Bone regeneration in diabetic patients. A systematic review

Background Oral bone regeneration techniques (OBRT) attempt to provide the appropriate bone volume and density to correctly accomplish dental implant treatments. The objective was to determine whether differences exist in the clinical outcomes of these techniques between diabetic and non-diabetic patients, considering the level of scientific evidence. Material and Methods A systematic review following PRISMA statements was conducted in the PubMed, Scopus and Cochrane databases with the search terms: “Diabetes Mellitus”, “guided bone regeneration”, “bone regeneration”, “alveolar ridge augmentation”, “ridge augmentation”, bone graft*, “sinus floor augmentation”, “sinus floor elevation”, “sinus lift”, implant*. Articles were limited to those published less than 10 years ago and in English. Inclusion criteria were: human studies of all bone regeneration techniques, including at least 10 patients and the using OBRT in diabetic and non-diabetic patients. Non-human studies were excluded. They were stratified according to their level of scientific evidence related to SORT criteria (Strength of Recommendation Taxonomy). Results The initial search provided 131 articles, after reading the abstracts a total of 33 relevant articles were selected to read the full text and analyzed to decide eligibility. Finally, seven of them accomplished the inclusion criteria: two controlled clinical trials, one cohort study and four case series. Conclusions A low grade of evidence regarding the use of OBRT in diabetic patients was found. The recommendation for this intervention in diabetic patients is considered type C due to the high heterogeneity of the type of diabetic patients included and the variability of the techniques applied. Key words:Diabetes Mellitus, guided bone regeneration, bone regeneration.


Introduction
Alveolar crest volume reduction is a common consequence of tooth loss and can be, not only a difficulty for the treatment planning, but also a contraindication for dental implants placement. For this reason, bone augmentation procedures may be required before implant therapy in areas with moderate to severe bone loss. Bone regeneration techniques, include alveolar bone augmentation (ABA), guided bone regeneration (GBR) and sinus lift (SL) procedures. Systemic diseases including diabetes mellitus (DM) could be formally considered a contraindication (1)(2)(3) for these interventions, especially in case of associated implant installation, due to its vascular and immune deficiencies. One of the most prevalent systemic diseases worldwide is diabetes mellitus (DM), a chronic metabolic disorder composed of two subtypes: Type 1 DM involves 5-10% of diabetic patients and is an autoimmune disorder related to the destruction of pancreatic β-cells and the consequent deficit in insulin production; Type 2 DM, involves 90-95% of diabetic patients and is a multifactorial disease caused by environmental factors (e.g. obesity and sedentary lifestyle, corticosteroids intake) which lead to peripheral or cellular insulin resistance in genetically predisposed cases (4). The final result of decreased pancreatic production (type 1 DM) or peripheral cellular insensibility to insulin (type 2 DM) is an increase in blood glucose levels (hyperglycemia). Treatment in both types of DM is focused on achieving a proper glycemic control in order to prevent the development of medical complications (3,5). In the long term, hyperglycemia promotes vascular complications which are one of the main causes of morbidity and mortality in this type of patients (6). Chronic hyperglycemia also affects different tissue structures and produces an inflammatory effect, which results in a negative imbalance in the process of bone remodelation due to a decrease in bone formation rather than an increase in reabsorption as a consequence of the inhibitory effect of hyperglycemia on osteoblastic differentiation, impairment of parathyroid hormone activity which regulates phosphorus and calcium metabolisms (7) and a reduction in adherence, growth and accumulation of the extracellular matrix, as it has been demonstrated in experimental models that mineral homeostasis and osteoid production are significantly decreased in DM patients (6). Conversely, such models also showed that a persistent normoglycemic levels is directly correlated with an increased bone matrix and osteoid generation at a rate similar to controls, increasing bone formation around the dental implants (6)(7)(8)(9). DM patients with good glycemic control also demonstrate a markedly reduced rate of periodontal bone loss, and a lower incidence of postoperative complications, compared to those with an inadequate one (3). Several studies have reported that the former group show successful dental implant rates similar to non-DM patients (4,11). The main objective of this work was to review the current literature, taking into account the level of scientific evidence, to ascertain the rate of success of the oral bone regeneration techniques (OBRT) in DM patients.

Material and Methods
In October 2017 an electronic search was performed using PubMed, Scopus and Cochrane databases, following the PRISMA statements (10), in order to answer the following PICO question: "In patients with DM compared with non-diabetics are there the same results of OBRT in terms of bone regeneration, complications and success of dental implants?" The search was limited to articles published in English between 2007 and 2017 with the search terms: "diabetes mellitus", "bone regeneration", "guided bone regeneration", "alveolar ridge augmentation", "bone graft*", "sinus floor elevation" and "implant*". A second search was carried out employing Boolean operators such as "OR/AND" and synonyms of the keywords to obtain articles that included two or more of the terms. Finally, the Mesh Terms of the keywords were looked for, and a final search was performed: (("Diabetes Mellitus"[Mesh]) AND ("guided bone regeneration" OR "bone regeneration" OR "alveolar ridge augmentation" OR "ridge augmentation" OR bone graft* OR "sinus floor augmentation" OR "sinus floor elevation" OR "sinus lift")) AND implant*. Inclusion criteria were: human studies, published in English from 2007 to 2017, regarding the use of OBRT in DM and non-DM patients. Exclusion criteria were non-human studies and case series including less than 10 patients or case-control studies. Articles were then stratified according to the level of scientific evidence using SORT criteria (11). On the basis of their scientific quality a grade of recommendation was given respect to the use OBRT in DM patients.

Results
The final electronic search performed on 31st October 2017 provided 58 articles from Pubmed, 72 from Scopus and 7 from Cochrane databases. Another three articles were added after an additional hand search based on the references of the papers already found. After removing duplicates 131 articles were obtained, and after reading the abstracts, a total of 33 relevant articles were identified and selected to read the full text. Finally seven articles fulfilling inclusion criteria were included (1,5,(12)(13)(14)(15)(16). The remaining 26 were excluded due to being descriptive studies (14,15), animal studies (16)(17)(18)(19)(20)(21)(22)(23)(24), no-DM patients (25), not performing bone e427 regeneration in the oral region (26) and not specifying whether OBRT was employed in DM patients (27)(28)(29)(30). The flow-chart of the review process modified from the PRISMA statement (10) is shown in Figure 1. Two out of the seven selected articles were controlled clinical trials (1,5), one a retrospective cohort study (12) and four were retrospective case series (13)(14)(15)(16). The selected articles were classified according to the level of scientific evidence following SORT criteria (11): 3 of scientific evidence level 2 (1,5,12), and the remaining ones (13-16) of level 3. Table 1 summarizes the level of evidence of each study and the reasons for classifications. Study design, duration, number of patients, gender, mean age, DM type, and OBRT applied are shown in Table 2.
The main characteristics of each study: number of patients who underwent OBRT (DM patients and non-DM ones), number of implants placed in native and regenerated bone, evaluation technique, failure criteria, and results are synthetized in Tables 3 and 4. Regarding OBRT in DM patients the strength of recommendation, on the basis of the level of evidence in the available data, is level C. Because the inconsistency of the patients' characteristics, the methodology used and parameters of comparison, it does not allow to carry on a methanalysis which could provide quantitative conclusions about the benefits of OBRT in DM patients. Due to the high heterogeneity of the included studies it is not possible to perform a meta-analysis of the data.

Discussion
Diabetic patients have an increased incidence of periodontal disease and bone reabsorption (5), greater loss of alveolar bone (33,34) and more post-operative com- Huynh et al. (12) Retrospective CS Type of DM not specified; variation in treatment procedures; only 3-6 months of follow-up; examiner not blinded.  plications following implant placement surgery than non-DM ones (6). Due to this increased incidence of risk factors and complications, it has been shown that the success rate of dental implants in DM patients should be lower than in non-DM population (1,5,6,19), nevertheless, a good metabolic control can improve the survival rate of dental implants in such patients (1,3,6,20,21). Wellcontrolled DM is therefore not considered a full contraindication for implant therapy even though current literature suggests a certain decrease in the success rate of concurrent surgical procedures as would be the case of OBRT (5).
In our review process it has been identified some studies evaluating the success of bone regeneration techniques in DM animals (22)(23)(24)(25)(26)(27)(28)(29)(30), however, there were few regarding DM in humans despite the safety of performing implant therapy in such condition having been proven. Studies in non-controlled DM patients are even scarcer, probably due to the previously mentioned complications and ethical reasons. Only one publication with respect to OBR in non-controlled DM patients (HbA1c > 9%) was identified and includes only one DM patient underwent surgery (1). The regeneration techniques applied in the seven selected studies for systematic review analysis include GBR, SL, and bone grafts. Out of the 7, only one (5) aimed at comparing OBRT clinical results in DM and non-DM patients. The objective of the remaining six was to identify the predictive failure factors of certain OBRTs (13,14) and for dental implants (1,12,16), as well to compare dental implant survival rate between native and regenerated bone (15). Some of these studies had a limited number of DM patients and a marked disproportion between both groups (DM and non-DM) (12)(13)(14). In addition, relevant DM patient data were only specified in two articles regarding illness duration, treatment applied to control the metabolic state, and pre/post-surgery HbA1c levels (1,5 Xenogeneic bone substitute mineral, bone replacement material, AB or mixture of these materials.   RFA: resonance frequency analysis.

Conclusions
As OBRT is a fairly new surgical intervention, and the available literature is not only scarce but extremely heterogeneous, it is not possible to categorically assert the reliability of this procedure in well-controlled DM patients. As consequence, and following the principles of evidence-based odontology, the present analysis reports a grade C of recommendation regarding its use.