The Possible Role of Vitamin D Deficiency in Early Implant Failure

Department of Oral & Maxillofacial Surgery, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran Department of Oral and Maxillofacial Surgery, School of Dentistry, Zahedan University of Medical Sciences, Zahedan, Iran Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Golestan University of Medical Sciences, Gorgan, Iran Department of Operative Dentistry, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran


Introduction
Tooth decay is one of the main problems in aged people worldwide [1]. It can affect their chewing and tooth function and, as a result, the quality of their lives [2,3]. Depending on the patient's clinical condition and needs, dentists use conventional tooth-supported, implant-supported, or combined tooth implant-supported prosthetic [4]. The implantsupported dental prosthesis is now widely used to replace one or more missing teeth [4]. Currently, dental implants are among the most successful treatments for restoring tooth function and beauty [5,6].
Osseointegration helps create a direct interface between the implant and the bone, an essential element for successful dental implant procedures. During the initial recovery period, it is crucial to (1) insert the implant into the bone correctly and (2) maintain the implant in its position over time [7][8][9]. The amount of bone accumulation in dental implants depends on several factors, including surgical and prosthetic factors (surgical technique and experience of the surgeon, timing and type of prosthesis, and also its quality), implantrelated factors (materials, design, and surface), and patientrelated factors (bone volume, the quality of the bone, and the host's response) [10][11][12].
Dental implant failure usually refers to implant failure to osseointegrate accurately with the bone, or vice versa, also when it is lost and mobile or indicates peri-implant bone loss of more than 1 mm in the first year and more than 0.2 mm in the second year [13]. Based on time criteria, failures can be classified as Early Dental Implant Failures (EDIFs) and Late Dental Implant Failures (LDIFs). EDIFs are due to unsuccessful reabsorption representing impairment in the bone repair, while LDIFs are due to loss of osseointegration [14,15]. Factors causing EDIFs include diabetes, tobacco use, history of periodontitis, length and diameter of the implant, foreign body reaction, and localized bone necrosis due to heat production during bone preparation or implant replacement [15,16].
Given that DIFs occur in a specific group of patients, this may be related to the patient's systemic health [17,18]. Therefore, identifying systemic risk factors may lead to a reduction in these failures. Some of these factors, especially vitamin D deficiency, can play an essential role in the development of EDIFs [14,15,18].
Vitamin D (vitamin D3 or cholecalciferol) is a steroid hormone that can be consumed orally or, to some extent, be made from cholesterol in the skin by exposure to sunlight (UV light) [19]. Cholesterol is converted to previtamin D3 and isomerized to vitamin D3, and then, after binding to its binding protein, it will be transported to the liver where hydroxylated CYP27A1 enzyme catalyzes its conversion to 25-hydroxy vitamin D3 [19]. Serum level of 25(OH)D or 25-hydroxyvitamin D less than 10 ng/ml is considered severe deficiency; 24-10 ng/ml, deficiency; and 25-80 ng/ml, normal [20].
Since dental protein rearrangement is determined by bone metabolism, low levels of vitamin D can negatively impact the process of repair and new bone formation on the implant surface [21]. Low vitamin D levels are associated with an increased risk of peripheral joint infections [22]. In rodents, vitamin D causes bone formation around the implant. Several studies reported the association between vitamin D deficiency and DIFs in animal models [23,24]. Some researchers examined the relationship between bone metabolism, vitamin D, and early implant failure in humans, but the reported association is still controversial [25][26][27]; therefore, a comprehensive study in this field seems necessary. The present study was aimed at evaluating the association between vitamin D and EDIFs.

Method and Material
2.1. Study Design. The present review was designed based on the PRISMA guideline [28].

Search
Strategy. Data was collected using keywords including vitamin D, vitamin D deficiency, dental implants, and implant failure in international databases including PubMed, Scopus, Web of Science, Cochrane, and Embase, until 1 February 2020. All the references were checked manually. For the PubMed database, this syntax was used: ("vita-

Inclusion Criteria.
First, the title and then the abstracts were independently reviewed by two authors (LHK and SB). Studies investigating the effect of vitamin D deficiency on dental implants and the failure of dental implants due to vitamin D deficiency in humans and animals were included in this study. The success of dental implants is commonly defined by implant survival. Serum level of 25(OH)D or 25-hydroxyvitamin D less than 10 ng/ml is considered severe deficiency; 24-10 ng/ml, deficiency; and 25-80 ng/ml, normal [20].

Exclusion Criteria.
The exclusion criteria consisted of topic irrelevance, duplicate, or incomplete data. Review articles were excluded from the study.

Data
Extraction. Data were extracted by year, location, the purpose of study, method of study, and results. Information was categorized by authors' name, year of publication, study location and type of study, and the number, age, and sex of patients.

Result
In the initial search, 1200 articles were found. After eliminating unrelated, duplicate, and incomplete information, twelve studies were finally entered in this study. The steps for selecting studies are given in Figure 1.
Tables 1 and 2 provide information on the 12 main studies, including the author's name, year of publication, location, sample size, method, and study results. These studies were selected from five different countries (Italy, Brazil, Spain, United States, Korea, and Germany). The highest number of studies was in Brazil, with four studies. This review included nine human studies in Table 1 and 3 animal studies in Table 2. In 6 studies (2 animal studies and four human studies), there was no significant relationship between vitamin D deficiency and dental implant failure. In the other six studies (1 animal study and five human studies), there was a significant relationship in this regard. The study quality was also checked, and low possibility of bias was reported for them.
In a review study of Tabanella, the author concluded that the numbers of osteoclasts formed and their resorption activity is enhanced by the addition of 1.25-(OH)2D3 [29]. In Insua et al.'s study, osteocytes and immune cells' influence was key regulators during dental implant osseointegration and maintenance [9].

Discussion
This review was aimed at studying the possible role of vitamin D in DIFs. In the present review, twelve original articles were studied. Despite the high success rate of dental implants, implant failure has been reported in some cases. Baqain et al. in Oman studied 169 patients with a total of 399 implants. They found that fifteen implants in 14 patients (8%) were unsuccessful [30]. In a study by Jafarian et al. in Iran, out of 1533 dental implants in 250 patients, 61 (4%) failed [31]. They observed that the maxilla had the highest fracture rate (9 out of 132 implants (6.8%)) [31]. There are several reasons for failure in dental implants, including vitamin D deficiency. There are also several studies indicating the high prevalence of vitamin D deficiency worldwide [32][33][34]. Vitamin D deficiency is a global health problem for all age groups, especially in the Middle East [35]. Due to the increasing prevalence of vitamin D deficiency worldwide, dental implant failure rates may increase over time. In the investigated researches, a remarkable variation in the studied populations was apparent. Mangano et al. reported the largest sample sizes with 885 samples.

BioMed Research International
On the other hand, Bryce and MacBeth's studies were conducted just by one sample involved [26,36]. Twentyfive percent of these studies used animal models, including dogs and rabbits. Human studies were performed as a randomized controlled trial, case control, and case report. These variations will make it difficult to make a solid conclusion on the subject. The most reliable studies after systematic review and meta-analysis are the RSTs. These types of studies can guide scientists accurately to resolve scientific gaps. However, case report studies in case of lacking good sample size can help the researchers. Cross-sectional studies are performed to study deceptive aspects of a population in a specific time but cannot determine the relation or cause of something.
Six of the investigated studies found a significant association between vitamin D deficiency and DIFs, but there was no significant relationship between these two criteria in the other six studies. Our results showed few pieces of evidence of the association between vitamin D levels and the success rate in dental implantation. Because of the contradictory results obtained from those studies, it is recommended to conduct comprehensive studies with larger sample sizes.
The role of vitamin D in the calcium economy is extremely important. During osteointegration, calcitriol affects the processes of activation and differentiation of osteoblasts and osteoclasts. Vitamin D has also been found to be essential for the maturation and proper functioning of bone cells by the production of a factor stimulating osteoclast precursor fusion and stimulation of osteoblast differentiation. Vitamin D also increases osteoid mineralization [37]. Also, this mechanism can play an important role in the stabilization phase of the implant, after stabilization is achieved by loading it with a prosthetic crown.
In addition to its role in calcium and bone homeostasis, vitamin D plays a vital role in modulating the innate and adaptive immune responses [38]. Recent studies suggest that vitamin D, as an essential immune response regulator, mostly targets innate immune response because all immune cells express the vitamin D receptor (VDR) response [39,40]. Changes in cytokine secretion due to vitamin D deficiency can impair osteoclast activation and differentiation through VDR activation [41]. It is hypothesized that metallic particles affect macrophages and lymphocytes to release inflammatory cytokines, leading to increased osteoclastogenesis and decreased osteoblastogenesis, which eventually results in peri-implant bone degeneration [42]. Vitamin D may also be essential for the antibacterial response because it affects the monocyte-macrophages [43]. Xu et al. showed that vitamin D could inhibit gingivalis-induced proinflammatory cytokine expression and, at the same time, improves the expression of anti-inflammatory cytokines in macrophages [44]. Studies included in qualitative synthesis (n = 12) Articles retrieved during database search including PubMed, Scopus, Web of Science, Cochrane ( n = 1200) Figure 1: Flowchart describing the study design process.  [48] 4

BioMed Research International
BioMed Research International Vitamin D affects different stages of peri-implant bone formation. It has become an active factor in dental and implant surgery because of its effects on bone metabolism and the immune system. Given the high percentage of patients with vitamin D deficiency, it seems necessary to examine vitamin D deficiency before implant and dental surgery. It is recommended to conduct comprehensive studies with larger sample sizes to determine the exact mechanism involved. The limitations of the study include the limited number of clinical studies and small sample sizes. Our search shows that there are few clinical studies in this field; also, some of them contain a small sample size; this point should be resolved in future studies.

Conclusion
It is difficult to conclude the association between vitamin D and implant failure based on the current research in the literature. The studies' findings were inconsistent, but some of this research noted the effect of vitamin D on implant failure. Vitamin D may play a role in improving implant success through its effects on the immune system modulation. This hypothesis needs more clinical studies to be approved.

Conflicts of Interest
The authors declare that they have no conflicts of interest.