimulates osteoclast activity [37-38]. But beyond modulationbone formation, vitamin D has an impact on the innate and adaptive immune response in the field of osteoimmunology and may therefore influence implant osseointegration [39-41]. During milling for implant installation, trauma occurs leading to immediate periimplant bone necrosis. This necrosis serves as a stimulus for osteoclastic activity, which is able to reabsorb the necrotic bone and thereby stimulate osteoblast action to thereby osseointegrate. An additional vitamin D deficiency may disrupt the sensitive balance between the immune system and bone metabolism during implant osseointegration due to direct or indirect alteration of osteoclast function. The removal of bone debris through osteoclasts could be hampered as vitamin D controls the migration of osteoclast precursor monocytes [42]. In addition, altered release of cytokines by immune cells caused by a low vitamin D level could dysregulation of osteoclast activation and differentiation [43]. Maier et al. demonstrated in an epidemiological study that vitamin D deficiency is associated with a higher risk of developing septic loosening around orthopedic implants caused by wear particles [44]. Vitamin D may also be essential for the antibacterial response, since the monocyte-macrophage reaction is influenced by vitamin D [45]. Xu et al. demonstrated that vitamin D can inhibit the expression of proinflammatory cytokines induced by Porphyromonas gingivalis and improve the expression of antiinflammatory cytokines in macrophages [46]. Masuyama et al. reported in their in vivo study using mice that 1.25- (OH) 2D3 exerted a regulatory effect on osteoblast and osteoclast chemotaxis during increased infiltration of vascular tissue [47]. Furthermore, these authors have shown that 1,25- (OH)2D3 could regulate collagen modification and maturation, which has been shown to be important in early bone formation since vitamin D's fundamental role in physiology is calcium homeostasis (Ca2+) at the skeletal system level [48]. This suggests one of the possible reasons for early implant failure in cases of vitamin D deficiency. To date, prospective studies in the literature investigating the correlation between serum vitamin D levels and osseointegration are scarce, and most of these studies are experimental in animals. The required normal serum levels of 25-dihydroxyvitamin should be at a minimum concentration of 28 ng / mL. If this is not the case, bone health could be negatively affected. However, in a recent consensus work, they defined that 25-hydroxyvitamin D concentrations below 20 ng / ml are considered insufficient in vitamin D [49]. There have been reports of implant failure in populations. with serum levels below this value [26] and also above 20ng / mL [25]. In a current prospective study, no statistically significant relationship was found between low serum vitamin D levels and increased risk of early implant loss. However, implant losses have been observed in patients with reduced vitamin D levels, although it is a case report of Fretwurtet al., vitamin D deficient patients who underwent dental implants and lost, after serum level normalization with oral vitamin D supplementation, the implant was successful in both cases presented by them. Administration and correction of vitamin D concentrations weeks before dental implant placement may be advantageous in patients with vitamin D deficient levels. Na Diabetes Mellitus, which is a systemic health disorder that may interfere with successful osseointegration of the teeth. In dental implants, studies have already shown that vitamin D supplementation can minimize the damage to osseointegration of these patients. In these, it is indicated that lifelong vitamin D supplementation should be maintained for good bone remodeling. However, further investigation is needed to confirm this hypothesis since vitamin D also plays an important role in bone resorption, especially at high therapeutic doses [30]. Thus, the selection of optimal concentration should be determined based on additional evidence. Few studies report this condition, requiring more epidemiological data to prove the prevalence of vitamin D deficiency in Brazilians. According to the Brazilian Society of Endocrinology and Metabology (SBEM, 2014) hypovitaminosis D is quite common in our country even in a tropical region. where the incidence of sunlight is high.

Vitamin D deficient levels may be a risk factor for failures in osseointegration of dental implants, but it is not yet a contraindication to treatment as evidence remains lacking. Further appropriately designed clinical trials such as prospective randomized controlled trials in a larger sample of vitamin D deficient patients are needed to better study these cases. Among health professionals there should be a recognition of the clinical importance of vitamin D in order to raise awareness of the nutritional benefits of this vitamin.

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