The Relationship Between Low Serum Vitamin D Level and Early Dental Implant Failure: A Systematic Review

The variety in shape and type of dental implants in the present time is considered one of the most successful evolutions in dentistry. This facilitates dental treatment options to restore patient function and appearance. However, numerous significant factors influence the predictability of survival or the success rates of dental implants, some of which, such as vitamin D levels, have not been included in many studies. The main purpose of this systematic review was to investigate whether there is a relationship between low serum levels of vitamin D and early dental implant failures (EDIFs). Our literature search involved international databases including PubMed, Directory of Open Access Journals (DOAJ), and Web of Science. Initially, according to our search criteria, 1200 studies were found. After excluding duplicates, incomplete studies, and studies not meeting our inclusion criteria, only six human studies were included in this research and analyzed. Finally, upon meticulous analysis of included studies, this systematic review revealed inconsistent results in articles with respect to the association between vitamin D deficiency and implant failures. Large-scale studies, especially clinically relevant studies, on this subject is recommended.

A dental implant failure can be classified as "early dental implant failure" (EDIF) or "late dental implant failure" (LDIF) based on chronological criteria. EDIF is caused by a lack of osseointegration and indicates inadequate bone healing; on the other hand, LDIF is caused by the breakdown of osseointegration over time [10,11]. EDIF, which happens in a specific group of patients (systemic health condition), is one of the most researched problems in modern implantology and is difficult to manage [11, 12,13].
Recognizing systemic risk factors may reduce implant failure and enhance predictability [12,13,14,15]. Some factors, such as a lack of vitamin D, may have a role in the emergence of EDIFs. In its inactive form (vitamin D3 or cholecalciferol), vitamin D is a steroid hormone that may be gained from diet or generated in the skin from cholesterol with adequate sun (ultraviolet light) exposure [16]. Vitamin D deficiency has long been known to impair the appropriate immune response to oral microbial infections and increase the risk of periodontitis [17]. Furthermore, vitamin D is required for bone metabolism and might impair healing and new bone formation on the implant surface [18]. Vitamin D stimulates osteoclast activity and the production of extracellular matrix proteins by osteoblasts. Currently, a serum 25(OH) level of 10 ng/mL is considered inadequate, while a level of 10-30 ng/mL is considered insufficient. The optimum serum level is more than 30 ng/mL [18,19,20,21].
Vitamin D deficiency is a global public health concern that can be caused by a combination of low food intake and insufficient sunlight exposure, obesity, and advanced age [22,23]. According to a recent Saudi Arabian study, women are four times more likely than males to have vitamin D insufficiency [24]. In addition, citizens in the eastern region are three times more at risk of developing vitamin D deficiency than those in other regions [25]. Recent review studies advocated for more research on vitamin D insufficiency in the context of dental implant failures [21,22,23]. More emphasis is being placed on encouraging the consumption of micronutrients, which may have health benefits and enhance resistance to diseases [26]. Furthermore, a certain diet and micronutrient may play a significant role in the different stages of dental implant healing and influence bone metabolism. A recent article, for example, has shown that there are direct impacts on the jaw and alveolar bone [27].
However, only a few well-designed investigations have looked into the relationship between vitamin D levels and EDIF. The majority were conducted on animal models, with only a few on humans [28,29,30,31]. The goals of this review were to evaluate the role played by vitamin D in implant survival rate, research the effects of low vitamin D levels on osseointegration, and determine the amount of vitamin D that can affect the implant survival rate.

Study Protocol and Research Question
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were used to perform a systematic review of research on the relationship between low serum vitamin D levels and EDIF [32]. The present systematic review investigated the following research question: Compared to a normal level of vitamin D, will a low level increase the risk of EDIF? The Population, Intervention, Control, Outcome (PICO) elements were identified as shown in Table 1.
Population Completely or partially edentulous human adults restored with implant-supported prostheses.

Exposure
Patients with low serum vitamin D level.

Control
Patients with normal serum vitamin D level.

Outcome
Dental implant failure (primary outcome), peri-implant marginal bone loss (secondary outcome), and biological (i.e., periimplant mucositis or peri-implantitis) or mechanical complications reported at the implant or patient-level (secondary outcome).

Selection Criteria
Inclusion criteria: The articles had to be in-vivo studies of male-female human adult patients ranging in age from 18 to 65 years old, written in English with full-text access, contain vitamin D-deficient individuals who received at least a single dental implant, and presence of hypothyroidism confirmed by laboratory testing (thyroid panel-TSH, free T4, free T3, or total T3) or medication. Papers were restricted to randomized controlled trials, case series, case reports, or prospective/retrospective studies. Finally, no time constraints were imposed in order to include as many studies as feasible in this systematic review ( Table 2).

Inclusion Criteria Exclusion Criteria
Human adult patients (male-female) ranging in age from 18 to 65 years. In-vitro and animal studies.
Studies written in English with full-text available. Studies written in languages other than English.
Studies including vitamin D deficient patients who received at least one dental implant.
Wrong comparator = no comparison between vitamin D and EDIF.
Randomized controlled trials, case series, case reports, and prospective and retrospective studies.
Irrelevant outcome = outcome was unrelated to low vitamin D/implant failure.
Presence of hypothyroidism confirmed by laboratory testing (thyroid panel -TSH, free T4, free T3, or total T3) or medication.
Journals of publication not cited in the open-access checklist for predatory publishers.
No restrictions were placed on year of publication.  Table 2).
Data were gathered using the terms "vitamin D," "vitamin D deficiency," "dental implants," and "implant failure" in international databases such as PubMed, Directory of Open Access Journals (DOAJ), and Web of Science. The study types identified were two case reports, two retrospective studies, one systematic search of peer-reviewed articles, and one scoping review. Data were collected according to different variables, such as year, location, the study's goal/methodology, and results. They were divided in order by the authors' name, year of publication, country, type of study, and the patients' sample size, age, and sex. A metaanalysis was not conducted in this study because of the inconsistency in the results.

Results
In the initial search, 1200 studies were found. After unrelated, duplicated, and incomplete information was eliminated, 31 studies were retained for the review. Of these, 25 were excluded because of not meeting the inclusion criteria. Finally, only six studies remained for review. The steps and criteria in selecting studies are given in Figure 1. The essential data of the six articles, including the author's name, year of publication, location, design/type of study, sample size, and study results are displayed in Table 3. The studies selected were conducted in three different countries: Germany, Italy, and France. The largest number of studies, three, was conducted in Italy. This review includes six human studies (in vivo). Of these, two studies found insignificant relation between deficiency of vitamin D and dental implants failure, while the others reported a significant association between the two factors. The studies were evaluated, and any bias they included is reported.

Discussion
Few articles in the literature have investigated the association between osseointegration and low levels of serum vitamin D; the majority of them are animal experimental studies, while some are clinical research studies done on people. The purpose of this systematic review was to see if there was a relationship between vitamin D deficiency and EDIF. This review looked at six reports.
Despite the high success rate of dental implants, failure of dental implants has also been observed in certain circumstances. In Iran, Mohajerani et al. observed that 73 cases (6.68 %) of the 1,093 implants assessed failed in the early phases [32]. According to a study by Jafarian et al. in Iran, 61 (4%) of 1533 dental implants in 250 patients failed; the maxilla was found to have the greatest fracture rate (9 of 132 implants (6.8 %)) [37].
There are many reasons for dental implant failure, including failure of the bone to heal around the implant and consequent failure of osseointegration, infection, smoking, and a narrow, keratinized gingiva [38], as well as vitamin D insufficiency. Recognizing risk factors might minimize failure rates and improve the predictability of dental implant treatment. Four of the six articles reviewed revealed a relationship between vitamin D insufficiency and dental implant failures, while the other two found no relation.
Bryce and colleagues investigated the link between vitamin D insufficiency and rapid dental implant insertion. According to their case report, the patient was significantly vitamin D deficient, which may have jeopardized the implant's effectiveness [33]. Another research [31] looked at the relationship between low blood vitamin D levels and EDIF in 822 participants. The authors discovered nine EDIFs in participants with blood vitamin D levels greater than 30 ng/mL, 16 EDIFs in respondents with levels between 10 and 30 ng/mL, and two EDIFs in subjects with levels less than 10 ng/mL [31]. As a result, while no statistically significant link was discovered between serum vitamin D levels and EDIF, we did find an increase in early failures related to serum vitamin D levels. The study's approach had various benefits, including the restriction of the research to "early implant failures" [31].
A retrospective study with 885 patients expanded on the prior study [34] and appeared to validate the data that had previously emerged. In individuals with sufficiently high serum vitamin D levels (>30 ng/mL), the failure rate was modest. Early failures almost doubled in individuals with inadequate blood vitamin D levels (10-30 ng/mL) and were approximately four times higher in those with severe vitamin D insufficiency (10 ng/mL). As a result, the study found a link between an increase in EDIFs and vitamin D deficiency in the blood [34]. Given the rising frequency of vitamin D insufficiency worldwide [39,40,41], we need more studies researching the links between vitamin D and EDIF.
There are other reports, besides the ones included by us in our review, that look into the relationship between vitamin D and factors that may cause EDIF. Several micronutrients (vitamin D, magnesium, resveratrol, and vitamin C) were thought to influence the skeletal system, especially jaw bone and alveolar bone, as well as dental implant osseointegration [42]. In addition, Wagner et al. demonstrated that osteoporosis has a significant detrimental influence on marginal bone loss surrounding implants and that vitamin D treatment counteracts such loss, with overall positive effects on peri-implant bone growth [43]. During osteointegration, calcitriol impacts the activation and differentiation of osteoblasts and osteoclasts. Vitamin D also increases bone mineralization [44]. Furthermore, vitamin D is essential for immunity and the inflammatory response, allergies, as well as increasing anti-inflammatory and decreasing pro-inflammatory cytokines [45]. Bashutski et al. revealed that a low level of vitamin D in the serum reduced the advantages of periodontal surgery and hampered post-surgical recovery. Vitamin D has also been found to be an important part in the maturation and appropriate function of bone cells since it creates a factor that drives osteoclast precursor fusion and osteoblast differentiation [46].
The limitation of this review is the small number of clinical trials with large sample sizes. Our search revealed that there is a low number of clinical studies in this sector, and It is recommended that more largescale studies with big sample numbers be carried out in the future to discover the specific relationship between vitamin D and EDIF.

Conclusions
There are several causes of dental implants failure. Improper bone healing around the implant, smoking, infection, low keratinized gingiva are the most common reasons for early implants loss. According to the findings of this study, it is difficult to find a direct relation or causality between the low serum vitamin D level and EDIF. However, the serum level of vitamin D may play an important role in osseointegration and dental implant success or predictability of dental implant survival rate through its effects in modulating the immune system and healing process. More large-scale clinical and prospective studies need to be conducted on this hypothesis.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.