Introduction

Dental implants have been used successfully for the replacement of tooth loss, however, adequate bone dimension is critical to successful placement of implants and their long-term maintenance in patients with severe atrophy of the jaws [1]. In cases of local bone deficiency, a variety of techniques and materials have been used for the reconstruction of bone defects in the maxillofacial area. Traditionally, autologous, allogeneic and xenogeneic bone grafts have been used for this purpose [2].

Current reconstructive strategies include alveolar distraction osteogenesis, bone block grafts and guided bone regeneration (GBR). These techniques have their advantages and disadvantages, including the need for a surgical wound in the donor site and its associated morbidity [3]. Autograft is considered the “gold standard” for its osteoconductive, osteoinductive and osteogenic characteristics. Moreover, according to the literature, the majority of bone substitutes have almost exclusively osteoconductive characteristics [4].

Recombinant human BMP-2 (rhBMP-2) and 7 have been reported as having potential use as bone substitutes in animal models [5]. BMPs stimulate angiogenesis as well as migration, proliferation and differentiation of mesenchymal stem cells into a phenotype of forming bone and cartilage cells [6].

Although rhBMP-2 alone is capable of promoting osteoinduction, a carrier is needed for adequate bone formation. Tipe I Collagen matrices are considered good carriers for growth factors due to the rheological properties, biocompatibility and absorbable nature6. In 2007, the association of rhBMP-2/absorbable collagen sponge (ACS) (INFUSE BONE GRAFT®, Medtronic, Memphis, Tennessee, USA) was approved by the Food and Drug Administration (FDA) as a substitute to autogenous bone for maxillary sinus floor graft and localized regeneration of the alveolar ridge for defects associated with post-extraction sockets [7].

The use of rhBMP-2 out of the indications approved by the FDA is considered “off label” [4]. Off label uses of rhBMP-2 includes cleft palate repair [8], reconstruction of severe atrophy of the jaws [9], segmental defects after tumor resection, treatment of osteonecrosis by bisphosphonates and osteoradionecrosis [1, 10] and total reconstruction of severely atrophic maxilla [11].

Although rhBMP-2 proved to be a promising osteoinductive material as a substitute for autogenous bone graft, questions were raised about the safety of using these growth factors. Carragee et al. [12] conducted a systematic review in which they evaluated controlled clinical trials that reported the complications and side effects of rhBMP-2 used in spinal surgery, finding an incidence of 10–50%, which included excessive bone growth, retrograde ejaculation and intense cervical edema with life-threatening airway obstruction. Moreover, the authors claim that high doses of rhBMP-2 may be associated with risk of developing malignant tumors. Woo [13], conducted a survey of adverse effects reported by the FDA in patients who received rhBMP-2 in the maxillofacial region, finding 83 reports of adverse effects, 66.3% of these in “off label” use of the material. In this paper, the authors performed a systematic review of the literature regarding the use of rhBMP-2 to reconstruct alveolar bone prior to the placement of dental implants.

Materials and Methods

Search Strategy

The MEDLINE (PUBMED) database was searched from 1980 through May 2015 for clinical studies evaluating the use of rhBMP-2 for alveolar ridge and maxillary sinus augmentation for implant placement. The search strategy included a combination of the following MeSH terms: “bone morphogenetic protein,” “rhBMP-2,” “alveolar ridge augmentation,” “bone regeneration”, “maxillary sinus augmentation” and “dental implants”. Cochrane Central Register of Controlled Trials, EMBASE, SciELO, and LILACS were also searched using similar strategy. Hand searching of the main journals in the field of dental implants and oral and maxillofacial surgery completed the search.

Inclusion Criteria

The search was limited to human studies and the following study types: clinical trials, controlled clinical trials, randomized controlled trial (RCT), case reports, clinical trial phase I, II, III, and IV. Only studies published in English were considered. Hand searching of the main journals in the field of dental implants and oral and maxillofacial surgery completed the search.

Exclusion Criteria

Studies in animals, reviews, and systematic reviews of literature. Articles that did not present data relevant to the aim of this study were excluded.

Selection of the Studies

Three reviewers (SBFQ, JQF and VNL) independently assessed the titles and abstracts of all the results identified in electronic databases, verified agreement in the pre-selection of articles, and when there was disagreement, proceeded to the joint reading of the full text of the article to the final selection. Studies that met the criteria for inclusion were obtained. From this search, a collection of studies to be evaluated by the reviewers was created.

Outcomes Evaluated

The primary outcomes evaluated was success rate of rhBMP-2 as a grafting material in reconstruction of alveolar ridge, dental alveolus preservation and inlay maxillary sinus grafts prior to the placement of dental implants. Secondary outcomes were: adverse effects and complications, region of the graft, association or not with other grafting materials, quantity and quality of the newly formed bone, clinical and radiographic follow up, success of implants and implant supported prosthesis in the areas grafted with rhBMP-2.

Data Collection and Analysis

The reviews were not masked regarding the authors or the results of the studies. Data were extracted independently by three reviewers (SBFQ, JQF and VNL) and crossed to verify the agreements and disagreements. Discordant results were resolved by consensus. Data related to the objectives, materials and methods, results and conclusions were extracted and tabulated. The evaluation of these items provided a new set of data for the present study. The results are presented through tables. Due to the heterogeneity of the data collected it was not possible to make a meta-analysis of the results.

Results

Results Regarding the Search of the Articles

The initial search in PUBMED returned 1310 publications related to rhBMP-2. No studies of alternative search strategies were added to this list, since the other research data bases returned the same results found in PUBMED. After detailed screening it was possible to select 11 studies that met the inclusion criteria of this systematic review. Two of the studies were eliminated because they were sub-analyzes of other already included in the review.

Number of Patients Evaluated and Clinical Applications of rhBMP-2 (Table 1)

The nine clinical studies involved a total of 527 patients of which 282 received rhBMP-2. The other 256 patients formed the control groups in which were used autogenous, allogenic or xenogeneic bone grafts or ACS without rhBMP-2. Regarding clinical applications, five of the selected studies showed applications considered “in label” [14–18] and four of the papers used the rhBMP-2 in off label applications [19–21].

Table 1 Studies included in the systematic review
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Implant Placement in Areas of Regenerated Bone with rhBMP-2 (Table 2)

A total of 635 implants were placed in 282 patients who received rhBMP-2 associated or not with other grafts materials. The minimum follow-up time was 4 months 15 and the maximum was 5 years and 10 months [17]. The minimum time between the reconstruction and the placement of the implants was 4 months [14], and the maximum 11.5 months [16], with an average time of 6.6 months. Regarding the successful treatment with rhBMP-2 (Table 3), we can separate this data in three different analysis: the success of bone reconstruction, i.e., the number of patients that was possible to place implants without the need for additional bone graft, being 193 of the 237 patients who received rhBMP-2 graft (81.45%); the success rate of the implants placed in the bone regenerated with rhBMP-2 was 87.4% (472 of 540 implants placed), and the success rate of prosthesis with functional load on the implants placed in regenerated areas with rhBMP-2 was 83.6% (128 of 153 patients).

Table 2 Number of patients, implants, follow up and average time until placement of implants in the cases treated with rhBMP-2
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Table 3 Success rates of reconstruction, implants placed and implant supported prosthesis in reconstructed areas with rhBMP-2
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Histological Analysis of Newly Formed Bone (Table 4)

In six of the nine studies included in the review core biopsies were obtained at the time of implant placement [14–17, 19, 21]. Histologically all samples showed bone formation, especially of exuberant trabecular bone, predominantly poorly organized primary bone, lamellar bone in low to moderate amounts, few to moderate osteoblasts and few to absent osteoclasts. The inflammatory infiltrate was scarce, as well as vascular proliferation. In none of the evaluated specimens were found residual bovine type I collagen.

Table 4 Data from studies that performed histological analysis of newly formed bone by rhBMP-2
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Amount of New Bone Formed (Table 5)

The amount of newly formed bone was evaluated by eight of the nine studies included in this systematic review [13–20, 22]. The average vertical bone formation was 8.01 mm and horizontal bone formation was about 4 mm. Regarding bone quality, few studies evaluated this variable [16, 19]. The evaluation methods were not clear and very heterogeneous, not allowing for a precise conclusion abut the results. In general the newly formed bone has been reported as soft during drilling for implant placement, being predominantly type II/III/IV according to Branemark classification [16].

Table 5 Average amount of bone formed in height and width in reconstructions with rhBMP-2
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Safety in the Use of rhBMP-2 (Table 6)

Safety using rhBMP-2 + ACS was assessed in the papers by Cochran et al. [14], Fiorellini et al. [15], Boyne et al. [16] and Triplett et al. [17]. This assessment was made by clinical and radiographic follow-up, signs and symptoms of local and systemic alterations (pain, swelling, erythema, infection, etc.), hematological and immunological tests to verify if the patients developed antibodies to any of the rhBMP-2 + ACS association components. Most of the adverse reactions were local and transitory, such as exacerbated edema and erythema. No studies identified antibodies to rhBMP-2, but some patients had antibodies to bovine collagen, however this response was transient and the antibodies were not detected after 2 months. One study [21] evaluated the postoperative edema in patients who received a combination of rhBMP-2 + PRP + allogeneic bone compared to patients who received only autologous graft in the reconstruction of extremely atrophic maxilla, finding statistically significant difference in favor of group using rhBMP-2 in the periods of 3, 8 and 15 days (p = 0.01).

Table 6 Data from studies reporting adverse effects and complications in reconstructions with rhBMP-2
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Discussion

In this systematic review we observed that much of the literature about the use of rhBMP-2 in implant dentistry lacks of appropriate methodology, and the studies presented very small sample sizes. It was possible to select only nine studies that met the inclusion criteria of this review [13–22]. Most of the articles in the initial search were case reports or case series with small sample size, experimental in vitro or animal studies, and studies in areas other than dentistry. This proves that most of the articles published on the subject do not have the criteria to be classified as good scientific information, i.e., controlled and randomized clinical trials with adequate sample and strict evaluation criteria. Therefore, more well-designed randomized controlled clinical trials are needed to give a better basis for clinical use of rhBMP-2 in implant dentistry.

There is much debate regarding the use of “off label” of rhBMP-2. Some studies show a higher incidence of complications with off-label use of Infuse Bone Graft for orthopedic and neurosurgical applications [12]. According to Misch et al. [22], the off-label use is not forbidden, but the patient should be fully informed about the risks and benefits of the technique and must sign an informed consent authorizing the use in the particular case. In four of the studies included in the review, the rhBMP-2 was used off label [19–22]. The success rates, adverse effects were similar to those reported with the use in label of rhBMP-2.

The studies included in this systematic review showed high rates of success in bone regeneration prior to implant placement. The average gain was 8.01 mm height ranging from 4.3318 and 10.4 mm [14]. In width, the average gain was 3.99 mm, ranging from 216 to 6.59 mm [18]. The success rate of osseointegration of implants placed in regenerated bone with rhBMP-2 (87.4%) and implant-supported prostheses submitted to masticatory load (83.65%) can be considered comparable to autogenous bone, with the advantage of not requiring a second surgical site to obtain it, and superior to xenogeneic and allogeneic grafts, due to its osteoinductive capacity, since the first two are only osteoconductive.

Few studies have specifically evaluated the side effects and complications associated with the use of rhBMP-2. As a growth factor with high chemotactic potential to inflammatory cells, it is expected that rhBMP-2 cause large leakage of fluids into the extravascular space, increasing the capillary permeability and local blood flow, which explains the exuberant edema and erythema present in patients who use rhBMP-2 [12, 13, 21, 22]. In fact, while all reviewed studies emphasize that the edema has no major consequence for the patient, there are reports of life threatening airway obstruction due to excessive soft tissue edema in the cervical spinal fusion surgery [12, 13]. Other serious adverse reactions reported in the orthopedic literature include ectopic calcification, excessive bone formation and increased incidence of cancer in patients grafted with rhBMP-2 [12], however, these severe side effects and complications have never been reported with the use of rhBMP-2 in dentistry.

In conclusion, clinical studies included in this systematic review of the literature showed that rhBMP-2 can be a good alternative to autogenous bone, promoting bone regeneration in height and width suitable to receive dental implants and implant-supported prosthesis with good stability at least 5 years.