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The International Journal of Periodontics & Restorative Dentistry

2011 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.NO PART OF MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.

Volume 32, Number 1, 2012

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The Negative Effect of Combining rhBMP-2 and Bio-Oss on Bone Formation for Maxillary Sinus Augmentation

Daniel W.K. Kao, DDS, MS, DMD*/Atsushi Kubota, DDS** Myron Nevins, DDS***/Joseph P. Fiorellini, DMD,DMSc****

Inadequate alveolar bone height is a common limitation in the place-ment of endosseous root-form den-tal implants in the posterior maxilla. Sinus floor elevation surgery has become a well-accepted prepros-thetic procedure for pneumatized sinus cavities in the posterior max-illa to increase bone height and allow the placement of a dental implant. The elevation of the sinus membrane for augmentation of the maxillary sinus was first presented by Tatum using autogenous bone from the iliac crest.1 However, har-vesting bone graft from a second surgical site may affect the length of the surgical procedure, postsurgi-cal morbidity, and patient comfort. Therefore, several bone replace-ment graft materials have been used in sinus elevation procedures, including allografts, xenografts, and alloplasts.28 Systemic re-views of sinus augmentations have shown that the implant survival rate was similar with xenograft when compared to autogenous bone graft.4,911 More recently, growth factors such as recombinant human bone morphogenetic protein 2

Sinus augmentation with various bone graft materials may be required in the posterior maxilla. This study compared bone formation in a lateral window sinus augmentation with recombinant human bone morphogenetic protein 2/acellular collagen sponge (rhBMP-2/ACS) combined with Bio-Oss or Bio-Oss graft alone. Patients were assigned to treatment with either rhBMP-2/ACS + Bio-Oss or Bio-Oss alone. After a healing period, bone cores were harvested. Histologic specimens demonstrated that new bone formation was less in those who received rhBMP-2/ACS + Bio-Oss than those with Bio-Oss alone. This study indicated that the addition of rhBMP-2/ACS to Bio-Oss has a negative effect on bone formation. (Int J Periodontics Restorative Dent 2012;32:6167.)

* Director of Predoctoral Periodontics, Department of Periodontics, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania.

** Private Practice, Matsuyama, Japan. *** Clinical Professor, Department of Periodontics, University of Pennsylvania School of

Dental Medicine, Philadelphia, Pennsylvania.**** Professor and Chair, Department of Periodontics, University of Pennsylvania School of

Dental Medicine, Philadelphia, Pennsylvania. Correspondence to: Dr Daniel W.K. Kao, University of Pennsylvania School of Dental Medicine, Room F-20, Evans Building, 240 S. 40th Street, Philadelphia, PA 19104; fax: 215-573-3939; email: [email protected].



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(rhBMP-2) and recombinant hu-man platelet-derived growth fac-tor BB (rhPDGF-BB) have been used in sinus augmentation.1215 rhBMP-2 is a tissue-engineering material and family member of transforming growth factor that stimulates endochondral and in-tramembranous bone formation from mesenchymal cells in situ. rhBMP-2 has been shown to initi-ate differentiation of mesenchymal cells into osteoblasts and bone for-mation in ectopic tissues.16 Several animal and human studies have shown rapid new bone formation by using rhBMP-2 and an absorb-able collagen sponge (ACS).14,1720 Recently, practitioners have used particulate bone graft material to increase the volume and rigid-ity of the rhBMP-2/ACS construct.

The aim of this human investi-gation was to evaluate histologic bone formation when comparing rhBMP-2/ACS (Infuse, Medtronic) combined with bovine bone xeno-graft (Bio-Oss, Geistlich) to Bio-Oss alone for sinus elevation proce-dures.

Method and materials

This investigation was approved by the institutional review board of the University of Pennsylvania. Twenty-two subjects 18 years of age or older with inadequate maxillary alveolar ridge height and in need of lateral window sinus augmenta-tion were eligible. Inclusion criteria included the presence of less than 5 mm of residual bone height, as

measured on radiographs. There were no contraindications for si-nus surgery. After clinical examina-tion with panoramic radiographs or cone beam computed tomography (CT) scans had indicated insuffi-cient residual bone height, patients who fulfilled the criteria provided informed consent for the proce-dures. The lateral window surgical approach used has been described previously21 (Figs 1a to 1f). Subjects were randomized into two groups based on the bone graft materials used: rhBMP-2/ACS mixed with Bio-Oss in an 80/20 ratio or Bio-Oss alone.

Histologic procedure and histomorphometry

Bone cores were harvested in the axial direction into the lateral si-nus elevation area. Samples were fixed in formalin and processed for ground sectioning. The samples were stained with toluidine blue and used for light microscopic ex-amination. The specimens were measured using a Leitz DM-RBE microscope (Leica) equipped with an imaging system (Q-500 MC, Leica). The proportions of Bio-Oss, lamellar bone, bone marrow, and connective tissue were determined using the mouth cursor to out-line the respective areas (25 and 100 magnification). The cores were then used to determine the vital bone content, connective tis-sue (bone marrow space) content, and residual graft material content of each sample.



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Statistical analysis

Demographic data were collected and summarized. Paired t tests were used to evaluate the percent-age of new bone, residual graft ma-terials, and bone marrow space.

Results

Twenty-two subjects (13 men, 9 women; age range, 34 to 67 years; mean age, 50.8 years) were enrolled

in the study. Group 1 consisted of 11 patents treated with rhBMP-2/ACS + Bio-Oss (7 men, 4 women; age range, 36 to 67 years; mean age, 51.09 years). Group 2 consist-ed of 11 patients treated with Bio-Oss alone (6 men, 5 women; age range, 34 to 62 years; mean age, 50.45 years).

The healing period progressed without any complications in both treatment groups. All implants achieved primary stability after 6 to 9 months of healing. Ten of 11 bone

samples (1 bone core could not be processed) from group 1 (BMP-2/ACS + Bio-Oss) and 10 of 11 bone samples (1 bone core could not be processed) from group 2 (Bio-Oss alone) were evaluated.

Bone biopsies were evaluated for the percentage of new bone, residual Bio-Oss material, and bone marrow/connective tissue. Upon histologic examination, it was shown that all graft sites with rhBMP-2/ACS + Bio-Oss and Bio-Oss alone healed uneventfully, with no signs

Fig 1 Lateral window surgical approach. (a) Baseline CT scan; (b) lateral window osteotomy; (c) sinus membrane elevation; (d) rhBMP-2/ACS combined with Bio-Oss; (e) graft materials placed into the sinus cavity; (f) 6-month postoperative CT scan.

a

d

b

e

c

f



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of inflammation (Figs 2a and 2b). In the histologic sections, relatively fewer remaining Bio-Oss particles were found in the rhBMP-2/ACS + Bio-Oss group than in the Bio-Oss alone group. Newly formed miner-alized bone consisted of a mixed type of bone that included woven bone and matured bone structure. Bio-Oss showed a very regular ar-rangement of lamellae and empty lacunae. Signs of bone deposition, such as osteoids lined with a con-tinuous layer of osteoblasts, were identified in close contact to the Bio-Oss particles. Histologic speci-mens demonstrated that new bone formation adjacent to Bio-Oss par-ticles and the percentages of new-

ly formed bone in the rhBMP-2/ACS + Bio-Oss group and Bio-Oss alone group were 16.04% 7.45% and 24.85% 5.82%, respective-ly. The percentages of remaining Bio-Oss particulate in the rhBMP-2/ACS + Bio-Oss group and Bio-Oss alone group were 15.70% 4.97% and 39.70% 7.27%, respectively. The percentages of bone mar-row space in the rhBMP-2/ACS + Bio-Oss group and Bio-Oss alone group were 68.26% 7.47% and 35.45% 4.91%, respectively. The new bone formation, residual Bio-Oss particulate, and bone marrow present were all statistically signifi-cantly different between the treat-ment groups (Table 1).

Discussion

Numerous bone graft materials are currently being used for maxillary si-nus floor augmentation with success. Traditionally, particulate bone grafts have been the standard of care. The utility of these materials has been generally measured by the success or survival of implants placed in grafted sinuses. Systematic reviews of implant survival in augmented sinuses indicate no significant dif-ferences between graft types.9,22 A commonly used sinus graft material is Bio-Oss. Preclinical and clinical in-vestigations indicate that Bio-Oss can predictably assist in bone for-mation with sinus augmentation.

Fig 2 Histologic images of bone cores from (a) the rhBMP-2/ACS + Bio-Oss in an 80/20 ratio group and (b) the Bio-Oss alone group.

a b



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In a systemic review, Jensen et al23 found no difference in implant treat-ment with Bio-Oss alone compared to Bio-Oss combined with autograft. The mean implant survival was 96% with Bio-Oss alone and 94% with a combination graft.

Recently, rhBMP-2/ACS has been used for the regeneration of bone in the maxillary sinus. In a preclinical study in rabbits, Wada et al24 compared rhBMP-2/ACS to particulate cancellous bone and marrow. The results suggest that the sinus augmentation produced similar volumes of bone. Nevins et al,18 in a goat sinus augmentation model, found that rhBMP-2/ACS was able to induce bone formation

as compared to the control ACS alone. Gutwald et al25 compared rhBMP-2 on a poly-d, l-lactic-co-glycolic acid gelatin (PLPG) scaffold with autologous pelvic cancellous bone in a sheep model. The study found that bone density and bone-to-implant contact were higher in the test group compared with the control.25

The application of a genetically engineered product (rhBMP-2) has shown the potential to accelerate the regenerative process and de-crease morbidity.14,26,27 In clinical sinus augmentation studies, the safety of rhBMP-2 at regenerative doses was assessed.14 rhBMP-2 was used with ACS at concentrations of

0.75 mg/mL or 1.50 mg/mL or with conventional bone graft. Alveolar ridge height, width, and density were measured on CT scans taken prior to treatment, 4 months after treatment, and 6 months follow-ing implant loading. Alveolar ridge height at 4 months was similar in all three groups (approximately 10 mm). The use of rhBMP-2/ACS was safe in terms of causing any side ef-fects or harm to patients. In a pivotal study, 160 patients were random-ized to either 1.50 mg/mL rhBMP-2/ACS or autograft.12 Efficacy criteria included bone height and density. The results of the multicenter study demonstrated that the induced bone density was greater in the

Table 1 Histomorphometric results of core samples taken from sinuses augmented with rhBMP-2/ACS + Bio-Oss in an 80/20 ratio and Bio-Oss alone

rhBMP-2/ACS + Bio-Oss Bio-Oss alone

Mean SD Range Mean SD Range P*

New bone (%) 16.04 7.45 3.8028.90 24.85 5.82 12.7031.88 .0014

Residual Bio-Oss (%) 15.70 4.97 8.2022.18 39.70 7.27 28.7052.70 .0001

Bone marrow (%) 68.26 7.47 59.9082.80 35.45 4.91 29.2845.14 .0001

SD = standard deviation.*Paired t test.



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rhBMP-2/ACS group than the con-trol group (autograft alone). Bone height in autograft-treated patients was slightly greater than that in rh-BMP-2 sinuses, but not significantly.

The advantages of using rh-BMP-2/ACS for sinus augmentation include de novo bone formation, ease of use, and no limit in quanti-ty. Disadvantages include cost and lack of rigidity to maintain volume. These deficiencies have led practi-tioners to bulk rhBMP-2/ACS with particulate bone graft materials. The addition of a material such as Bio-Oss extends the volume and in-creases the stability/ability to main-tain space. In the present study, the effect of bulking rhBMP-2/ACS with Bio-Oss was evaluated. The results indicate that the combination of Bio-Oss and rhBMP-2/ACS had a negative effect on bone formation. The histologic evaluation of the combined treatment has not been published previously; however, sev-eral investigations have document-ed bone formation with Bio-Oss alone.28 These clinical evaluations have demonstrated a range of per-cent new bone, bone marrow, and remnant particulate material. The percentages found in the present investigation are within that range. Specifically, the new bone forma-tion of 24.85% 5.82% was similar to that found in previous studies. The percent bone marrow and rem-nant graft may be related to par-ticulate size.

The reduction in bone forma-tion of the combination graft could be related to rhBMP-2 enhance-ment of osteoclast differentiation.

Jensen et al28 found that osteo-clasts express BMP-2 receptors. In another study, Tachi et al29 found that maximum osteoclast formation was found when BMP-2 was pres-ent in cell cultures. It was conclud-ed that BMP-2 enhances osteoclast formation by the up-regulation of receptor activator of nuclear factor kappa-B ligand (RANKL).

Conclusion

The combination of rhBMP-2/ACS and Bio-Oss produces significantly less new bone formation than Bio-Oss alone. These results indicate that the clinician should consider the use of these materials in a sin-gular manner to optimize bone re-generation in the maxillary sinus.

References

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