Does the Use of Tacrolimus Influence Alveolar Bone Metabolism?

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Article Information:


Group: 2012
Subgroup: Volume 10, Issue 1, Winter
Date: January 2012
Type: Review Article
Start Page: 429
End Page: 434
DOI: 10.5812/ijem.2555

Authors:

  • Rogerio Lacerda Dos Santos
  • Department of Orthodontics, Federal University of Campina Grande, Patos, Brazil
  • Matheus Melo Pithon
  • Department of Orthodontics, State University of Sudoeste da Bahia, Jequie, Brazil
  • Maria Claudia Mesquita Lacerda
  • Department of Letters, University of State of Minas Gerais, Divinopolis, Brazil
  • Antonio Carlos De Oliveira Ruellas
  • Department of Orthodontics and Pediatric Dentistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
  • Lucianne Cople Maia
  • Department of Orthodontics and Pediatric Dentistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

      Correspondence:

      Affiliation: Department of Orthodontics and Pediatric Dentistry, Federal University of Rio de Janeiro
      City, Province: Rio de Janeiro,
      Country: Brazil
      Tel: +21-25622101
      Fax: +21-25622098
      E-mail: rorefa@terra.com

Abstract:


Background: Tacrolimus is commonly used in the medical area to avoid the rejection of grafted organs. Some studies have suggested that tacrolimus is an immunosuppressor that increases bone turnover and the development of severe osteopenia. In dentistry this effect may interfere with oral treatments.
Objectives: A systematic literature review to test the hypothesis that treatment with immunosuppressor tacrolimus may interfere with alveolar bone metabolism.
Search Strategy: Research in the health science databases was performed and includes articles published up to August 2011.
Selection Criteria: Studies in animals and humans using tacrolimus as an immunosuppressor and capable of interfering with alveolar bone metabolism were included.
Data Collection and Analysis: The key words used were: tacrolimus and alveolar bone or tacrolimus and alveolar bone loss or FK506 and alveolar bone or FK506 and alveolar bone loss. The articles were initially selected by title and abstract and then potentially eligible articles were read and those that fulfilled the inclusion criteria were carefully analyzed and classified (A, B and C).
Results: From a total of 745 references, only 6 articles fulfilled the eligibility criteria. Three articles were classified as A and 3 as C. In spite of the methodological differences in the 6 articles (3 animal and 3 human) tacrolimus was not found to cause damage to alveolar bone tissue.
Conclusions: In humans the results are still not conclusive.
In animals: tacrolimus does not produce alveolar bone loss, whereas in humans there is no evidence that this immunosuppressor produces alveolar bone loss.


  • Implication for health policy/practice/research/medical education:
    Monitoring of bone mineral density starting at: histopathology, densitometry, radiographs and biochemical methods, allows to determine with precision the Influence of tacrolimus on alveolar bone.
  • Please cite this paper as:
    Dos Santos RL, Pithon MM, Lacerda MCM, Oliveira Ruellas ACD, Maia LC. Does the Use of Tacrolimus Influence Alveolar Bone Metabolism? Int J Endocrinol Metab. 2012;10(1): 429-34. DOI: 10.5812/ijem.2555

Copyright © 2012 Kowsar M. P. Co. All rights reserved.


Keywords: Tacrolimus;Bone;Drug

Manuscript Body:


1. Introduction

There are medications capable of affecting bone metabolism and the rate of tooth movement (1). Tacrolimus (FK506) is an immunosuppressor agent isolated from Streptomyces tsukubaensis (2). It is widely used in patients who have undergone organ transplants (3). Some authors (4) have suggested that FK506 has an anti-inflammatory effect, which acts primarily by interfering in T cell activation, suppressing the production of pro-inflammatory cytokines particularly TNF-α, IL-1β, IL-2 and IL6, modulating inflammation and minimizing tissue destruction and bone resorption. Studies have reported that FK506 increases bone turnover and the development of severe osteopenia (5-8), other studies have found that FK506 induces osteoclastic apoptosis (9-11).
Tacrolimus is commonly used to avoid rejection of the grafted organ, but it may cause harmful effects on bone mineral homeostasis (12) and consequently influences tooth movement (1). Therefore, the aim of this study was, by means of a systematic literature review, to test the hypothesis that treatment with tracrolimus immunosuppressor may interfere in alveolar bone metabolism.

2. Materials and Methods

For this study, bibliographic surveys were performed in the following databases: Ovid MEDLINE (1950-2011), EMBASE (1980−2011) (via DIMDI / EMBASE Alert / Elsevier / Scirus), Scopus and PubMed. All articles published up to August 2011 were included. After previous testing of some key words, four of these were used to obtain better results. The terms used in the bibliographic survey were: tacrolimus and alveolar bone or tacrolimus and alveolar bone loss or FK506 and alveolar bone or FK506 and alveolar bone loss. Other key words were not used because they did not fulfill the inclusion criteria. The references of the selected articles were assessed to identify other relevant publications. The inclusion criteria were as follows: experimental studies in animals and humans, which tested tacrolimus as an immunosuppressor capable of affecting alveolar bone metabolism; analysis of experimental data by histopathology, with/without densitometry, periapical or bite-wing radiographs and biochemical methods to measure bone loss. The exclusion criteria were as follows: studies that did not show the influence of the immunosuppressor on bone metabolism; experimental analysis with only a quantitative description of data; in vitro studies (cell cultures) ; case reports; review articles; abstracts and letters to the editor. The articles were selected by the title and abstract, without any restriction on language and those that were within the exclusion criteria were eliminated at this stage. Articles that appeared in both research databases were only considered once. After initial selection, the articles were read and those that fitted with the inclusion criteria were carefully analyzed and classified according to their level of scientific relevance (Table 1).

Table 1. Criteria Used to Classify the Articles.

Classification

(Grades)

Classification Criteria

A

Randomized controlled clinical studies in (humans) and in vivo experimental studies (non-human) with good control of variablesa, using histopathology with/without densitometry, periapical or bite-wing radiographs and biochemical methods.

B

Non-randomized controlled clinical studies in (humans) and in vivo experimental studies (non-human) with moderate control of variablesa, using periapical or bite-wing radiographs with/without densitometry, and biochemical methods.

C

Non-randomized controlled clinical studies in (humans) and in vivo experimental studies (non-human) with poor control of variablesa, using periapical or bite-wing radiographs with/without densitometry, and biochemical methods.

a Control of variables: Blinding in the data analysis, comparability among the groups, representative sample, adequate research time. Classification Criteria: (A: fulfills 3-4 variables) ; (B: fulfills 2 variables) ; and (C: fulfills 0-1 variable).

The articles were assessed and classified by two independent researchers (RLS) and (MMP). In the event of discordance between the examiners, the articles were reviewed in conjunction to obtain a decision and consensus. In cases of studies that gave rise to the need for a more succinct explanation concerning the research, the authors of the study were contacted.

3. Results

The initial research showed 745 potentially relevant articles identified and screened for retrieval from the Ovid MEDLINE and EMBASE databases, after reading the titles, 28 articles remained. At the end, after reading the title and abstract, only 6 articles were selected in accordance with the eligibility criteria (Figure 1). All the articles found in the Ovid MEDLINE and EMBASE databases, selected by title and abstract, were repeated in the Scopus and PubMed databases. The articles selected were carefully read and classified according to the criteria shown in Table 1. This resulted in six reviewed articles, three articles were classified as having a level of scientific relevance as A and three articles as C. In the sample there were three studies conducted in animals (13-15) and three in humans (16-18), with points and important methodological features shown in Table 2.

 

  Figure 1. Figure 1. Flow chart of manuscripts screened through the review process.

 

 

   Table 2.Study characteristics of the articles selected.

a Statistically significant difference between control and experimental groups.
b Abbreviations: S.c, Subcutaneous; SAP, Serum bone-specific alkaline phosphatase; TRAP-5b, Osteoclast-derived tartrate-resistant acid phosphatase; BMD, Bone mineral density; IRMA, Immunoradiometric assay; DPD, Deoxypyridinoline.

The articles selected showed that tacrolimus does not cause significant deleterious effects on the alveolar bone tissue in animal studies, but in the studies in humans there was no evidence that this immunosuppressor could cause alveolar bone loss.

4. Discussion

There is increasing clinical use of tacrolimus, at present considered the basic immunosuppressor drug in over 80% of transplants (19), in addition to being used in treatments for atopic dermatitis and vitiligo, among other dermatological disorders (20).
When considering that the majority of patients who used this immunosuppressor drug require dental treatment, knowledge about its action on bone tissue will allow doubts to be cleared up with regard to performing dental procedures, such as periodontal and orthodontic procedures in specific cases, since the alveolar bone is directly involved. The articles selected (13-18), showed that tacrolimus does not stimulate alveolar bone loss. Three non-randomized controlled clinical articles were classified as C. The first non-randomized controlled clinical study (18) classified as C was conducted in patients who had undergone liver transplants with the presence of moderate chronic to severe periodontitis. Deleterious effects on bone tissue were observed during the follow-up period. However, according to the authors (18), some women patients were in the post-menopausal stage and they were not receiving hormonal therapy. Furthermore, the reduced size of the sample and the changes in medication therapy during the course of the study increased the variables of this study. The association of other medications with tacrolimus made it impossible to assess it individually. The authors (18) reported having associated prednisone, a potent corticoid, with tacrolimus or cyclosporine in 10 patients, but it is not clearly indicated in which patients. The glycocorticoids are the most common cause of secondary osteoporosis, particularly affecting the trabecular bone (21), which could influence the results found. As a control group, the authors used the same group that received the drug and at the end of the experiment, they compared the initial and final assessments. Therefore, this did not allow a comparison with healthy patients. In the first (18), as well as in the second (16) and third study (17), the assessment method used was not satisfactory. In these studies (16-18) the authors used a panoramic radiography to measure the alveolar bone, but the radiographs of choice were periapical and bite-wing radiographs, as they show fewer distortions. The studies discussed in the second and third articles (16, 17) were also conducted using patients who had undergone liver transplants. They showed that there was diminishment of alveolar bone loss after the transplant associated with the beginning of the treatment with tacrolimus or cyclosporine. On the other hand, it is not clearly indicated which patients only received tacrolimus. This affected the isolated analysis of the effects of tacrolimus on bone tissue. According to the authors of these studies (16, 17), not only the immunosuppressor effect, but also recovery of the hepatic function seems to have the potential to invert the condition of bone loss.
Three articles were classified as A, and they were all randomized controlled studies in rats (13-15). The first (15) compared the effect of tacrolimus and cyclosporine on the bone and showed that differently from cyclosporine, tacrolimus did not cause alveolar bone loss. The cyclosporine dosage used (10 mg/Kg/day) was higher in comparison with tacrolimus (1 mg/Kg/day), but if one considers that tacrolimus is 10 to 100 times more potent than cyclosporine (22), the relationship between dosage x potency becomes equivalent and therefore comparable.

The three articles used quantitative histology (13-15) as one of the exams to verify the effect of tacrolimus on bone tissue. This exam is fundamental for the classification of these studies as A. The quantitative histological exam, in turn, provides the best parameter to show the effects of the drug on the tissue when compared with the subjectivity of qualitative exams.
The second study (14) used a model of induced experimental periodontitis. This study showed evidence of a reduction in alveolar bone loss and diminishment of the inflammatory process (4) in the face of induced periodontitis, through a reduction in the concentration of PGE2 and myeloperoxidase activity. In addition to preventing the increase of seric levels of IL-1β (50.4 ± 21 pg/mL ), IL-6 (26.5 ± 14 pg/mL ) and TNF-α (51.5 ± 3 pg/mL ) in the two dosages tested, 1 and 2 mg/Kg/day. According to the authors (14), there appears to be a potential anti-inflammatory action of FK506 on periodontitis, however further studies could explain this hypothesis better, which would be extremely important in the periodontal treatment of transplant patients. In histology and histomorphometry, the third article (13) showed a preventive capacity of tacrolimus against alveolar bone loss, showing a reduction in the number of osteoclasts and maintenance of the number of osteoblasts. This led to a greater volume of bone when compared with the control group, however the authors themselves emphasized the need for further studies that could reiterate the bone-inducing capacity of tacrolimus on alveolar bone tissue. The studies conducted in animals (13-15) showed a better methodology design, nevertheless, there is a lack of studies with well-designed methodologies, particularly in humans to assess this immunosuppressor agent due to the association between different medications, comparability and variability of groups. Although studies in animals have shown favorable results with regard to not stimulating alveolar bone loss, it is necessary to conduct future well-designed clinical studies to support the safe use of this drug as an immunosuppressor agent that does not cause negative effects on alveolar bone homeostasis. Within the limitations of this study, it can be concluded that: in animals the tacrolimus does not cause alveolar bone loss. In the studies in humans: there is no evidence that this immunosuppressor agent can cause alveolar bone loss. However, there is a lack of methodologically well-designed studies to support its real action in human bone tissues.

  • Acknowledgements
    We would like to thank the Department of Orthodontics and Pediatric Dentistry of Federal University of Rio de Janeiro (UFRJ) and CAPES for the research funding.
  • Financial Disclosure
    None declared.
  • Funding/Support
    None declared.

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