Coll. Antropol. 38 (2014) 1: 325–330

Case Report

Use of Recombinant Human Bone Morphogenetic

Protein (rhBMP2) in Bilateral Alveolar Ridge

Augmentation: Case Report

Davor Katanec1, Marko Granić1, Dragana Gabrić Pandurić1, Martina Majstorović2

and Zdenko Trampuš3

1University of Zagreb, School of Dental Medicine, Department for Oral Surgery, Zagreb, Croatia

2University of Zagreb, School of Dental Medicine, Department of Pediatric and Preventive Dentistry, Zagreb, Croatia

3Private Dental Clinic, Zagreb, Croatia

A B S T R A C T

In recent years, the delivery of osteoinductive factors such as bone morphogenic proteins (BMPs) has become an alter- native approach to traditional bone grafting due to their capacity to produce bone healing and new bone formation. BMP-2 has proved to possess the highest osteoinductive potential among BMPs. The case reported the clinical use of recombinant human BMP-2 for bilateral vertical alveolar ridge augmentation. In a case of 61 year-old patient with a significant bilateral vertical bony deficiency of the mandible, rhBMP-2 administered via an absorbable collagen sponge carrier (ACS) was used for bilateral alveolar ridge bone induction. Augmented sites were covered and fixed with tita- nium mesh. Augmented sites were reopened 6 months after surgery. Titanium membrane and retaining screws were removed and three dental implants were placed. The tissue samples for the histologic analysis were harvested. Following 3 months healing period, the submerged implants were uncovered and restored with zirconium-ceramic crowns. Cone beam computed tomography (CBCT), panoramix and 3D radiographic evaluation were obtained prior to and after the surgical procedure. Vertical gain of the bone was 5.5 mm on the left and 5 mm on the right side, with 6 mm width of the bone. Histologic analysis revealed formation of mature trabecular bone with signs of osteoblastic proliferation. Implant stability quotient (ISQ) values were in the range between 69 and 75 for all three implants. No suppuration, gingival recession or pain were present 24 months after surgery. Vertical bone augmentation using rhBMP-2 is optional treatment modality to consider when planning dental implant placement in sites where severe vertical insufficiency exists.

Key words: rhBMP-2, collagen sponge carrier, vertical alveolar ridge augmentation, implant placement

Introduction

Use of autogenous block grafts has long been accepted as the gold standard for reconstruction of deficient alveo- lar ridge dimension. However, its numerous risks, such as pain, infection, and morbidity, combined with a limi- ted quantity of available donor site tissue have led many to employ alternative regenerative materials including allografts, xenografts or synthetic materials. In recent years, the delivery of osteoinductive factors such as bone morphogenic proteins (BMPs) have become an alterna- tive approach to traditional bone grafting due to their ca- pacity to enhance the natural ability of the surrounding tissues to produce bone healing and new bone forma- tion1,2. BMP-s are members of the transforming growth

factor-b (TGF-b) family of proteins3. Their activity rela- ted to bone induction remained unknown until 1988. when first recombinant BMPs were cloned4, BMP-2 has proved to possess the highest osteoinductive potential among BMPs and thus plays an important role in the early phase of proliferation and differentiation of me- senchymal progenitor cells into osteoblasts5,6. Prior to FDA approval, extensive preclinical and animal studies were conducted to examine the efficacy and limitations of BMP-2 in promoting bone formation7. Animal models have demonstrated that fracture healing can be acceler- ated by local administration of rhBMP-28,9. Most recently, the effects of rhBMP-2 on the osseointegration of tita-

Received for publication February 10, 2014

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D. Katanec et al.: Use of rhBMP2 in Alveolar Ridge Augmentation, Coll. Antropol. 38 (2014) 1: 325–330

Fig. 1. Clinical findings in the 61-year-old patient pre-surgery and postoperatively.

nium implants have also been investigated in the experi- mental animal studies. Basic clinical research showed that newly formed bone is woven bone with vital osteo- blasts and adequate vascularisation, thus representing a favorable environment for implant placement2,10–13. The safe application of rhBMP-2 has further been confirmed in human studies14,15.

In this report, a case of clinical usage of rhBMP-2 for bilateral alveolar ridge bone induction following dental implants placement, was presented.

Case Report

A 61-year-old man was referred to the Department of Oral Surgery University of Zagreb by his general dentist for treatment of severe vertical bone deficiency in both the mandibular molar regions (Figure 1). The patient’s medical history was not contributory. CBCT and pano- ramix mandibular scans were obtained preoperatively and showed 5-6 mm of bone superior to the mandibular canal which was insufficient to enable dental implant placement without augmentation procedures (Figure 2a). The patient underwent initial periodontal therapy prior to surgery. A written consent was obtained by the patient prior to surgical treatment.

A broad-spectrum antibiotic was administered preop- eratively. Anesthesia was achieved via mandibular block (Articaine 1:200000, 3M ESPE AG, Seefeld, Germany). Full thickness horizontal incision was made along the edentulous crest and extended intrasulcularly at the lin- gual aspect of the mandibular premolars on each side. Ver- tical releasing incisions, located at the mesio-buccal line angles of the adjacent anterior teeth, were created to facil- itate surgical access and tension-free flap closure. Bone

augmentation of the mandibular alveolar ridge was per- formed using rhBMP-2 (1.5 mg/mL) in combination with an absorbable collagen sponge (ACS) carrier (INFUSE® Bone Graft, Medtronic Spinal and Biologics, Memphis, TN, USA). 2.5 mL of the solution was applied to the car- rier for treatment of the right side and 1.5 mL for the left side, according to the manufacturer prescribed protocol. Augmented sites were covered with a rigid titanium membrane, 0.1 mm thick (Titanium Mesh, 25x30 mm, Salvin, USA), and fixed using screws located in the antic- ipated sites of the future dental implants. Two screws were secured through the mesh to support the height of the al- veolar ridge, and two tacks were also placed to secure the edges to the native bone. Periostal releasing was done to allow for passive primary closure using silk sutures (Mersilk, 4/0, Ethicon, INC, New Jersey, USA). Moderate edema and erythema were observed on day 2 following surgery and persisted for 2 weeks. Sutures were removed ten days after surgical procedure.

Six months after surgery, reopening of the augmented sites were performed when the titanium membrane and the stabilizing screws were removed (Figure 3). Newly formed bone appeared immature, trabecular in appear- ance and did not have a dense outer cortical layer in com- parison to the adjacent native bone and felt soft in con- sistency relative to the subjacent native bone when being drilled during implant sites preparation. The osteoto- mies for the implants placement were prepared through previous screws sites following drilling with the trephine due to harvesting regenerated bone samples for histolo- gical analysis. Dental implants (NobelReplace™ Tapered Groovy, Nobel Biocare AB,Göteborg, Sweden) were pla- ced (Figure 3) in the sites 36 (4.3x13 mm), 46 (4.3x13 mm) and 47 (4.3x10 mm) and good primary stability was

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Fig. 2. Radiographic evaluation. a) Panoramix prior to surgery representing significant vertical bony deficiency in both mandibular right and left molar regions. b) Panoramix 3 months post surgery representing bone growing into space delineated by titanium membrane. c) Panoramix 6 months post surgery representing significant bone growth into space delineated by titanium membrane. d) Panoramix after placement of dental implants representing bone overgrowing the top of the implant cover screws. e) CBCT taken 12 months post surgery representing vertical gain of newly formed bone.

achieved. The bone quality was evaluated by resonance frequency device Osstell (Osstell AB, Goteborg, Sweden). ISQ values were in the range between 73 and 76 for all three implants. The surgical site was sutured using silk sutures (Mersilk, 4/0, Ethicon, INC, New Jersey, USA). Plaque control was maintained by daily rinses of the oral cavity with 0.2% clorhexidine (Corsodyl, GlaxoSmith- Kline, UK) and hyaluronic acid agent (Gengigel, Medis Adria, Italy),which were used separately 3 times a day until suture removal. Sutures were removed 10 days post-surgery. Three months following implant place- ment, second surgical phase was performed. Thin layer of soft tissue of fibrous consistency was noted overlying the surface of the regenerated bone which, when re- moved, revealed bone overgrowing the top of the implant cover screws. Healing abutments were placed for a pe- riod of two weeks after which ceramic abutments were placed on the implants, and finally restored with zirco- nia-ceramic restorations.

CBCT radiographic evaluation was obtained prior to and 1 month following dental implants placament, as well as on the 24 month recall. Panoramics radiographs

were obtained prior to and 6 months following ridge aug- mentation, and then at 12 and 24 months after implants placamento (Figure 2). ISQ values were in the range be- tween 69 and 74 for all three implants during follow-up period of 12 months.

Histological analysis revealed the architecture of har- vested bone tissue comprised of mainly lamellar bone and smaller amount of woven bone (Figure 4). Woven bone showed signs of trabecular remodelling as differen- tiated by the pattern of osteoclasts and moderate osteo- blastic proliferation. The newly formed bone was more similar to trabecular bone typical of the maxilla and was represented by higher percentage of bone marrow suo- rounding bone fragments. Bone fragments with signs of mechanically damaged structure (basophilic areas) were randomly present in the medullary space with signs of mechanical damage due to using the trephine drill. In- flammatory cells were not present and bone voids were not detected.

No suppuration, gingival recession, pain or ongoing pathologic processes were present on the time of fol- low-up 24 months after surgery.

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Fig. 3. Second surgical procedure, removal oft he titanium mesh, sample for the histological analysis harvesting and dental implants placement.

Discussion

Several groups of authors showed in animal modesl that rhBMP-2 induced bone formation accommodates not only installation and osseointegration, but also long- term functional loading of endosseous implants2,10–13. Early rh-BMP use in humans was reported in case report whereby reconstruction of a large mandibular resection defect was done following removal of an ameloblastoma16.

The Food and Drug Administration approved rhBMP-2 for autograft replacement in spinal fusions in 2002, in 2004 for open tibia fractures, and in 2007 for sinus aug- mentations, and for localized alveolar ridge defects, when for the first time were used for reconstruction of mandibular bone defects in humans17. Most of the au- thors found several problems when using rhBMP-2 in human surgical procedures. Some disadvantages of the collagen carrier proved to be related to its lack of struc-

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D. Katanec et al.: Use of rhBMP2 in Alveolar Ridge Augmentation, Coll. Antropol. 38 (2014) 1: 325–330

Fig. 4. Histological evaluation of newly formed bone revealing ma- ture cancellous bone with mature lacunar stracture of osteocites.

tural stability and inability to maintain space as it is compressed by soft-tissues overlying the defect10–13. For these reasons, current research attempts are directed to- ward developing a matrix with more structural ability ca- pable of maintaining the space for bone induction during healing17. For this reason the treatment we presented in this case report included the use of a pure titanium mem- brane which was secured prior to placing the loading col- lagen carrier as a means of creating a physical structure to maintain space for regeneration to occur. Further- more, rhBMP-2/ACS in the amount of 1.5 mg/cc was used, which has been proved to be optimal for bone augmentation7. Based on the comparison of two doses of rhBMP-2/ACS (0.75 and 1.5 mg/cc) for treating post-ex- traction defects, a higher dose seems to affect the amount and velocity of the newly formed bone18. How- ever, peri-implant bone remodelling and seroma forma- tion has been observed to be considerably more extensive and aggressive at a higher rhBMP-2 concentration10. The results reported by Carter17, attributed some failures of bone regenaration using rhBMP-2 due to infection. Doc- umented adverse events linked to rhBMP-2 include bone resorption or remodelling at the graft site, severe neck swelling, hematoma, painful seroma, ectopic bone forma- tion and severe dysphagia14-18. The most frequent com- plication is edema, noted in our case as well, which may occur partially due to fast releasing of of the full dose of rhBMP-2 from ACS once being placed in the defect. A dis- advantage of rhBMP-2/ACS is its half-time of approxi- mately 7–16 minutes with a burst release within 1 hour

R E F E R E N C E S

1. JUNG RE, THOMA DS, HAMMERLE CH, J Clin Periodontol, 35 (2008) 255. DOI: 10.1111/j.1600-051X.2008.01270.x. — 2. SCHWARZ F, FERRARI D, SAGER M, HERTEN M, HARTIG B, BECKER J, Clin Oral Implants Res, 20 (2009) 1219. DOI: 10.1111/j.1600-0501.2009.01796.x. — 3. KING GN, Curr Pharm Biotechnol, 2 (2001) 131. DOI: 10.2174/1389 201013378716. — 4. WOZNEY JM, ROSEN V, CELESTE AJ, MITSOCK LM, WHITTERS MJ, KRIZ RW, HEWICK RM, WANG EA, Science, 242

of implantation and lacks any controlled releasing prop- erty. Further research is indicated to better understand and determine optimal dose of rhBMP-2, timing of its re- lease and carrier vehicle to yield predictable and reliable bone regeneration.

Although the expectation was to gain approximatelly 8–9 mm of bone height, the final outcome was repre- sented by gaining 5–5.5 mm of the newly formed bone in the posterior mandible. Vertical gain of newly formed bone was 5.5 mm on the left and 5 mm on the right side, which was comparable with the similar results achieved by using the conc. of 1.5 mg/cc in the case of sinus aug- mentation, representing newly formed bone height of 7.83 mm and 9.46 mm respectively14. It could be also as- sumed that the type of bone in the surgical site may af- fect induction of the bone formation.

ISQ values, which in our study ranged from 69–76,were comparable with the study of Alsabeeha19, in which the ISQ values ranging between 75–85 acquired for the pos- terior portion of the mandible presented the native bone standard mesurement. The lower ISQ values were ob- tained due to the type of newly formed bone induced by rhBMP-2, rather than related to the implant site prepa- ration.

Radiographic findings in our study revealed improved density of newly formed bone, which in structure was very similar to the native bone. These results contribute to previous findings that rhBMP-2 induced bone contin- ues maturing and by 12-24 weeks post implantation can- not be radiogrhically differentiated from the resident bone20. Radiolucent voids in rhBMP-2 induced bone have been observed in mutiple studies utilizing a variety of carriers in suprealveolar or saddle-type defects in dogs, being detected as seromas or sterile accumulations of se- rum in a circumscribed location20,21. However, no voids were detected in our study, which is in accordance with findings from other human reports following the use of us rhBMP-222.

Conclusion

Vertical bone augmentation using rhBMP-2 is optional treatment modality to consider when planning dental im- plant placement in sites where severe vertical insufficien- cy exists. However, further research is indicated to better understand and determine optimal dose of rhBMP-2, tim- ing of its release and carrier vehicle to yield predictable and reliable bone regeneration.

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MR, SANDOR GK, CLOKIE CM, J Craniofac Surg, 12 (2001) 119. DOI: 10.1097/00001665-200103000-00005. — 17. CARTER TG, BRAR PS, TO- LAS A, BEIRNE OR, J Oral Maxil Surg, 66 (2008) 1417. DOI: 10.1016/j. joms.2008.01.058. — 18. FIORELLINI JP, HOWELL TH, COCHRAN DL, MALMQUIST J, LILLY LC, SPAGNOLI D, TOLJANIC J, JONES A, NE- VINS M, J Periodontol, 76 (2005) 605. DOI: 10.1902/jop.2005.76.4.605. — 19. ALSABEEHA NH, DE SILVA RK, THOMSON WM, PAYNE AG, Clin Oral Implants Res, 21 (2010) 563. DOI: 10.1111/j.1600-0501.2009.01890. x. — 20. HUNT DR, JOVANOVIC SA, WIKEJSO UM, WOZNEY JM, BERNARD GW, J Periodontol, 72 (2001) 651. DOI: 10.1902/jop.2001.72. 5.651. — 21. WIKEJSO UM, QAHASH M, THOMSON RC, COOK AD, ROHRER MD, WOZNEY JM, HARDWICK WR, Clin Oral Implants Res, 15 (2004) 194. DOI: 10.1111/j.1600-0501.2004.00971.x. — 22. JUNG R, GLAUSER R, SCHARER P, HAMMERLE CH, SAILER HF, WEBER FE, Clin Oral Implants Res, 14 (2003) 556. DOI: 10.1034/j.1600-0501.2003. 00921.x.

D. Gabrić Pandurić

School of Dental Medicine, Department of Oral Surgery, Ivana Gunduli}a 5, 10000, Zagreb, Croatia e-mail: dgabric@sfzg.hr

UPOTREBA REKOMBINATNOG HUMANOG MORFOGENETSKOG PROTEINA (rhBMP-2) U OBOSTRANOJ AUGMENTACIJI ALVEOLARNOG GREBENA – PRIKAZ SLUČAJA

S A Ž E T A K

U posljednjih nekoliko godina upotreba oseoinduktivnih faktora rasta kao što su BMP-i, postali su alternativni izbor u odnosu na tradicionalnom koštanom presa|ivanju zbog svoje sposobnosti formiranja novog koštanog tkiva. Najveći oseoinduktivni potencijal me|u BMP pokazuje BMP-2. U ovom prikazu slučaja prikazujemo upotrebu rekombinatnog humanog BMP-2 (rhBMP-2) u kombinaciji sa kolagenom spužvicom za obostranu vertikalnu augmentaciju alveolarnog grebena kod pacijenta starog 61 godinu sa znaćajnim obostranim vertikalnim nedostatkom kosti u donjoj čeljusti. Augmentacijska mjesta su prekrivena i fiksirana titanskom mrežicom. 6 mjeseci nakon augmentacije titanska mrežica je uklonjena i na njenom mjestu su postavljena 3 dentalna implantata. Prilikom preparacije ležišta implantata uzet je dio novostvorenog tkiva za histološku analizu. Nakon tromjesečnog perioda cijeljenja postavljene su cirkon-keramičke krunice. CBCT i panoramske snimke su poslikane prije i nakon opracije. Vertiklani dobitak kosti je bio 5,5 mm za lijevu i 5 mm za desnu stranu donje čeljusti sa širinom od 6 mm. Histološka analiza je pokazala formiranje zrele spužvaste kosti sa znakovima proliferacije osteoblasta. ISQ vrijednosti su u rasponu od 69 do 75 za sva tri implantata. Nakon 24 mjeseci nije opisane nikakve komplikacije u vidu gnojenja, recesije ili boli. Vertiklana augmentacija pomoću rhBMP-2 može se uzeti u obzir za liječenje većih vertikalnih koštanih insuficijencija prije implantoprotetske rehabilitacije.

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