Journal of Osseointegration by Ariesdue srl

journal of osseointegration issn 2036-412I

marCH 2012

w w w. j o ur nal of oss e o inte gr ati o n .e u

n. . . . .

vol. . .

journal of osseointegration

Editorial board editors-in-chief

associate editors

Adriano Piattelli

Arthur Belem Novaes Jr.

Biomaterials Ana Pontes Barretos (BRA) Yasumasa Akagawa Hiroshima (JPN) Pâmela L. Santos Araçatuba (BRA) Victor Arana Chavez Sao Paulo (BRA) Sérgio L. Scombatti Carlos Roberto Grandini de Souza Ribeirão Preto (BRA) Ilha Solteira (BRA) Pascal Valentini Paris (FRA) Adalberto Luiz Rosa Ribeirão Paul Weigl Frankfurt am Main (DEU)

novaesjr@forp.usp.br

Lior Shapira Jerusalem (ISR) Paulo Tambasco de Oliveira

Professor of Oral Pathology and Medicine Dental School, University of Chieti Pescara (Italy) apiattelli@unich.it

Dental School of Ribeirão Preto, University of São Paulo (Brazil)

Preto (BRA)

Ribeirão Preto (BRA)

Heverson Tavares Araraquara (BRA) Van P. Thompson New York (USA)

associate editors Biomaterials

Clinical Research

New York (USA)

Rochester (USA)

Biomaterials and Tissue Engineering

Implant Science

Paulo Coelho

Georgios Romanos

Marco Degidi

Jose M. Granjeiro

Bologna (Italy)

Carlo Mangano

Guarulhos (Brazil)

Niterói (Brazil)

Jamil Shibli

Gravedona (Italy)

Clinical Innovations

Basic Research

Devorah Schwartz-Arad

Tel Aviv (Israel)

Pablo Galindo Moreno Granada (ESP)

assistant editors Vittoria Perrotti

Department of Dentistry and Oral Science, Dental School, University of Chieti-Pescara (Italy) v.perrotti@unich.it

Nilson T. C. Oliveira

Biomaterials Group “IQ” UNESP Araraquara, SP (Brazil)

n.oliveira@journalofosseointegration.eu

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Biomaterials and Tissue Engineering

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Giuseppe Cardaropoli New York (USA) Francesco Carinci Ferrara (ITA) Joni A. Cirelli Araraquara (BRA) Magda Feres Guarulhos (BRA) Giovanna Iezzi Chieti (ITA) Ramon Martinez Corrià Lerida (ESP) Gabriella Mincione Chieti (ITA) Raffaella Muraro Chieti (ITA) Gianpaolo Papaccio Naples (ITA) Rachel Sammons Birmingham (GBR) Clinical Research

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Ole Jensen Denver (USA) Gregorio Laino Naples (ITA) Voja Lekovic Belgrade (SRB) Eloà R. Luvizuto Araçatuba (BRA) Elcio Marcantonio Jr Araraquara (BRA) Ziv Mazor Ra'anana (ISR) Valdir Antonio Muglia Ribeirão

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Joerg Neugebauer Cologne (DEU)

redazione

Barbara Bono

Cristina Calchera

Franco De Fazio Simona Marelli

Preto (BRA)

Implant Science

Carlos R.P. Araujo Bauru (BRA) Bartolomeo Assenza Chieti (ITA) Luigi Califano Naples (ITA) Jose Luis Calvo Guirado Murcia (ESP) James Doundoulakis New York (USA) Massimo Frosecchi Florence (ITA) Enrico Gherlone Milan (ITA) Ana Becil Giglio New York (USA) Graziano Giglio New York (USA) Luigi Guida Naples (ITA) Giulio Leghissa Milan (ITA) Giuseppe Luongo Naples (ITA) Rogério Margonar Araraquara (BRA) Emeka Nkenke Erlangen (DEU) Marco E. Pasqualini Milan (ITA) Thallita Pereira Queiroz Araraquara (BRA) Lorenzo Ravera Chieti (ITA) Gilberto Sammartino Naples (ITA) Antonio Scarano Chieti (ITA) Tiziano Testori Milan (ITA) Stefano Tetè Chieti (ITA) Clinical Innovations

David Anson Beverly Hills (USA) Zvi Artzi Tel Aviv (ISR) Giuseppe Corrente Turin (ITA) Nilton De Bortoli Jr São Paulo (BRA) Paolo Della Casa Genoa (ITA) Stefano Fanali Chieti (ITA) Carlos Ademar Ferreira Tucuruvi (BRA) Luis Fujimoto New York (USA) Heracles Goussias Athens (GRC) Robert Horovitz New York (USA) Fouad Khoury Münster (DEU) Glenn Mascarenhas Mumbai (IDN) Georg H. Nentwig Frankfurt (DEU) Vula Papalexiou Curitiba (BRA) Waldemar Polido Porto Alegre (BRA) Nigel Saynor Woodford (GBR) Ludovico Sbordone Pisa (ITA) David Simmons New Orleans (USA) Aris Tripodakis Athens (GRC)

journal of osseointegration

Michele De Franco1, Francesco Guido Mangano2, Alessandro Mangano2, Andrea Pigato3, Manuela Rapani4, Giuseppe Luongo5, Carlo Mangano1 1

Dental School, University of Varese, Varese, Italy Private Practice, Gravedona (Como), Italy 3 Private Practice, Magenta (Milan), Italy 4 Private Practice, Chieti, Italy 5 Dental School, University of Naples, Naples, Italy 2

Prospective clinical evaluation of 273 modified acid-etched dental implants: 1- to 5- year results to cite this article De Franco M, Mangano FG, Mangano A, Pigato A, Rapani M, Luongo G, Mangano C. Prospective clinical evaluation of 273 modified acid-etched dental implants: 1- to 5- year results. J Osseointegr 2012;1(4):3-8.

ABSTRACT Aim The aim of this study was to evaluate the implant survival and the implant-crown success of implants with surface treated with organic acids. Materials and methods A total of 273 implants (Implus®, Leader-Novaxa, Milan, Italy) were inserted in 63 patients, from June 2006 to June 2010, in a single clinical centre. In each annual follow up session, clinical, radiographic and prosthetic parameters were evaluated. The implant-crown success criteria included the absence of pain, suppuration and clinical mobility, a distance between the implant shoulder and the first visible bone contact (DIB) <2.0 mm from the surgery and the absence of prosthetic complications at the implantabutment interface. Prosthetic restorations were 32 fixed partial prostheses, 48 single crowns and 16 fixed full arches. Results the cumulative survival rate was 95.70% (93.81 maxilla, 98.24% mandible). Among the surviving implants, the implant-crown success was 96.07%. At the 5-year control, the mean DIB was 1.2 mm (± 0.5). Conclusion Implants with surface treated with organic acids seem to represent a good solution for the prosthetic rehabilitation of partially and completely edentulous patients.

Keywords Dental implants; Implant surface; Implant survival; Organic acids; Surface geometry.

INTRODUCTION The high, medium and long-term success rates of prosthetic rehabilitations supported by osseointegrated

March 2012; 1(4) © ariesdue

implants in partially and totally edentulous subjects has confirmed the correctness of the principles at the basis of the biological process of osseointegration, as defined by the international scientific community (1-3). In a 5-year study on 1583 implants with different prosthetic indications, Davarpanah et al. (1) reported a cumulative implant survival of 96.5%, with a mean crestal bone loss of 0.2 ± 1.7 mm. Similar results were reported by Naert et al. (2) with implants supporting fixed partial prostheses, and an implant success rate of 95% after a mean follow-up period of 6 years (2). In a recent systematic review on the 5-year survival rates of implants supporting single crowns, Jung et al. (3) reported a survival rate of 96.8%. Titanium has excellent biocompatibility and mechanical properties, and for this reason it is the material of choice in bone implant surgery (4). After the insertion of a titanium implant, performed in respect of tissue biology and primary implant stability, the related tissue response is ankylotic with subsequent de novo bone formation around the alloplastic device (4, 5). This condition influences the healing processes giving a direct boneto-implant contact with no fibro-connective tissue interposition. Over the recent years, it has been demonstrated that the bone apposition on implant surfaces can be influenced by surface macro- and micro-topographical features, and by implant surface roughness (6, 7). The presence of a rough surface is able to accelerate the process of bone healing and promote osseointegration (6, 7). Microrough surfaces show an increased absorption of functional biomolecules from external environment and seem able to modify the cell response supporting the deposition of new bone on the implant (6-8). Many different histological studies unequivocally demonstrated that microrough implant surfaces are able to promote a greater apposition of new bone on the implant surface, promoting a rapid ostseointegration, when compared to smooth implant surfaces (8). The results of these

journal of osseointegration De Franco M. et al.

histological studies were confirmed by the clinical results obtained with microrough implant surfaces, showing excellent long-term survival and success rates (1, 2, 8). Among the modern implant surfaces there are blasted or etched ones (6-9). Acid etched surfaces were introduced in order to avoid some problems caused by blasting, such as the contamination of the titanium by particles used during the blasting procedure, the different homogeneity on the blasted surfaces and the potential risk of material loss from the blasted implant, that could jeopardize the long-term clinical results (9). In general, the acid etching is obtained either with a mix of hydrochloric and sulphuric acid (HCl/H2SO4) or using a mix of hydrofluoric and nitric acid (HF/HN3) (6-9). To obtain blasted and etched implants, surfaces are first treated with materials that produce a macro-rough surface and then immersed into an acid solution producing micro-irregularities with subsequent increase of the implant surface area (6-8). A treatment option for the implant surface is represented by etching with organic acids, such as ossalic and maleic acids (9-12). This procedure results in a surface with a specific geometry represented by a sequence of repeated concavities of homogeneous and controlled dimensions (9-12). Histomorfometrical studies with organic acid etched implants on baboons showed a substantial bone apposition after a healing period of 3 months, with high bone-to-implant contact values, regardless the loading protocol (immediate loading or submerged healing) (10). In a previous comparative study on humans and baboons, the surface treated with organic acids revealed a higher bone-to-implant contact, when compared to a smooth surface (11). The presence of a repeated sequence of superficial concavities seems to be linked to the excellent results in terms of new bone apposition on the implant surface obtained by organic acid treatment (10-12). The aim of this clinical study was to evaluate the survival and implant-prosthetic success of implants with a modified acid-etched surface obtained by organic acids treatment.

MATERIALS AND METHODS Patient selection

Between June 2006 and June 2010, all patients who referred to one single clinical centre for fixed prosthetic restoration supported by dental implants were selected to take part in the present prospective clinical study. Inclusion criteria were adequate bone height and width for the placement of an implant of at least 3.3 mm in diameter and 8.0 mm in length. Exclusion criteria were: poor oral hygiene, active periodontal infections, uncontrolled diabetes, bruxism, heavy smoking habit (more than 10 cigarettes/day). All the selected patients were fully informed about the study and signed an informed consent form for implant treatment.

Sixty-three patients (25 males and 38 females, aged between 31-78 years; average: 54.5 years) were enrolled in this study. Two-hundred and seventy three implants were placed. A total of 160 implants were inserted in the maxilla, while 113 implants were inserted in the mandible. Fifty-two implants were placed in the maxillary anterior region, while 108 implants were placed in the maxillary posterior region; 35 implants were placed in the mandibular anterior region and 78 in the mandibular posterior region. The distribution of implants by length and diameter is shown in Table 1. The most frequent indication was the restoration of partially edentulous patients, while the least frequent indication was the treatment of single tooth gaps. The prosthodontic restorations comprised 32 fixed partial prostheses (FPPs), 48 single crowns (SCs) and 16 fixed full-arch prostheses (FFAs). Each fixed full-arch prosthesis was supported by 8 implants.

Implant surface

The new BOAT implant surface (Biological Organic Acid Treatment, Implus®, Leader-Novaxa, Milan, Italy) was obtained after an organic acid treatment with a mixture of organic acids (oxalic acid/maleic acid), according to the following procedures: › sonic bath in distilled water at a temperature of 25°C for 5 minutes to remove residuals deriving from manufacturing; › immersion in NaOH (20 g/L) + H2O2 (20 g/L) at a temperature of 80°C for 30 minutes; › sonic bath in distilled water at a temperature of 25°C for 5 minutes; › acid etching in an organic mixture of 50% oxalic acid and 50% maleic acid at a temperature of 80°C for 45 minutes; › washing in distilled water and sonication for 5 minutes; › immersion for 30 minutes in a solution of 65% nitric acid and distilled water with a volumetric range of 1 to 1 at a temperature of 100°C; › washing in distilled water. The organic acid treatment provided an implant surface with the mean of absolute values average of all profile points (Sa), root-mean-square of the values of all points (Sq) and the average value of the absolute heights of the five highest peaks and depths of the five deepest valleys (Sz) of 0.9, 1.1, 6.9 µ, respectively.

Pre-operative examinations

A complete examination of the oral hard and soft tissues was carried out for each patient. Panoramic radiographs formed the basis for the primary investigation, together with periapical radiographs using a Rinn alignment system (Rinn®, Dentsply, Elgin, IL, USA) with a rigid filmobject-X-ray source coupled to a beam-aiming device in order to achieve reproducible exposure geometry; where necessary, computed tomography (CT) scans were used

journal of osseointegration Prospective clinical evaluation of modified acid-etched dental implants

as the final investigation. Pre-operative examination included an assessment of the edentulous ridges using casts and diagnostic wax-up.

Implant placement

Local anaesthesia was obtained by infiltrating articaine (4%) containing 1:100.000 adrenaline (Ubistesin®, 3M Espe, St. Paul, MN, USA). A midcrestal incision was made at the sites of implant placement. The mesial and distal aspects of the crestal incision were connected to two releasing incisions. Full thickness flaps were reflected exposing the alveolar ridge, and the preparation of implant sites was carried out with spiral drills of increasing diameter (2.6 mm to place an implant with 3.3 mm diameter; 2.6 and 3.2 mm, to place an implant with 3.75 mm diameter; 2.6, 3.2 and 3.8, to place an implant of 4.5 mm diameter; an additional 4.8 mm drill was used to prepare the site for 5.5 mm diameter implants), under constant irrigation. Implants were positioned at the bone crest level. Finally, sutures were performed (Supramid®, Novaxa Spa, Milan, Italy).

Post-operative treatment

All patients received oral antibiotics, 2 g each day for 6 days (Augmentin®, Glaxo-Smithkline Beecham, Brentford, UK). Postoperative pain was controlled by administering 100 mg nimesulide (Aulin®, Roche Pharmaceutical, Basel, Switzerland) every 12 hours for 2 days, and detailed instructions about oral hygiene were given, including mouthrinsing with 0.12% chlorhexidine (Chlorexidine®, OralB, Boston, MA, USA) administered for 7 days. Suture removal was performed after 8-10 days.

Healing period

A two stage technique was used to place the implants. The healing time was 2-3 months in the lower jaw and 3-4 months in the upper jaw. Second-stage surgery was conducted to gain access to the underlying implants and healing abutments were placed. In all fixed prosthetic rehabilitation protocols (fixed partial prosthesis, FPPs; fixed full arches, FFAs; single crowns, SCs), the abutments were placed and activated 2 weeks after the second surgery. Acrylic resin provisional restorations were used to monitor implant stability under a progressive load and to obtain good soft tissue healing around the implant before fabrication of the definitive restorations. The temporary restorations remained in situ for 2-3 months, and after this period definitive restorations were placed and cemented with zinc phosphate cement (Harvard®, Richter & Hoffmann, Berlin, Germany).

Clinical and radiographic evaluation

At each annual follow up session, for each single implant, the following clinical parameters were investigated: › presence or absence of pain and/or sensitivity (13); › presence or absence of suppuration and/or

March 2012; 1(4) © ariesdue

exudation; or absence of implant mobility, tested manually using the handles of two dental mirrors (13). Moreover, intraoral periapical radiographs were taken for each implant, using a Rinn alignment system (Rinn®, Dentsply, Elgin, IL, USA) with a rigid film-object-X-ray source coupled to a beam-aiming device in order to achieve reproducible exposure geometry. Radiographs were taken at baseline (immediately after implant insertion) and at each annual follow up session, for two purposes: › to evaluate the presence/absence of continuous peri-implant radiolucencies; › to measure the distance between the implant shoulder and the first visible bone contact (DIB) in mm, at the mesial and distal implant site (13). For this measurement, crestal bone level changes were recorded as changes in the vertical dimension of the bone around the implant, so that an evaluation of peri-implant crestal bone stability over time was obtained. In order to control the dimensional distortion in the radiographs, the apparent dimension of each implant (directly measured on the radiograph) was compared with the real implant length, introducing the following proportion: R x implant length : Real implant length = R x defect : Real defect. In that way it was possible to establish, with adequate precision, the eventual amount of vertical bone loss at the mesial and distal site of the implant (13).

› presence

Prosthesis function

To test prosthesis function, at each annual scheduled check, static and dynamic occlusion were evaluated, using standard occluding papers (Bausch articulating paper®, Bausch inc, Nashua, NH, USA). Careful attention was dedicated to the analysis of prosthetic complications at the implant-abutment interface (abutment loosening, abutment fracture).

Implant survival and implant-crown success criteria

Implants were basically divided into two categories: “survived” and “failed” implants. An implant was classified as a “survived implant” when it was still in function at the last follow up session. Indeed, implant losses and implants presenting pain upon function or clinical mobility were all included into the “failed” categories. The conditions for which implant removal could be indicated included the failure of osseointegration or infection, recurrent peri-implantitis, or implant loss due to mechanical overload. Statistical analysis was carried out with the life-table analysis described by Cutler and Ederer (14). Among the survived implants, an implant was classified in the implant-crown success group when it fulfilled all the following clinical, radiographic and prosthetic success criteria (15):

journal of osseointegration De Franco M. et al.

Diameter Length 8.00 10.0

11.5

13.0

Total

Overall life-table Months Implants Drop-outs At risk Failures Survival Cumulative

3.30

0-12

273

272

97.06% 97.06%

3.75

116

12-24

246

243

99.18% 96.24%

4.50

24-36

186

184

99.46% 95.70%

5.50

36-48

100.0%

95.70%

Total

273

48-60

100.0%

95.70%

tab. 1 Implant distribution by length and diameter (in mm).

tab. 2 Overall life-table analysis for implant survival.

maxilla Months Implants Drop-outs At risk Failures Survival Cumulative

mandible Months Implants Drop-outs At risk Failures Survival Cumulative

0-12

160

159

96.23% 96.23%

0-12

113

12-24

142

140

98.58% 94.81%

12-24

104

103

100.0%

98.24%

24-36

101

100

99.00% 93.81%

24-36

100.0%

98.24%

36-48

100.0%

93.81%

36-48

100.0%

98.24%

48-60

100.0%

93.81%

48-60

100.0%

98.24%

tab. 3 Cumulative survival rate in the maxilla.

› › › › › ›

absence of pain or sensitivity; absence of suppuration or exudation; absence of clinically detectable implant mobility; absence of continuous peri-implant radiolucency; DIB < 2.0 mm from the implant insertion ; absence of prosthetic complications at the implantabutment interface. The implant-crown success was defined by all these conditions, otherwise implants were classified in a second group, defined as the compromised survival.

RESULTS Implant survival

At the end of the study, the overall cumulative implant survival rate was 95.70%, with 262 implants still in function (Table 2). In the maxilla, the cumulative survival rate was 93.81%, with 9 implants failed and removed (Table 3). In the mandible, the survival rate was 98.24%, with 2 implants failed and removed (Table 4). With regard to the position of the failed implants, 7 were in the posterior maxilla, 2 in the anterior maxilla and 2 in the posterior mandible. Eight implants failed during the first year after insertion. Among these, 6 implants were classified as “early failures”, showing clinical mobility due to lack of osseointegration (4 implants) or recurrent infections with pain and suppuration (2 implants) before the connection of the abutment. Five implants were classified as “late failures”, after the abutment connection, 3 showed untreatable recurrent peri-implant infections, and 2 failed because of progressive bone loss due to mechanical overloading, without clinical signs of peri-implant infection (Table 5).

98.24% 98.24%

tab. 4 Cumulative survival rate in the mandible.

failures Months

Mobility

Iinfection

Bone loss

Total

0-6

6-12

12-24

24-36

36-48

48-60

Total

tab. 5 Overall failures during the healing and follow-up period

Implant-crown success

Two-hundred and sixty-two implants were still in function at the end of the study. Three patients (7 implants), however, failed to attend the annual recall visits and were classified as drop-outs. Among 255 checked implants, 245 (96.07%) were classified in the implant-crown success group. All these implants did not show pain or clinical mobility, suppuration or exudation, with a DIB <2.0 mm, and did not have any prosthetic complication at the implant-abutment interface. Only 10 implants (3.93%) were classified in the second group, among the compromised survival implants. These implants did not show any pain, suppuration, or mobility, but they had a DIB >2.0 mm; 2 of these implants had a history of exudation. At the 5-year follow up recall, the radiographic evaluation of the implants revealed a DIB of 1.2 mm (± 0.5). No complications were observed at the implant-abutment connection.

journal of osseointegration Prospective clinical evaluation of modified acid-etched dental implants

DISCUSSION This prospective study aimed at evaluating the implant survival and implant-crown success of implants with a surface obtained by treatment with a mixture of organic acids (oxalic acid and maleic acid). The clinical results of the present study are consistent with those reported in the literature on modern osseointegrated implants (1-3, 5-9), and support the evidence emerged in a previous work on systems with a BOAT surface (16), showing how the use of systems with surface treated with organic acids can be a safe and successful procedure. The present clinical results seem also to support previous histological and histomorphometric studies in animal models and humans, where a substantial apposition of new bone on surfaces treated with a mixture of organic acids, with high values of contact between bone and implant, regardless of the loading protocol applied (immediate loading or submerged healing) was shown (9-12). Indeed, several studies have shown, in terms of success, the high clinical predictability of implantsupported rehabilitations (1-3,5-7). Implant survival in the international literature varies between 96% and 97% and the success rate of implantsupported rehabilitations varies between 87% and 97% after 5 years of functional loading (17). The implant survival and success criteria generally used in clinical studies are those proposed by Albrektsson in 1986 (18) and then resumed in 1989 by Smith and Zarb (19). These criteria can still be considered valid even if, more recently, additional parameters were proposed for evaluating the success of implants (20). Originally, it was perceived that an implant system could be considered valid and reliable when the overall success rate was at least 85%, 5 years after implant placement (18, 19). Subsequently, Misch has modified this percentage into 90% (5 years) and 85% (10 years) (21); finally, the same author reported that the expected implant survival and implant-crown success should be of approximately 90% (10 years) (22). The present study shows similar results to those reported by Misch in 2005 (22), with a 95.70% cumulative overall implant survival rate. In order to obtain a successful implant-supported prosthetic restoration, it is mandatory to consider several variables, including biological and biomechanical features at different levels, i.e. bone-implant interface, implant-abutment connection, abutment-prosthesis interface (20-22). The literature has suggested that the implant surface geometry may affect the basic steps of osseointegration, such as fibrin clot extension (23, 24) and the creation of a favourable microenvironment for the osteoblastic activity, which is essential for osseointegration (25, 26). Implants treated with a mixture of organic acids present a surface with a peculiar geometry, characterised by a homogeneous and uniform micro and macro-

concavities. This geometric structure is able to support and sustain the rapid growth of new bone, starting from the concavities (25-32).

Conclusion In the present clinical study, implants with surface treated with organic acids seem to represent a good solution for the prosthetic rehabilitation of partially and completely edentulous patients.

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consecutivamente in un periodo di 5 anni. Implant Tribune It Ed 2008; 1: 13-14 17. Zarb GA, Schmitt A. The longitudinal clinical effectiveness of osseointegrated dental implants in posterior partially edentulous patients. Int J Prosthodont 1993;6(2):189-96. 18. Albrektsson T, Zarb G, Worthington P, Eriksson AR. The long-term efficacy of currently used dental implants: a review and proposed criteria of success. Int J Oral Maxillofac Implants 1986; ;1(1):11-25. 19. Smith DE, Zarb GA. Criteria for success of osseointegrated endosseous implants. J Prosthet Dent 1989; 62(5):567-72. 20. Misch CE, Perel ML, Wang HL, et al. Implant success, survival, and failure: the International Congress of Oral Implantologists (ICOI) Pisa consensus conference. Implant Dent 2008; 17: 5-15 21. Misch CE. Conteporary implant dentistry. Elsevier-Mosby: St Louis; 2000. 22. Misch CE. Dental implant prosthetics. Elsevier-Mosby: St Louis; 2005. 23. Park JY, Davies JE. Red blood cell and platelet interactions with titanium implant surfaces. Clin Oral Implant Res 2000;11(6):530-9. 24. Kanagaraja S, Lundström I, Nygren H, Tengvall P. Platelet binding and protein adsorption to titanium and gold after short time exposure to heparinized plasma and whole blood. Biomaterials 1996; 17(23):2225-32. 25. Ripamonti U. Soluble and insoluble signals sculpt osteogenesis in angiogenesis. World J Biol Chem 2010 ;1(5):109-32. 26. Trueta J. The role of the vessels in osteogenesis. J Bone Joint Surg 1963;54B:402–418 27. Chicurel ME, Singer RH, Meyer CJ, Ingber DE. Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions. Nature 1998 ;392(6677):730-3. 28. Sinha RK, Tuan RS. Regulation of human osteoblast integrin expression by orthopedic implant materials. Bone 1996; 18(5):451-7. 29. Ingber DE. Tensegrity I. Cell structure and hierarchical systems biology. J Cell Sci 2003; 116(Pt 7):1157-73. 30. Ingber DE. Tensegrity II. How structural networks influence cellular information processing. J Cell Sci 2003;116(Pt 8):1397-408. 31. Canabarro A, Crippa GE, Shirozaki MU, Sampaio EM, Lefebvre L-P, de Oliveira PT, Beloti MM, Rosa AL. Effect of porous titanium coating thickness on in vitro osteoblast phenotype expression. J Osseointegr 2011;1(3):17-23. 32. Farina E, Menditti D, De Maria S, Mezzogiorno A, Esposito V, Laino L, Carinci F. A model of human bone regeneration: morphological, cellular and molecular aspects. J Osseointegr 2009;2(1):42-53.

journal of osseointegration

Aris Petros Tripodakis1, Georgios Kamperos2, Nikolaos Nikitakis3, Alexandra Sklavounou-Andrikopoulou4 Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece 1 Associate Professor, Department of Prosthodontics and Department of Oral Medicine and Pathology 2 Postgraduate Student 3 Assistant Professor 4 Professor

Implant therapy on patients treated with oral bisphosphonates to cite this article Tripodakis AP, Kamperos G, Nikitakis N, Sklavounou-Andrikopoulou A. Implant therapy on patients treated with oral bisphosphonates. J Osseointegr 2012;1(4):9-14.

ABSTRACT Aim Bisphosphonates represent a group of drugs with a significant effect on bone structure preventing bone remodelling. They can be administered for the treatment of osteoporosis, Paget’s disease, osteogenesis imperfecta, osteopenia and bone metastases. The aim of this study was to discuss the necessary precautions for successful implant therapy on patients treated with per os bisphosphonates. Case reports Two female patients, both in the seventh decade of life, requested implant therapy. Their medical history was significant for osteoporosis, managed with per os bisphosphonates (Risedronate and Alendronate, respectively), without other risk factors for osteonecrosis. The duration of bisphosphonate administration was 4 years and 2 months respectively. After consultation with the treating physician, the patients stopped the bisphosphonates 3 months before and 3 months after the placement of the implants. The patients received antibiotic coverage for the surgical interventions. The treatment plan was completed uneventfully with placement of fixed prostheses without complications during a 2-year follow-up period. Conclusion The greatest dental treatment-related risk for patients on bisphosphonate therapy is bisphosphonate-associated osteonecrosis, which presents with exposure of avascular bone of the jaws and, according to the clinical stage, pain, inflammation, fractures and/or extensive osteolysis. Most of reported cases of bisphosphonate-associated osteonecrosis consist of patients on intravenous drug therapy who had undergone dentoalveolar surgery. Patients on per os bisphosphonates may undergo all types of dentoalveolar surgery, including implant placement, as long as the necessary precautions (bisphosphonate discontinuation, antibiotic coverage, meticulous oral hygiene) are taken.

Keywords Dental implants; Oral bisphosphonates; Osteonecrosis.

Introduction The use of bisphosphonates is increasing rapidly. These drugs are being prescribed for osteoporosis, osteogenesis imperfecta, bone metastases of various malignancies (most commonly prostate or breast cancer), multiple myeloma and other diseases (1-4). The vast majority of patients on bisphosphonates are osteoporotic and receive per os treatment in order to prevent bone fractures (5). These patients frequently require dental treatment with or without dental implants (6). Nevertheless, many case reports of jaw osteonecrosis in patients on bisphosphonate therapy (bisphosphonate-related osteonecrosis of the jaws – BRONJ) have been published since 2003, and various prevention and treatment protocols for this condition have been advocated (1-4,7-9). The aim of this paper was to present and discuss the necessary precautions for a successful dental treatment including implant placement and prevention of BRONJ in patients receiving per os bisphosphonates.

Case reports Case report 1

A 70 years old woman already treated with implant supported prostheses in the past, requested a fixed partial denture supported by additional dental implants. Her medical history was significant for hypertension and hyperlipidemia, both controlled by medications. For the past 2 months, she was managed for osteoporosis with oral bisphosphonates (Risedronate), calcium and vitamin D3 supplements. The patient was informed of the possible risks and, after consultation with her physician, she agreed to a drug holiday of 3 months before and 3 months after implant surgery. After careful clinical and radiographic evaluation involving orthopantomogram (Fig. 1) and 3D Volumetric Tomography (Morita Acuitomo, Japan) (Fig. 2, 3, 4), the treatment plan consisted of extraction of the right

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1 2

3 4 fig. 1 Preoperative panoramic radiograph. fig. 2 Volumetric view of site 14. fig. 3 Volumetric view of site 15. fig. 4 Volumetric view of site 17. fig. 5 Panoramic radiograph two years postoperatively.

maxillary first premolar and first molar because of their poor prognosis and placement of 3 dental implants in the right posterior maxilla (sites 14, 15, 17) (Branemark System Mk III Groovy,NobelBiocare, Goteborg, Sweden). The patient was under antibiotic coverage (Amoxicillin 500mg three times daily; GlaxoSmithKline, Athens, Greece) that started 24 hours before the surgical intervention and finished ten days postoperatively. The final prosthetic restoration was a fixed metalceramic partial denture that was inserted 3 months after implant placement, directly attached on the implants without the application of transmucosal abutments. The treatment plan was completed uneventfully. No complications were noted during a 2-year follow-up period (Fig. 5).

Case report 2

A 65 years old woman requested fixed prosthetic restorations supported by dental implants. Her medical

history was significant only for osteoporosis, which was managed with oral bisphosphonates (Alendronate) for the past 4 years. The patient was informed of the possible risks and consulted her treating physician concerning the temporary discontinuation of the drug. The physician agreed for a drug holiday of 3 months before and 3 months after surgery to ensure uneventful healing and successful osseointegration of the implants and to minimize the risk of BRONJ. After careful clinical and radiographic examination, including orthopantomogram (Fig. 6) and 3D Volumetric Tomography (Dental scan Newtom, Italy) the treatment plan consisted of extraction of the right maxillary canine and second premolar because of their poor prognosis. The first surgical intervention involved all maxillary implants. The placement of 4 dental implants in the right posterior maxilla followed immediately after the extractions (sites 13, 14, 16, 17). The implant on site 13 (SPI, Alpha Bio, Petach Tikva Israel) 16 mm was placed by a flapless approach and was immediately connected to a prefabricated Ti abutment and attained immediate provisionalization and passive immediate loading

ÂŠ ariesdue March 2012; 1(4)

journal of osseointegration Implant therapy and oral bisphosphonates

avoiding any centric or functional occlusal contact. Implants in sites 14, 16 and 17 (Branemark System Mk III Groovy, NobelBiocare, Goteborg, Sweden) 13 mm were applied by the traditional two-stage approach along with closed sinus augmentation through the alveolar crest (Summers’ technique) (Fig. 7). The placement of the 4 implants in the left posterior maxilla (sites 25, 26, 27, 28) was accomplished, simultaneously with sinus augmentation via lateral approach (osteotomy window technique) (Fig. 7). In the second surgical session (one month later) 6 implants were placed in the posterior regions of the mandible (sites 36, 37, 38, 46, 47, 48) by the traditional two-stage approach (Fig. 7). The patient was under antibiotic coverage Amoxicillin 500mg three times daily (GlaxoSmithKline, Athens, Greece) that started 24 hours before each of the surgical interventions and finished 10 days postoperatively. The final prosthetic restorations were fixed metalceramic partial dentures that were inserted 6 months after placement in the maxilla and 3 months after placement in the mandible, directly attached on the implants without the application of a transmucosal abutment. The treatment plan was completed uneventfully. No complications were noted during a 4-year follow-up period (Fig. 8).

Discussion Bisphosphonates may be administered per os or intravenously (IV) (3,4). Alendronate, Risedronate

7 fig. 6 Preoperative panoramic radiograph. fig. 7 Panoramic radiograph after the second surgical procedure. fig. 8 Panoramic radiograph four years postoperatively.

and Ibandronate are commonly administered per os for treating osteoporosis, while other drugs (such as Zolendronate and Pamidronate) are administered IV mainly for treating bone malignancies (4). The major difference between per os and IV administered bisphosphonates lies in their bioavailability (0.64% and 60% respectively) (10-12). Bisphosphonates accumulate in the bone matrix and prevent the function of osteoclasts, leading them to apoptosis (13,14). Bone vascularity is decreased and bone remodelling and healing are hindered (2-4,7,15). Bisphosphonates may be detected in the bone even many years after the end of treatment (4, 7, 14, 15). The frequency of BRONJ is unknown. Various studies on IV administered bisphosphonates report BRONJ rates of 1.9 – 28% with the most common causative factor being dentoalveolar surgery (16-23). As a result, dentoalveolar surgery and placement of dental implants in patients on IV bisphosphonates is generally contraindicated (1623). As for oral bisphosphonates, BRONJ rates of 0.090.34% after tooth extraction have been reported (4). In a large Australian study, the frequency of BRONJ occurring after extractions was estimated at 1 in 296 to 1 in 1,130 extractions in patients taking oral bisphosphonates (24). Marx et al. presented 30 cases of BRONJ in patients taking oral bisphosphonates (90% Alendronate, 10% Risedronate) for more than 3 years (12). Khosla et al. claimed that only a total of 64 cases of BRONJ in patients taking oral bisphosphonates had been reported in the literature until 2007 (25). Consequently, the risk of BRONJ in patients on per os bisphosphonates may be considered low but cannot be ignored (25). The risk factors for developing BRONJ can be divided into drug-related, local and systemic factors (4). Systemic risk factors include other drugs (chemotherapeutics, corticosteroids), diabetes mellitus, smoking, as well as other conditions (2-4,7,26-28). In the cases presented here, no other systemic factors were identified. On the other hand, local triggering agents include

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dentoalveolar surgery (e.g. tooth extraction or dental implant placement) or denture-induced traumatic ulcers, along with poor oral hygiene (2-4,8,12,15,29). In 20-25% of BRONJ cases, no triggering agent can be identified (8,12). BRONJ commonly presents as an unhealed extraction socket or a poorly healed surgical site (2-4). The mandible is usually affected in 65-70% of the cases (4). In the early stages, BRONJ may be presented as mucosal inflammation without bone exposure (2-4). After a period of time, necrotic bone will be seen in the oral cavity (avascular necrosis) (8,12). BRONJ is usually painless, unless it is infected or there are sharp bone fragments that cause additional trauma in the adjacent mucosa (2-4). During the progression of BRONJ, other signs may appear such as fistula, jaw fractures and excessive osteolysis, even involving the lower border of the mandible (2-4). Ruggiero et al. (4) divide BRONJ into 4 stages. ‹ Stage 0, no clinical evidence of necrotic bone, but non-specific clinical findings and symptoms. ‹ Stage 1, exposed and necrotic bone in asymptomatic patients without evidence of infection. ‹ Stage 2, exposed and necrotic bone associated with infection as evidenced by pain and erythema in region of exposed bone with or without purulent drainage. ‹ Stage 3, exposed and necrotic bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone, resulting in pathologic fracture, extraoral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible or the sinus floor. The AAOMS position paper claims that patients may be considered to have BRONJ if all of the following 3 characteristics are present: current or previous treatment with a bisphosphonate, exposed bone in the maxillofacial region that has persisted for more than 8 weeks, no history of radiation therapy to the jaws (4). Biopsy of the lesion is not routinely recommended, because the histopathologic features are not unique, and the trauma inflicted may worsen the condition (4,9). Notwithstanding the minimal risk of patients on per os bisphosphonates for developing BRONJ, a thorough examination of the oral cavity is advised (4,12). The decreased risk of developing BRONJ in the first 3 years of therapy gives the dentist the necessary time to treat any site of inflammation (4,12). These patients must have a meticulous oral hygiene and a regular dental followup schedule (4,7,8). Patients on per os bisphosphonates may receive any non-surgical dental treatment (4,7,8,15). For individuals who have taken oral bisphosphonates for fewer than 3 years and have no clinical risk factors, any surgical procedure may be performed (4). If the duration of bisphosphonate treatment exceeds a 3 years period

or there are other systemic risk factors (such as chronic corticosteroid use), it is preferable for the patient to be on a drug holiday in order to undergo oral surgery (4,7,8,12,15). If systemic conditions permit, the clinician might consider discontinuation of oral bisphosphonates for a 3-month period before and a 3-month period after surgery to lower the risk of BRONJ and ensure successful healing (4). The surgical intervention should be minimally invasive and performed with antibiotic coverage (7,8,15). If systemic conditions do not permit the drug discontinuation, necessary surgical procedures should be performed after patient’s approval (7,8,15). Marx et al. proposed a new method for evaluating the bone remodeling ability by observation of the morning fasting serum C-terminal telopeptide (CTX) (12). This method has not yet been approved by the majority of the scientific community. If BRONJ develops in a patient receiving per os bisphosphonates, drug discontinuation is advisable for a period of 6-12 months, thus facilitating successful healing or sequestration if the necrosis is small (4,12,15,29). In case of large necrosis, the drug discontinuation may not be enough for successful healing (12). If the exposed bone becomes mobile or shows radiographic evidence of sequestration, then a local debridement can be accomplished after a drug holiday of 6-12 months (12). Apart from the discontinuation of oral bisphosphonates, the following procedures have been proposed by AAOMS, according to the stage of the disease. ‹ Stage 0, systemic management, including use of pain medication and antibiotics. ‹ Stage 1, antibacterial mouth rinse (chlorhexidine 0,12%). ‹ Stage 2, systemic antibiotics, antibacterial mouth rinse, pain control; stage 3, all of the above along with possible surgical debridement / resection (4). Regardless of disease stage, mobile segments of bony sequestrum, as well as sharp bone fragments, should be removed and symptomatic teeth within exposed, necrotic bone should be extracted (3,4,9). Osteonecrosis may also be covered by a special splint to avoid further trauma (7). Strict follow-up schedule is also advised (every 3 weeks) (2,7). Newest methods for the treatment of BRONJ include ozone, hyperbaric oxygen and laser therapy (30,31). Ozone and hyperbaric oxygen therapy, both combined with conservative removal of necrotic tissue, may stimulate cell proliferation, soft tissue healing and angiogenesis (30,31). On the other hand, laser applications at low intensity (Low Level Laser Therapy - LLLT) as well as Er:YAG laser have been reported in the literature for the treatment of BRONJ. Laser therapy improves the reparative process, stimulates lymphatic and blood capillaries growth and can be used for conservative removal of necrotic bone (30). Long-term, prospective studies are required to establish the efficacy

journal of osseointegration Implant therapy and oral bisphosphonates

of these methods (30,31). Dental implants have a high rate of success (95% or better) when correctly implanted into the jaws (32). The successful integration and function of an implant involves 3 phases: osteoconduction, osteogenesis, bone remodelling (33). Bisphosphonates significantly reduce bone turnover and as a result they may interfere with integration (34,35). The occurrence of dental implant failure with or without osteonecrosis due to per os bisphosphonates is not known; yet several surveys have indicated that it may be considered rare (6, 35-38). Leonida et al. reported a 100% success rate without implant loss or BRONJ development in a pilot study of patients on oral bisphoshonates for osteoporosis after immediate loading of dental implants in mandible full arch (39). Bedogni et al. reported a case of BRONJ after implant placement in patients receiving oral nitrogen-containing bisphosphonates; they highlighted the need to offer a full explanation of the potential risks of BRONJ development and implant failure in patients receiving per os bisphosphonates and stressed the importance of meticulous long-term oral hygiene of implant-prosthetic restorations (40). A large Australian survey in 16,000 patients who had received dental implants showed that only 7 patients on per os bisphosphonate therapy experienced implant failure or BRONJ and the implant failure rate was calculated 1 in 114 (0.89%) (32). Five of these patients had been on bisphosphonate therapy for 3 years or more (32). In 3 patients one implant failed to integrate, while in 4 patients one or more implants lost their osseointegration and were removed (32). Madrid et al., 2009, in a systematic review stated that the placement of implants may be considered a safe procedure in patients taking oral bisphosphonates for less than 5 years (41). In general, it is advised to discontinue the per os bisphosphonate treatment, after consultation with the treating physician and if systemic conditions permit, for at least 3 months before the placement of the implants and until osseointegration is achieved, especially in patients receiving oral bisphosphonates for more than 3 years and/or treated jointly with corticosteroids (4,12,42,43). Serologic bone turnover tests have been proposed, but their clinical value is uncertain, unless more surveys are conducted (32). Informed consent must be obtained before placing dental implants on patients receiving per os bisphosphonates (4,43). Last but not least, prolonged follow-up is indicated (44).

conclusion In conclusion, the risk of BRONJ in patients on per os bisphosphonates may be considered minimal but cannot

be ignored (41,45). Dental implants can be placed in these patients as long as they are aware of the possible risks and the necessary precautions are taken.

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18. Maerevoet M, Martin C, Duck L. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005; 353(25):2728. 19. Dimopoulos MA, Kastritis E, Anagnostopoulos A, Melakopoulos I, Gika D, Moulopoulos LA, Bamia C, Terpos E, Tsionos K, Bamias A. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Haematologica 2006; 91(7):968-71. 20. Tosi P, Zamagni E, Cangini D, Tacchetti P, Di Raimondo F, Catalano L, D’Arco A, Ronconi S, Cellini C, Offidani M, Perrone G, Ceccolini M, Brioli A, Tura S, Baccarani M, Cavo M. Osteonecrosis of the jaws in newly diagnosed multiple myeloma patients treated with zoledronic acid and thalidomidedexamethasone. Blood 2006; 108(12):3951-2. 21. Pozzi S, Marcheselli R, Sacchi S, Baldini L, Angrilli F, Pennese E, Quarta G, Stelitano C, Caparotti G, Luminari S, Musto P, Natale D, Broglia C, Cuoghi A, Dini D, Di Tonno P, Leonardi G, Pianezze G, Pitini V, Polimeno G, Ponchio L, Masini L, Musso M, Spriano M, Pollastri G; Gruppo Italiano Studio Linfomi. Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients. Leuk Lymphoma 2007; 48(1):56-64. 22. Ibrahim T, Barbanti F, Giorgio-Marrano G, Mercatali L, Ronconi S, Vicini C, Amadori D. Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study. Oncologist 2008; 13(3):330-6. 23. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008; 44(9):857-69. 24. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007 65(3):415-23. 25. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E. American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22(10):1479-91. 26. Bagán J, Blade J, Cozar JM, Constela M, García Sanz R, Gómez Veiga F, Lahuerta JJ, Lluch A, Massuti B, Morote J, San Miguel JF, Solsona E. Recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates. Med Oral Patol Oral Cir Bucal 2007; 12(4):E336-40. 27. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006; 24(6):945-52. 28. Wessel JH, Dodson TB, Zavras AI. Zoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: a case-control study. J Oral Maxillofac Surg 2008; 66(4):625-31. 29. Brooks JK, Gilson AJ, Sindler AJ, Ashman SG, Schwartz KG, Nikitakis NG. Osteonecrosis of the jaws associated with use of risedronate: report of

2 new cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103(6):780-6. 30. Vescovi P, Nammour S. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) therapy. A critical review. Minerva Stomatol 2010; 59(4):181-203, 204-13. 31. Chiu CT, Chiang WF, Chuang CY, Chang SW. Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw--a serial case analysis. J Oral Maxillofac Surg 2010; 68(5):1055-63. 32. Goss A, Bartold M, Sambrook P, Hawker P. The nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in dental implant patients: a South Australian case series. J Oral Maxillofac Surg 2010; 68(2):337-43. 33. Davies JE. Understanding peri-implant endosseous healing. J Dent Educ 2003; 67(8):932-49. 34. Javed F, Almas K. Osseointegration of dental implants in patients undergoing bisphosphonate treatment: a literature review. J Periodontol 2010; 81(4):479-84. 35. Starck WJ, Epker BN. Failure of osseointegrated dental implants after diphosphonate therapy for osteoporosis: a case report. Int J Oral Maxillofac Implants 1995;10(1):74-8. 36. Fugazzoto PA, Lightfoot WS, Jaffin R, Kumar A. Implant placement with or without simultaneous tooth extraction in patients taking oral bisphosphonates: postoperative healing, early follow-up, and the incidence of complications in two private practices. J Periodontol 2007; 78:1664-9. 37. Wang HL, Weber D, McCauley LK. Effect of long-term oral bisphosphonates on implant wound healing: literature review and a case report. J Periodontol 2007; 78(3):584-94. 38. Shin EY, Kwon YH, Herr Y, Shin SI, Chung JH. Implant failure associated with oral bisphosphonate-related osteonecrosis of the jaw. J Periodontal Implant Sci 2010; 40(2):90-5. 39. Leonida A, Vescovi P, Baldoni M, Rossi G, Lauritano D. Immediate loading of dental implants in mandible full-arch: pilot study in patients with osteoporosis treated with bassoonists therapy. J Oral Implantol. 2010 Jun 16. doi.org/10.1563/AAID-JOI-D-09-00132.1 40. Bedogni A, Bettini G, Totola A, Saia G, Nocini PF. Oral bisphosphonateassociated osteonecrosis of the jaw after implant surgery: a case report and literature review. Oral Maxillofac Surg 2010; 68(7):1662-6. 41. Madrid C, Sanz M. What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review. Clin Oral Implants Res 2009; 20 Suppl 4:87-95. 42. Scully C, Madrid C, Bagan J. Dental endosseous implants in patients on bisphosphonate therapy. Implant Dent 2006;15(3):212-8. 43. Flichy-Fernández AJ, Balaguer-Martínez J, Peñarrocha-Diago M, Bagán JV. Bisphosphonates and dental implants: current problems. Med Oral Patol Oral Cir Bucal. 2009; 14(7):E355-60. 44. Lazarovici TS, Yahalom R, Taicher S, Schwartz-Arad D, Peleg O, Yarom N. Bisphosphonate-related osteonecrosis of the jaw associated with dental implants. J Oral Maxillofac Surg 2010; 68(4):790-6. 45. Goiato MC, dos Santos DM, Rondon BC, Moreno A, Baptista GT, Verri FR, Dekon SF. Care required when using bisphosphonates in dental surgical practice. J Craniofac Surg 2010; 21(6):1966-70.

journal of osseointegration

Marco Degidi1, Adriano Piattelli2, CLAUDIO Marchetti3, vittoria Perrotti2, giovanna Iezzi2 1

Private Practice, Bologna, Italy Dental School, University of Chieti-Pescara, Italy 3 Dental School, University of Bologna, Italy 2

Histology of peri-implant bone in a failed implant retrieved from an area of osteonecrosis of the jaw in a patient suffering from multiple myeloma and treated with intravenous bisphosphonates to cite this article Degidi M, Piattelli A, Marchetti C, Perrotti V, Iezzi G. Histology of peri-implant bone in a failed implant retrieved from an area of osteonecrosis of the jaw (ONJ) in a patient suffering from multiple myeloma and treated with intravenous bisphosphonates. J Osseointegr 2012;1(4):15-20.

Keywords Intravenous bisphosphonates; Dental implants; Failed implants; Osteonecrosis of the jaws.

ABSTRACT Background Osteonecrosis of the jaw (ONJ) has been reported in the past few years in patients undergoing treatment with bisphosphonates (BP). Few published histological studies of ONJ can be found in the literature and no study has been reported on the peri-implant bone around a dental implant retrieved from an area of ONJ. The aim of the present case was to report the histology of the peri-implant bone around an implant retrieved from an area of ONJ. Materials and methods Multiple myeloma was diagnosed to a 72-year-old male. The patient underwent treatment with intravenous pamidronate for 2 years and with intravenous zoledronate for additional 3 years. Five years after the diagnosis, 7 immediately loaded dental implants were inserted in the mandible. A preoperative panoramic radiography did show no pre-existing bone lesions. No healing of the post-extraction sockets of the right third molar and of the left second molar was observed. Three years after the implant insertion a breakdown of the oral mucosa covering the implants was observed. The most distal implant was retrieved with a trephine bur, due to mobility. Discussion The histological findings showed some areas with osseointegration in patients undergoing BP treatment for malignant disease. Conclusion There is certainly a temporal association between BP use and development of ONJ, but a correlation does not necessarily mean causation. Moreover, generalisations about this complex relationship cannot be made on the basis of a single case report. In patients undergoing intravenous treatment, clinicians must be aware of the increased risk of implant failure and, probably, implant insertion should be avoided at all, until more conclusive data are available.

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INTRODUCTION Nitrogen-containing bisphosphonates (BP) possess a pyrophosphate-like chemical substructure that confers a strong affinity for calcium (1). Nitrogen-containing BPs reduce osteoporotic fracture risk by 50-60% and skeletal-related events by more than 30% (1). In recent years, a complication, consisting in the presence of a non healing oral mucosal ulcer with underlying necrotic bone has been reported in the literature (2, 3). This lesion has been termed Osteonecrosis of the Jaw (ONJ) (2,3). Ninety-four percent of published cases has been reported in multiple myeloma or metastatic bone diseases in patients who received intravenous aminoBPs like zoledronic acid, pamidronate, ibandronate and alendronate (4). The most common site was posterior/ lingual mandible, in the area of the mylohyoid ridge (5), and areas with thin mucosa overlying bone prominences such as tori, exostoses (6, 7). The pathogenesis remains unclear and is probably multifactorial (8-11). BPs could act on the inhibition of osteoclast recruitment, diminution of osteoclast life span and inhibition of the osteoclast activity at the bone surface (2). The profound inhibition of osteoclast function can also inhibit normal bone turnover to an extent that local microdamage from normal mechanical loading or injury cannot be repaired and this can ultimately lead to bone necrosis (6, 7, 11). Moreover, BPs inhibit endothelial function, diminish levels of Vascular Endothelial Growth Factor (VEGF) and, in rat, decrease the rate of capillary formation (12).

journal of osseointegration Degidi M. et al.

BPs have a selective concentration at the interface of the active osteoclast and the bone-resorption surface (8). There is evidence that internalization of the BPs in active osteoclasts disrupts the cytoskeleton and vesicular trafficking, leading to cessation of resorption and induction of apoptosis (3 ,4, 13). Treatment with BPs will be aimed also to disrupt the osteocyte signalling (14), and, furthermore, evidence of osteoblastic dysfunction in multiple myeloma has been reported (15). Another action could be on osteoclast precursors to prevent osteoclast formation (4). BPs have also an antiangiogenic effect, being able to decrease endothelial cell proliferation (3, 7) and contributing to the apparent ischemic changes (6). Moreover, they could produce a direct induction of avascular necrosis, an increase in the rate of apoptosis, and a decrease in capillary tube function (8). A worsening of ONJ during treatment with a novel antiangiogenic drug has been reported (16), and data confirm the possibility that BPs could have a suppressive effect on angiogenesis through an action on IL-17, a proangiogenic cytokine (17). Some drugs could potentiate the known antiangiogenic properties of zoledronate (18). At a molecular level, it has been shown that BP influence osteoclast activity through the modulation of a cell surface receptor or an intracellular enzyme (3). The decrease in bone cellularity and blood flow could lead to a generalized impairment of bone remodelling and of the response to skeletal injury (5). The jaws are constantly undergoing impact loading, which may require a remodelling response and are frequently the site of trauma, such as tooth extraction (5). Furthermore, BPs may prevent hydroxyapatite crystal formation, aggregation and dissolution (19). High concentrations of alendronate and zoledronate were cytotoxic for the osteoblasts (20). In multiple myeloma there is an osteoblast inhibition with absence of bone regeneration and of functional exhaustion and apoptosis of osteoblasts (21). The available data would, however, suggest that the pathogenesis of ONJ is related more likely to a process in which mucosal damage is the event preceding infection and subsequent bone damage (22). BPs may be toxic to oral epithelium and delayed epithelization may result in exposed bone that, in the presence of oral bacteria, increases the risk of infection (22). A global inhibition of the genes involved in bone remodelling in patients with ONJ has been reported (23). Patients who take oral BPs are no more at risk of implant failure than other patients (24) and implant success was comparable between patients receiving oral BP therapy and those not receiving this type of therapy (25). Recently, a case was reported of a patient, undergoing oral treatment with BP, who presented a significant bone defect with necrosis after implant placement (26). Clinically, ONJ is characterized by the presence of ulcerated mucosa and exposed, white-yellow,

devitalized bone (5,7). The surrounding soft tissues are often inflamed due to a secondary mucosal infection (5, 6). Pain, oral discomfort, purulent discharge, exudates and fistula are common (5, 6, 8, 27). The most important clinical characteristic of ONJ is the finding of exposed bone in the oral cavity (28). Patients may be considered to have ONJ if all the following 3 features are present: 1) current or previous treatment with a BP; 2) no history of radiation therapy to the jaws; 3) exposed necrotic bone in the maxillofacial region that has persisted for more than 8 weeks (6, 9, 15, 21, 28). Tooth extractions were the predominating event preceding ONJ (29), although other causes, such as periodontal disease, dental implant procedures, illfitting dentures, were also reported (22). It is unclear why ONJ is limited to the craniofacial bones (19). Probably, there is a unique environment in the oral cavity (6). Patients with a history of periodontal and dental abscesses are at a 7-fold increased risk of developing ONJ (6). Where possible, extractions should be avoided and it is probably best to avoid all elective oral surgery in patients on BP, including endosseous implant placement (30). Few published histological studies of ONJ can be found in the literature, no microscopic features unique or diagnostic (6). These studies have shown vital cells and bone in more than half the patients (12, 22), pronounced inflammatory changes (12, 22), bone necrosis and infection (2, 28), numerous osteoclasts present in close contact with bone (12), minimal presence of Howship lacunae, congested venules and bacterial infiltrate within deep bone trabeculae (26), an absence of osteoblasts or vascularization (5), fibrosis of marrow spaces in nearly all cases, obliteration of blood vessels only in a few specimens, increased cellularity in the intima and media of the artery, and actinomyces colonies in all cases (12). The aim of the present case was to report the histology of the peri-implant bone around an implant retrieved from an area of ONJ.

Case report Multiple myeloma was diagnosed to a 72-year-old male. The patient underwent treatment with intravenous pamidronate for 2 years (90 mg every 2 months) and with intravenous zoledronate (4 mg every 2 months) for an additional 3 years. Five years after the diagnosis, 7 immediately loaded dental implants (XiVEÂŽ, DENTSPLY-Friadent, Mannheim, Germany) were inserted in the mandible (Fig. 1, 2). At suture removal, a delayed healing of the postextraction sockets of the right third molar and of the left second molar was observed. A bilateral osteonecrosis

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journal of osseointegration On a failed implant in a patient with multiple myeloma and ONJ secondary to intravenous bisphosphonates

fig. 1 Preoperative panoramic x-ray. fig. 2 Postoperative panoramic x-ray.

fig. 3 The osteonecrosis progressively involved the two distal implants on each side.

fig. 4 The bone was present only around the apical portion of the implant. Acid fuchsin-toluidine blue, 10 X. fig. 5 At higher magnification, bone was present in contact with the implant surface. Acid fuchsin-toluidine blue, 40 X. fig. 6 In some portions of the interface, this bone was still vital, with a normal structure and normal staining characteristics. The osteocyte lacunae were filled by osteocytes. Acid fuchsin-toluidine blue, 100 X.

was then diagnosed. During the three years after implant placement, the extension of the lesions increased and finally involved the most distal implant in each side (Fig. 3). These two implants were removed; one still had some bone attached to it. The specimen underwent light microscopical analysis. The implant and the surrounding tissues were stored immediately after removal in 10% buffered formalin and processed to obtain thin ground sections with the Precise 1 Automated System (Assing, Rome, Italy) (31). The specimen was dehydrated in an ascending series of alcohol rinses and embedded in a glycolmethacrylate resin (Technovit 7200 VLC, Kulzer, Wehrheim, Germany). After polymerization, the specimen was sectioned longitudinally along the major axis of the implants with a high-precision diamond disc at about 150 Îźm and ground down to about 30 Îźm. Three slides were obtained, which were stained with acid fuchsin and toluidine blue.

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RESULTS At low power modification, bone was present only around the apical portion of the implant (Fig. 4). At higher magnification, bone was present in contact with the implant surface (Fig. 5). In some portions of the interface, this bone was still vital, with a normal structure and normal staining characteristics. A close connection was observed between this bone and the implant surface, and no gaps were found at the interface; also absent were inflammatory infiltrate, connective tissue and epithelial downgrowth. At higher magnification, the osteocyte lacunae were filled by osteocytes (Fig. 6). Osteoid matrix was present in some portions of the interface; no osteoblasts were, however, present. In a few areas bone remodelling and osteons were present. In other areas, non vital bone was present at the interface and also at a distance from the metal surface (Fig 7). This latter type of bone did not show a normal staining and a normal bone. Moreover, this bone appeared to be

journal of osseointegration Degidi M. et al.

fig. 7 In other areas, non vital bone was present at the interface and also at a distance from the metal surface. Acid fuchsin-toluidine blue, 40 X.

fig. 8 In some portions, the bone appeared to be partially demineralized. Acid fuchsin-toluidine blue, 40 X.

fig. 9 At higher magnification, Howship lacunae, but no osteoclasts, were observed. Acid fuchsin-toluidine blue, 100 X.

fig. 10 In other areas, non vital bone was present and the osteocyte lacunae were empty. Acid fuchsin-toluidine blue, 200 X.

fig. 11 In some areas of the interface, it was possible to see the presence of a connective tissue with a slight inflammatory cell infiltrate. Acid fuchsin-toluidine blue, 200 X.

fig. 12 Only in a few areas, a few small vessels were present; their wall was constituted by a few layers of endothelial cells. Acid fuchsin-toluidine blue, 200 X.

partially demineralized (Fig. 8). No newly-formed bone or osteoblasts were present around this bone. At higher magnification, Howship lacunae, but no osteoclasts, were observed (Fig. 9). The osteocyte lacunae were empty (Fig. 10). In some areas of the interface, it was possible to see the presence of a connective tissue with a slight inflammatory cell infiltrate (Fig. 11). Only in a few areas, a few small vessels were present; their wall was constituted by a few layers of endothelial cells (Fig. 12).

DISCUSSION

Long-term intravenous BP use, especially with zoledronate and pamidronate, seems to be the most important risk for complications (8). Cumulative hazard seems to be 1% after 12 months, 10% after 2 years, and 20% after 3 years (8). After 2 years of treatment, the cumulative hazard of developing ONJ was estimated to be 3% which increased to 11% after 4 years (4). In a retrospective study on 4019 patients, 1.2% of patients

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journal of osseointegration On a failed implant in a patient with multiple myeloma and ONJ secondary to intravenous bisphosphonates

with breast cancer and 2.4% of patients with multiple myeloma developed ONJ (32). A rate of 1 event per 100.000 person-years of exposure for oral BPs has been reported (22). Variables predictive of developing ONJ in multiple myeloma have been reported to be treatment with pamidronate/zoledronate, dental extraction, longer follow-up time, and older age at diagnosis (4,9). There is evidence that BP use is a contraindication to oral implants (22), like all oral surgical procedures, while other researchers reported no causal relationship between oral BPs and implant failure (24). One patient developing ONJ after implant placement has been reported (33). It is best to avoid all elective oral surgery in patients on BP, including endosseous implant placement (30) above all in patients taking intravenous BP. The present histological findings, that is the presence both of well osseointegrated portions of the implant with a close connection with the surrounding bone and of a gap between bone and implant, with connective tissue and inflammatory cells at the interface, and with the presence of non vital bone, demonstrate that implant osseointegration can occur in patients undergoing BP treatment for malignant disease. A bone regeneration was then present, contrary to reports of a lack of it in patients with multiple myeloma (21). In the present case, no osteoblasts nor osteoclasts were observed; similar results were reported by Badros et al. (33). The present histological results were similar to those reported by Bedogni et al., (27) who found that areas of bone with empty osteocyte lacunae coexisted with areas of bone with viable osteocytes. No inflammatory infiltrate was found in the peri-implant tissues, contrary to the results reported by Badros et al. (33) who, in many cases, found foci of mixed inflammatory cellular infiltration near to the necrotic bone. BPs are probably involved in the development of ONJ (34), even if a direct causal relationship has yet to be determined (24). While there is clearly a temporal association between BP use and development of ONJ, a correlation cannot be assumed to mean causation (4). It must also be underlined that ONJ is seen overwhelmingly in an oncologic population, where patients are often receiving concomitant chemotherapy and immunosuppressants (35). The combination of compromised immunity and medications, which affect wound healing, suggests that a multifactorial model is required to explain the pathogenesis of ONJ (22). In the literature it is also possible to find cases of ONJ that developed in the absence of BPs and ONJ has been reported to occur only after chemotherapy with no BPs use (10). Osteonecrosis in other sites than the jaws may be produced also by a long-term high-dose glucorticoids use (10). Moreover, patients with malignancies have a risk of developing osteomyelitis of the jaws that is 4 times higher than the normal, healthy population (10). The clinical picture of ONJ is similar to conventional osteomyelitis of the jaws (10). Moreover, ONJ may be

caused by combined and environmental and genetic risk factors (34). Moreover, toxic effects of chemotherapy have been described in the past 20 years. In conclusion, there is certainly a temporal association between BP use and development of ONJ, but a correlation does not necessarily mean causation (4). In patients undergoing intravenous treatment, clinicians must be aware of the increased risk of implant failure and retarded wound healing and, probably, implant insertion should be avoided at all, until more conclusive data are available. ONJ must be differentiated from osteomyelitis, delayed healing of extraction sockets, sequestra development, the presence of fistulae (28, 33).

Acknowledgments This work was partially supported by the National Research Council (CNR), Rome, Italy, and by the Ministry of Education, University, Research (MIUR), Rome, Italy.

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