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Clinical Science and Techniques

Effect of rhBMP-2 Upon Maxillary Sinus Augmentation: A Comprehensive Review

Torrecillas-Martinez, Laura DDS*; Monje, Alberto DDS; Pikos, Michael A. DDS; Ortega-Oller, Inmaculada DDS*; Suarez, Fernando DDS; Galindo-Moreno, Pablo DDS, PhD§; Wang, Hom-Lay DDS, MS, PhD‖,¶

Author Information
doi: 10.1097/ID.0b013e31829262a8
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Abstract

The edentulous posterior maxilla often presents a challenge for implant treatment due to the location of the maxillary sinus and its pneumatization caused by tooth loss1 and aging.2 To overcome these drawbacks, the introduction of various regenerative techniques, such as vertical bone augmentation, distraction osteogenesis, and sinus augmentation, have all been proposed in an attempt to provide adequate width and height for appropriate implant placement. However, despite of all the options available, sinus augmentation still represents the most predictable technique.3

Sinus augmentation is achieved with the elevation of the Schneiderian membrane and consequent insertion of a grafting material to increase the alveolar bone height. This approach was first described by Boyne and James4 and later on modified by Tatum5 using autogenous bone from the iliac crest to properly place endosseous implants in the posterior maxilla. Subsequently, Summers6 developed a new technique in an attempt to propose a more conservative crestal approach using osteotomes. Other modifications of this technique have been proposed throughout the years, making it a predictable technique with low incidence of complications and high success rates.3

Various grafting materials have been developed and used for this technique. Autogenous bone, however, is still considered the “gold standard” because of its osteogenic, osteoinductive, and osteoconductive capacity.7,8 However, the necessity of a second surgical site, limited availability, and morbidity of the donor site have limited its application.9 Other grafting materials that have been widely used include allogeneic bone graft, with osteoconductive capacity and possible osteoinductive potential,10,11 and xenogeneic grafts12,13 and alloplastic grafting materials,14 both with osteoconductive potential. All of these materials are acceptable to be used as grafting materials in the maxillary sinus augmentation procedure; however, material selection is ultimately dependent on patient-based necessities and overall patient-operator agreement.3

Growth factors and bone morphogenetic proteins (BMP) are currently being studied to replace bone graft materials and are considered a valid alternative option for maxillary sinus augmentation. In 1965, Urist15 demonstrated that BMP extracted from bone could induce bone and cartilage formation when implanted in animal tissue. The application of BMP, a protein belonging to transforming growth factor-β family,16 has been broadly studied for bone regeneration.17–19 Within this family of proteins, BMP-2 has been the most studied and has been shown to have osteoinductive property and to promote de novo bone formation.17 This protein is capable of initiating, stimulating, and amplifying the normal bone formation cascade.9 In addition, this protein also induces chemotaxis,16 cell proliferation, and cell differentiation.18

Nowadays, BMP-2 is commercially available as INFUSE bone graft (Medtronic, Inc., Minneapolis, MN), and it is distributed as rhBMP-2 at a concentration of 1.5 mg/mL delivered on an absorbable collagen sponge (ACS). In 2002, rhBMP-2 (INFUSE bone graft) was approved by the US Food and Drug Administration (FDA) as an alternative for autogenous bone graft in spine surgery.20 In 2007, the FDA approved the use of rhBMP-2 as an alternative for autogenous bone grafting in alveolar ridge augmentation for defects associated with extraction sockets and for sinus augmentation.20 Since then, clinical studies have supported both indications illustrating that rhBMP-2 induces suitable bone formation for implant placement and subsequent osseointegration.21 Additionally, it seems that the newly formed bone has similar properties as native bone, and thus, it is able to withstand the occlusal forces of dental prostheses.22

Henceforth, the present review aimed to clarify the current status of rhBMP-2 as a grafting material for sinus augmentation procedure published in both human and animal trials.

Materials and Methods

Search Strategy

An electronic literature search for relevant articles published in English was conducted in the PubMed database from February 1996 to August 2012. The key words used in the search included “bone morphogenetic protein,” “rhBMP-2,” “sinus lift,” and “sinus augmentation.” Boolean operators, “OR” and “AND”, were used to combine the literature searches. Randomized clinical trials (RCTs) or prospective human clinical trials with a minimum of 10 subjects enrolled, and animal trials were included with the clear aim to compare and evaluate the effectiveness of rhBMP-2 with other grafting materials for sinus augmentation. All the studies were pooled in 2 tables according to the model used. Case reports, case series, literature reviews, and studies that did not provide enough or clear data were also excluded. The first search came up with 43 titles of potential publications. After a thorough review of titles and abstracts, only 7 potential relevant articles fulfilled the inclusive criteria for full-text review (Fig. 1).

Fig. 1
Fig. 1:
Flow chart that outlines the screening process of the published human clinical trials and animal studies that fulfilled the inclusion criteria established for the study.

Results

A total of 3 human clinical trials22–24 (Table 1) and 4 animal trials21,25–27 (Table 2) fulfilled the inclusion criteria.

Table 1
Table 1:
Summary of the Data Extracted from the Human Clinical Trials Included in the Systematic Review to Figure Out theIn Vivo Effect of the Different Factors Influencing the Use of rhBMP-2 for Sinus Augmentation
Table 2
Table 2:
Summary of the Data Extracted from the Animal Studies Included in the Systematic Review to Figure Out theIn Vitro Effect of the Different Factors Influencing the Use of rhBMP-2 for Sinus Augmentation in Various Animal Models

Human Clinical Trials

The selected studies indicated that rhBMP-2 was associated with regular bone formation. When autogenous bone grafts are compared with rhBMP-2 grafts in humans, despite of the higher levels of initial bone gain and density associated with autogenous bone, histological analysis reveal higher cell activity, osteoid lines, and vascular richness in sinus grafted only with BMP-2, showing no differences between new bone and native bone. In addition, when rhBMP-2 is used, bone formation seems to be faster. On the contrary, when rhBMP-2 is mixed with anorganic bovine bone (Bio-Oss; Geistlich Pharma AG, Wolhusen, Switzerland),24 results were totally different, demonstrating less bone formation. In addition, safety of rhBMP-2 has been demonstrated with no immune response reported.

Animal Model Trials

Animal studies showed comparable results when sinuses are grafted with rhBMP-2 or autogenous bone (mainly from iliac crest). The new bone formation seems to be more regular and faster in the formation for sinuses treated with rhBMP-2. In addition, this formation is followed by regular bone maturation. Higher levels of vertical bone gain as well as higher bone density were associated with rhBMP-2 grafted sinuses when compared with the use of autogenous bone graft. New bone formation in sinuses grafted with rhBMP-2 is continuous and has similar characteristics to pristine bone. Furthermore, it shows more osteoblastic and osteoclastic activity, suggesting a continuous bone remodeling process.

Discussion

Human Clinical Trials

In 1997, Boyne et al28 performed the first human study to assess the behavior of rhBMP-2/ACS as grafting material for sinus lifting. Eight of 12 patients (73%) obtained adequate bone to facilitate ideal 3-dimensional implant placement, reaching a mean bone gain of 8.51 mm. These results might be due to the lack of slow-resorption biomaterial. Subsequently, the same group22 designed the first RCT to compare different doses of rhBMP-2 (0.75 and 1.5 mg/mL) with autogenous graft alone or a mixture of autograft and allograft (control group). It was shown that there was no difference in height gain demonstrated among the groups (11.29, 9.47 and 10.16 mm, respectively, for rhBMP-2/ACS 0.75 mm/mL, rhBMP-2/ACS 1.5 mg/mL, and the control group). However, the rhBMP-2 combined group had better results in width and bone density than the control group. Triplett et al23 obtained similar results with no significant differences in bone height when compared 1.5 mg/mL of rhBMP-2/ACS with a control group based on autogenous bone graft or a mixture of autograft and allograft. Nonetheless, more newly induced bone density was obtained in the control group 6 months after the surgery. However, after 12 months, the test group had denser bone then the non-BMP–treated control group. It is interesting to note that there is a trend of rhBMP-2–treated sites to achieve similar native bone density. Despite the good results in terms of osteoinduction obtained thus far, a study by Kao et al24 showed a statistically lower volume of newly formed bone when blended with bovine-derived hydroxyapatite bone graft (eg, Bio-Oss, Geistlich Pharma AG). These results might be due to the enhancement of osteoclast differentiation by the regulation of receptor activator of nuclear factor kappa-B ligand (RANKL).29 Hence, the incorporation of rhBMP-2 with bovine-derived hydroxyapatite bone graft material should be performed with caution. More studies are needed to thoroughly study the effect of rhBMP-2 in bovine-derived bone graft materials.

Histological findings suggest that depending on the stage of osseous regeneration, different patterns of healing were seen. As shown by Boyne et al,22 11 months after the grafting surgery, no differences were observed between the group with BMP-2 and the control group. However, it has been demonstrated that sinuses grafted with rhBMP-2/ACS had rich and vascular marrow spaces with moderate amounts of osteoblasts and osteoclasts in smaller proportions. In addition, fibrous tissue was found in 16% of bone graft samples. Furthermore, no immune response for rhBMP-2 was observed in any of the studies included.

Animal Model Trials

Nevins et al21 were the first group to study the behavior of rhBMP-2 as grafting material for sinus augmentation in the animal model (goats). Both sinuses were grafted with either rhBMP-2/ACS (test group) or ACS/buffer (control group). After 12 weeks, CT scans demonstrated higher radiopacity for the test group. Similar findings were also showed by Hanisch et al25 in a CT study assessing rhBMP-2 in nonhuman primates. The study showed that vertical bone gain was greater when rhBMP-2 was used (6.0 ± 0.3 vs 2.6 ± 0.3 mm in the control group). In addition, no significant differences in bone density between the groups were observed. This was in agreement with the study performed by Wada et al26 in the rabbit model. In this study, right sinuses were grafted with particulate cancellous bone and marrow (PCBM) obtained from the rabbit iliac crest, whereas left sinuses were grafted with only rhBMP-2/ACS. Higher bone formation was observed in sinuses that were treated with rhBMP-2/ACS (22.4 ± 4.4 mm), although no statistical difference was noted in both the treatment groups. Hence, it was concluded that both rhBMP-2 and PCBM graft induced comparable bone formation in rabbit sinuses. Recently, another study performed in the mini-pig model27 showed higher bone height (9.3 ± 0.5 and 8.6 ± 0.7 mm, respectively) and density (51.9 ± 3 and 32.9 ± 2.5 mm, respectively) for sinuses grafted with rhBMP-2/ACS than those grafted with PCBM graft.

Histological analyses were performed in all the animal studies included in this review. Nevins et al21 concluded in their study that bone formation was faster when BMP-2 was used, and it was followed by normal bone maturation. Their biopsies showed the presence of osteoblasts and osteoclasts indicating bone forming activity and a slow remodeling process. Subsequently, Hanisch et al25 demonstrated that the newly formed bone in nonhuman primates sinuses grafted with rhBMP-2 was histologically indistinguishable from native bone. Alike, Wada et al26 showed histological and histomorphometric characteristic of rhBMP-2 similar to the ones obtained by grafting with autogenous bone graft. Additionally, equal bone formation was observed between both grafting materials used. Moreover, Lee et al27 also observed more regular bone formation, new bone continued with native bone, and favorable bone to implant contact along the entire implant body when rhBMP-2 graft was used. However, autogenous bone graft did not enhance significantly local bone formation.

Conclusions

Human recombinant BMP-2 shows an excellent capacity to induce adequate bone quality formation in the sinus augmentation procedure. Furthermore, it induces bone formation with similar characteristics to native bone and bone induced by autogenous bone. Therefore, rhBMP-2 can be considered an equivalent graft material as autogenous bone for sinus graft procedures. Nonetheless, the behavior of rhBMP-2 seems to be worsened when it is associated with bovine organic osseous matrix graft or Bio-Oss. Additional RCT and long-term results in the human model are required to validate the use of rhBMP-2 as a grafting material for sinus grafts.

Disclosure

The authors claim to have no financial interest, either directly or indirectly, in the products or information listed in the article.

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Keywords:

grafting; bone; augment bone graft; sinus floor augmentation; human recombinant bone morphogenetic protein 2

© 2013 by Lippincott Williams & Wilkins, Inc.