Bone Substitutes Graft for Regeneration of the Anterior Maxillary Alveolar Process: A Systematic Review Open Access

Many cases of partial edentulism, especially in the esthetic area at the anterior maxilla, require reestablishment of the lost bone volume of atrophic alveolar ridges in both horizontal and vertical directions to allow the successful rehabilitation with implants.^1,2 

In both arches, the horizontal resorption is initiated on the buccal bone surface, progressing in lingual and palatal directions and occurs in 50% of cases.^3,4  During the resorption process, it is common to observe insufficient bone quantity on the alveolar ridge for implant placement at the anterior maxilla, with a mean horizontal reduction of 3.8 mm and mean vertical reduction in height of 1.24 mm in the first 6 months after extraction.^5,6  Unavailability of bone is one of the most important factors precluding the rehabilitation with endosseous implants.

Therefore, the anatomical limitations, knowledge on bone metabolism, evolution of bioengineering in the reconstruction of bone tissues, and intensification of investigations in the search for new grafting materials have led to a new era in implantology,⁷  allowing the successful rehabilitation of patients with extensive areas of bone resorption. Thus, the utilization of autogenous bone graft (ABG) is considered the gold standard to reconstruct the severely resorbed alveolar ridge in totally or partially edentulous patients, and its use has been encouraged, emphasizing the viability of autogenous bone grafts in Implantology.

The ABG presents growth factors for osteoinduction, cells for osteogenesis and structure for osteoconduction,⁸  biocompatible properties, and lack of antigenicity.⁹  It may be obtained from extraoral¹⁰  or intraoral sites.¹¹  However, it presents fast remodeling and limited availability, due to the need of a donor site, being often associated with high surgical risk and morbidity, encouraging the use of bone substitutes with osteoinductive and osteoconductive properties.

The bone substitutes (BSs) are viable options from human (allogeneic), animal (xenogeneic), vegetal or synthetic origin (alloplastic), and bone morphogenetic proteins targeted to placement in humans for reconstitution of bone defect, reinforcement of bone structure, or filling of bone defects of traumatic or orthopedic origin.¹²  They have received attention in the last years because of its advantages, such as easy achievement in large quantity, reduction of morbidity and surgical time, and absence of a second donor surgical site.¹³  Most materials in the market present osteoconductive property and few present osteoinductive properties.^14,15 

To date, no systematic review comparing the use of ABGs with BSs for regeneration of horizontal bone resorption at the anterior region of maxillary alveolar processes, aiming at rehabilitation with endosseous implants, has been conducted.

This systematic review aimed to respond the following question: are BSs as effective as ABGs for regeneration of anterior areas in the maxilla and mandible with horizontal bone resorption, aiming at the rehabilitation with implants, eliminating the need of a second surgical site and providing a more comfortable postoperative period for the patient?

This systematic review was registered on the database PROSPERO (International Prospective Register of Systematic Review, under CRD 42017070574) and was conducted in accordance with the PRISMA guidelines (2020).

This study followed other models proposed in the literature.^16,17  The PICO question was designed (Population/Intervention/Comparison/Outcome), and the selected studies met the established criteria: (1) population, patients submitted to regeneration surgery at the anterior region of maxillary alveolar processes with horizontal bone resorption; (2) intervention, patients who received bone grafts; (3) comparison, patients who received grafts with bone substitutes compared to patients who received autogenous bone graft; (4) outcome, the main results were comparison of the increase in bone width at the anterior maxillary region (BSs and ABGs) and, secondarily, the survival rate of implants.

The inclusion criteria were as follows: papers published in English language; controlled and randomized clinical trials; prospective studies; retrospective studies; studies comparing at least 2 techniques (BS and/or techniques for bone regeneration vs ABG with and without membranes); studies with macroscopic, clinical, and tomographic evaluation, with implant placement after bone graft. The study also included patients with horizontal deficiency who received bone graft at the edentulous anterior maxillary region (from canine to canine).

The following exclusion criteria were considered: (1) case reports; (2) literature reviews; (3) patients with systemic disorders or malformations; (4) patients with clinical evidence of periodontitis or oral infections; (5) studies without control group (ABG); (6) experimental studies on animals; (7) studies on patients who received bone graft (BS and ABG) at the posterior maxillary region; (8) studies with vertical deficiency on the anterior maxilla who received bone graft; and (9) studies with microscopic analysis (histologic, histomorphometric and immuno-histochemical).

In the process of paper search and selection, the study included the databases PUBMED/MEDLINE (Medical Literature Analysis and Retrieval System Online, via PubMed), EMBASE (Excerpta Medica Database), SCOPUS, SCIENCE DIRECT, WEB OF SCIENCE, and CENTRAL (Cochrane Central Register of Controlled Trials). There was no restriction concerning the year of publication of included studies. The search process was conducted between up to September 2020.

The keywords available in medical databases (MeSH, PubMed) related to BS and ABG were selected. Boolean operators were used, with the keywords “bone substitutes–bone replacement material” [MeSH Terms] OR (“biomaterials” [All Fields] OR (“guided bone regenerations” [All Fields] AND “autograft–autologous transplants” [MeSH Terms] OR (“autogenous bone graft” [All Fields] OR “bone augmentation” [All Fields] OR “bone graft” [All Fields] AND “bone regeneration–osteoconduction” [MeSH Terms] OR (“bone stimulation” [All Fields] OR “bone formation” [All Fields] OR “dental biomaterials” [All Fields] AND “osseintegration” [All Fields] OR “osseointegrated implants” [All Fields] OR “anterior maxillary implants” [All Fields] AND “alveolar bone loss–bone atrophies, alveolar” [MeSH Terms] OR (“atrophic anterior maxilla” [All Fields] OR “alveolar ridge defect” [All Fields] OR “horizontal bone defects” [All Fields] OR “horizontally deficient maxillary alveolar ridges” [All Fields] OR “horizontal guided bone regeneration” [All Fields].

A manual search was performed according to the descriptors of publications from the last 5 years: Journal of Periodontology, Journal of Clinical Periodontology, Journal of Periodontal Research, Clinical Oral Implants Research, Clinical Implant Dentistry and Related Research, Clinical Oral Investigations, Oral and Maxillofacial Surgery, Journal of Dentistry, Journal of Dental Research, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Surgery, Biomaterials, International Journal of Oral & Maxillofacial Surgery, Periodontology 2000, and The International Journal of Periodontics & Restorative Dentistry. The gray literature was searched on websites as Google Scholar, ProQuest, and Open Gray using the following search strategy: (autogenous bone graft OR bone augmentation OR bone graft) AND (anterior maxillary region OR esthetic zone OR premaxilla OR maxillary atrophy OR alveolar ridge augmentation OR alveolar bone loss) AND (horizontal bone defects OR horizontal ridge defect OR horizontal ridge augmentation OR horizontal guided bone regeneration OR horizontal bone augmentation OR horizontally deficient maxillary alveolar ridges) AND (osseointegrated implants OR dental implants OR osseointegration OR anterior maxillary implants) AND (guided bone regenerations OR guided bone regeneration augmentation OR biomaterials bone OR bone substitutes OR bone regeneration techniques).

The studies were selected in 2 stages. In the first stage, all titles and abstracts identified on the databases were independently surveyed by 2 calibrated examiners. The studies that did not meet the eligibility criteria were excluded. In the second stage, the same examiners applied the eligibility criteria to the full text of studies. Two examiners were asked in case of discordance, when there was no consensus between the first 2 examiners. Interexaminer tests (κ) were applied to evaluate the selection of titles and abstracts, and to complete the reading with interpretation of the paper, with a consensus meeting. All titles and abstracts analyzed as possibly eligible were completely separated and analyzed. There was agreement between examiners for all studies (κ = 1.0) and for abstracts (κ = 1.0), without discordance between them.

The following data were obtained from each study: author; year; country; groups (ABG and BS); number of patients; age; donor site or biomaterial; use of membrane; clinical width of the alveolar process (before, mm) for group ABG and group BS; radiographic width of the alveolar process (before, mm) for group ABG and group BS; clinical width of the alveolar process (after, mm) for group ABG and group BS; radiographic width of the alveolar process (after, mm) for group ABG and group BS; signs and symptoms; survival rate of grafts (%); drugs prescribed before the procedure; drugs prescribed after the procedure; complications; type of study; level of evidence; total number of patients and number of patients who received previous grafts; number of implants placed (control group and test group); Newtons of stabilization; length of implants; diameter of implants; time elapsed between grafting and implant placement; number of implant losses; survival rate of implants (control group and test group); and follow-up period (Tables 1 and 2).

The clinical studies were evaluated as to the methodologic structure, sample size, and sample calculations. For the type of sample evaluation, the level of evidence bias scale was adopted as proposed by the Australian National Health and Medical Research Council (NHMRC).¹⁸  Each design of clinical study was assessed, and only studies with control groups were included in the systematic review, according to the PRISMA and PICO criteria.¹⁹  The quality and risk of bias of randomized controlled trials (RCTs) included in this systematic review were assessed by the Cochrane Risk of Bias Tool,²⁰  which evaluated the following: (1) generation of sequence and allocation of randomization (selection bias); (2) blinding of allocation (selection bias); (3) blinding of participants and professionals (performance bias); (4) blinding of examiners of results (detection bias); (5) incomplete outcomes (attrition bias); (6) selective report (report bias); and (7) other biases (other sources of bias).

The quantitative data collected from papers were tabulated to analyze the relative risk (RR) or risk difference (RD) and 95% confidence interval (CI); the weight of contribution of each study was considered to calculate the meta-analysis. Data were analyzed using the relative risk (RR), risk difference (RD), and 95% CI. Continuous data were analyzed using the mean difference (MD) and 95% CI. For all analyses, significant values were considered if P < .05. The software Review Manager (RevMan) 5 (Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for meta-analysis and design of graphs. To analyze the heterogeneity, a significant heterogeneity was considered if P < .1 (I² > 75%), in this case, using the concept of random analysis, in accordance with previous studies.^21–25 

The primary outcome was to evaluate the efficacy of different BSs compared with ABGs for regeneration of maxillary alveolar processes with horizontal bone resorption, aiming at the rehabilitation of edentulous patients with endosseous implants. The secondary outcome was to evaluate and compare the quality and quantity of newly formed bone, evaluate the time after bone graft for implant placement, and evaluate and compare the survival of implants, morbidity, cost, and surgical complications.

A total of 514 papers were found on 6 databases (Medline: 161, Cochrane: 36, Embase: 64, Scopus: 37, Web of Science: 115, Science Direct: 101) by manual search according to the descriptors of publications in the last 5 years. The gray literature was also searched, and 10 studies were retrieved. After analysis of titles according to the inclusion and exclusion criteria and elimination of duplicated references, 24 papers were selected from complete texts evaluated by their eligibility. Finally, 6 studies were included in the qualitative synthesis (Figure 1).

Eighteen full-text studies were excluded for the following reasons: single edentulous area,^25–28  studies with control group,^29–31  studies without experimental group,^32–37  study only addressing the association of xenogeneic graft and bloc graft,³⁸  studies on posterior edentulous area or total edentulism,^39–41  and only histologic analysis⁴²  (Figure 1).

The selected studies were classified as follows: randomized controlled clinical trial,^43–45  retrospective,^1,46  and prospective¹³  (Table 1). A total of 182 patients were followed for a period of 6 to 48 months. The mean age of patients was 46.46 years. Overall, 383 implants were placed in the patients, with 152 implants at the anterior region, according to the description of authors (Table 2).

The evidence scale level of the NHMRC was used to evaluate the quality of studies (additional evidence levels and grades for recommendations for guideline developers). The studies achieved Grade II,^43–45  and 3 studies achieved low scores (Grade III-2; Table 2).^1,13,46 

Among RCTs, a low risk of bias was observed for sequence generation, randomization allocation, and allocation hiding. High risk of bias was found concerning the blinding of participants and professionals and blinding of outcome examiners in 1 study, and the other 2 studies presented low risk of bias. For the analysis of incomplete outcomes, the study of Freitas et al⁴³  revealed low risk of bias, and the study of Lumetti et al⁴⁴  had uncertain bias. Uncertain bias was also observed for both studies in the selective report and low risk of bias for both studies in other biases (Figure 2).

In an analysis considering the 6 studies, the quantity of failures of autogenous bone grafts was compared with bone substitutes. No failure was observed in 41 cases evaluated with autogenous bone, and only 1 failure was reported among 34 cases with bone substitute, without significant difference in the comparison of groups with an RR of 7.00 (95% CI, 0.38–127.32; P=.19) as shown in Figure 3.

In an analysis considering the number of complications, only 1 complication was observed in the evaluation of 26 cases of graft with bone substitute. Similarly, in the group receiving autogenous bone, only 2 complications were observed among 29 cases, without significant difference in the comparison of groups with an RR of 0.50 (95% CI, 0.05–4.81; P = .55), as presented in Figure 4.

In 3 studies,^43,45,46  it was possible to analyze the placement of endosseous implants, evidencing that 50 implants were placed in the graft group with BS, and in the autogenous group 62 implants were placed, and no implant failure was observed in both (risk difference [RD], 0.00; 95% CI, −0.05 to 0.05; P = 1.00), as shown in Figure 5.

Evaluation of the possible gain in clinical measurement using the caliper (20 ABGs and 20 with BSs) revealed that, in both studies, it was possible to measure the data 6 months after grafting, and no significant difference was identified in this gain in both groups (mean difference, 0.41; 95% CI, −1.54 to 2.36; P = .68; heterogeneity for χ², 4.81; P = .03, I² = 79%), as presented in Figure 6.

However, it should be emphasized that, on the initial evaluation (time 0) of the same measurement obtained in these clinical studies, a significant difference was observed in the initial presence of bone tissue, indicating that the BS group presented a smaller clinical measurement (−0.89 mm) compared with the autogenous group (mean difference, −0.89; 95% CI, −1.45 to 0.33; P = .002; heterogeneity for χ², 1.04; P = .31; I² = 4%), as presented in Figure 7.

In the comparison between the initial and 6-month periods of the ABG and BS groups, a significant difference in bone gain values was identified (mean difference, 2.72; 95% CI, 0.72 to 4.71; P = .008; heterogeneity for χ², 41.95; P < .0001; I² = 93%; Figure 8).

The papers addressed in this systematic review and meta-analysis were obtained from an intense search in high impact journals in the fields of periodontology and oral and maxillofacial surgery, aiming to achieve updated and more reliable information. There were no restrictions concerning the date of publications to include all literature available, because studies evaluating ABG or BS in patients with horizontal deficiency at the edentulous anterior maxilla are still scarce and are mostly animal studies or case series.

The greatest interest is to define whether the BSs are as effective as ABGs for regeneration of the anterior region of maxillary alveolar processes with horizontal bone resorption, aiming at rehabilitation with endosseous implants, and to analyze the survival rate of implants in the different types of bone grafts.

Tooth losses, trauma, systemic factors, and/or edentulous arches in the long term may lead to alveolar bone resorption in width and height.⁴⁷  The alveolar crest presents an average of 3.8 mm of horizontal reduction 6 months after tooth extraction.⁴⁸  In cases with extensive resorption impairing implant placement, procedures for alveolar ridge augmentation may be necessary.⁴⁹  Autogenous bone is considered the gold standard for regenerative and reconstructive surgeries because of its biological properties for bioactivity, biocompatibility, osteogenesis, osteoconduction, and osteoinduction. However, it also presents disadvantages such as the limited quantity of available donor tissue and postoperative morbidity⁵⁰  and presenting up to 30% of complications, regardless of the selected donor site.⁵¹  Thus, there is great emphasis on the development of alternative techniques, such as the use of several bone substitutes, to reduce the discomfort to the patient and the chair time, morbidity, and consequently opening new possibilities to the treatment of atrophic maxillae with acceptable success rates.⁵² 

The meta-analysis showed similarity in the parameters of failures and complications between the bone grafts used (Figures 3 and 4). However, the ABG presented a favorable tendency with displacement of the diamond shown in Figure 3. The BS achieved a favorable tendency, with displacement of the diamond concerning the complications of grafts (Figure 4).

Spin-Neto et al¹³  reported that most grafter allogenous bone grafts (ALs) were remodeled and presented characteristics of vital bone. Conversely, some studies demonstrated that the allogeneic grafts are incorporated to the host more slowly than autogenous bone, and some authors reported that they induce an immunologic response that might delay the incorporation stage of the bone graft.⁵³  Other studies in the literature did not report an immunologic response when this type of graft was used in humans.^54,55  Utilization of the bloc graft of allogeneic frozen fresh bone increased in the last decades, especially because of the implementation of strict guidelines for donor selection and material processing, which nearly eliminated the risk of disease transmission.⁵⁶ 

Regarding the rates of implant success in the different types of grafts/bone substitutes for horizontal augmentation at the anterior maxilla, the reported success rates of implants with ABGs were 75% in the study of Astrand et al⁵⁷  and close to 95.9% in the study of Boronat et al⁵⁸ ; regarding the ALs, Nissan et al⁵⁹  achieved 98.8%. Furthermore, ALs^46,60  and xenogenic bovine bone (OX),⁴⁵  corroborating the present results, without identification of implant failures (Figure 5).

Regarding the gain in bone thickness, de Freitas et al⁴³  (one of the few RCTs evaluated with this indication) compared the effect of recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge [rhBMP-2/ACS] with ABGs for augmentation of the atrophic edentulous anterior maxilla and did not observe significant differences between treatments regarding the clinical evaluation observed at 6 months. The group treated with rhBMP-2/ACS presented significant augmentation in the radiographic evaluation of horizontal bone gain compared with ABGs at the subcrestal level, and no significant differences were observed in the middle and apical levels. The authors concluded that rhBMP-2/ACS is a promising option for this type of treatment. However, only this clinical study compared the use of rhBMP-2/ACS with ABGs in anterior atrophic maxillae; thus, comparison with other studies is not possible. Regarding the findings of other studies included in this review that used the AL graft, Kao et al,⁴⁶  Khojasteh et al,¹  Lumetti et al,⁴⁴  and Spin-Neto et al¹³  demonstrated that this bone substitute may be effective, constituting a reliable treatment option for extensive rehabilitation of anterior atrophic maxillae. Other studies demonstrated promising results for AL compared with ABGs^55,56  and when there is limited availability of intraoral autogenous graft.¹³  In the study of Lima et al,⁴⁵  the bloc OX graft was an adequate option for reconstruction of horizontal defects in the anterior maxilla with extensive resorptions, and there was no statistical difference in bone width immediately and 6 months after grafting. However, additional RCTs using bloc OX in patients with extensive anterior horizontal resorptions are needed to evaluate the effectiveness of this type of BS, especially because the anterior maxilla is subjected to considerable muscle forces from the lip, which may impair the stability and promote resorption of the grafted bone.

It should be highlighted that the 2 studies^43,45  presenting gains in clinical measurements at baseline and 6 months after grafting did not observe significant differences in gain in either group 6 months after grafting (Figure 6), and the initial evaluation (time 0) revealed significant difference in bone tissue thickness, indicating that the BS group presented smaller thickness (−0.89 mm) compared with the ABG group (Figure 7). The comparison between the initial period with 6 months after ABGs and the initial period with 6 months after BSs revealed a significant difference in bone gain values (Figure 8).

Thus far, few studies compared the use of bone substitutes/grafts for horizontal bone regeneration at the anterior atrophic maxilla. These studies used different materials in the experimental designs, with different shapes and sizes of particles configuring a limitation because each biomaterial can have distinct properties and different particle sizes. As for the bone graft, its shape (block or particle) may be an additional factor that should be considered in future studies. Further randomized controlled trials studies are necessary to evaluate the long-term effects of these treatments on the survival rate implants.

Within the limits of the present study, it may be concluded that BS and ABG seem to be a viable treatment option for patients with horizontal resorption at the anterior maxilla, yet the BS presented a favorable tendency concerning gain between the initial and final periods. However, there is a limited number of clinical studies evaluating the success of grafts with biomaterials, autogenous bone grafts, or a combination of both. RCTs are needed to elucidate the controversies about the best type of bone graft to be used and which type of graft provides a better survival rate of implants.

The authors acknowledge the following contributors: Mariella Peralta Mamani, Maria Giulia Rezende Pucciarelli, Miguel Augusto Riquelme Rodas, Izabel Regina Fischer Rubira-Bullen, Élcia Maria Varize Silveira, and Hélio Massaiochi Tanimoto.