Maxillary Sinus Lift Material Comparison

Noumbissi et al Figure 11: DMBBX particle surrounded by new bone, no Figure 12: Low magni cation MSDBA. DFDBA present at 10 months. at least 3 days after surgery, and to cough or (1) delipidization, (2) osmotic contrast treat- sneeze with an open mouth to prevent dis- ment, (3) oxidation treatment with hydrogen lodging the graft. In addition, the application peroxide, (4) solvent dehydration and (5) lim- of pressure and ice at the surgical site, eleva- ited dose Gamma irradiation (17.8 GY).23 The tion of the head and rest were recommended. third set of grafts observed consisted of a 1:1 To control pain and discomfort, ibuprofen was combination of DMBBX (Bio-Oss, Geistlich, prescribed as a postoperative analgesic (800 Wolhusen, Switzerland) and DFDBA (Mus- mg: 1 tablet 3 times daily for at least 3 days). culoskeletal Transplant Foundation, Holmdel, The sutures were removed approximately NJ; particle size 750-1000 microns). If the one week later after soft tissue maturation. Schneiderian membrane tore during surgery, a bioabsorbable collagen membrane (Bio- Treatment Phase II Mend, Zimmer Dental Inc., Carlsbad, CA) was The patients were reappointed periodically placed over the perforation with a 2-3 mm over- every forty five days for a period ranging from lap beyond the tear prior to graft placement.24 6 to 12 months after graft placement and a panoramic radiograph and/or cone beam com- After grafting, the lateral sinus wall was cov- puted tomography scan (Prexion 3D, Tera ered with a collagen membrane (Bio-Mend), Recon) was taken to assess the radiographic and the soft tissues were approximated and appearance and bone density of the grafted sutured (5-0, Vicryl, Ethicon, Sommerfield, sinuses as well as the volume and/or height NJ). Postoperative instructions included rins- of new bone between the residual crest ridge ing 3 times daily for 2 weeks with 0.12% and the elevated sinus floor. The DMBBX/ chlorhexidine gluconate (Peridex, Procter DFDBA cores were all harvested at ten (10) and Gamble, Cincinnati, OH). Patients were instructed to try not to blow their noses for 52 • Vol. 2, No. 5 • June 2010

Noumbissi et al Figure 13: Polarized view of NB formation around and Figure 14: x10 magni cation showing various stages of within MSDBA particles. MSDBA turning over into NB. Figure 15: MSDBA particle almost completely turned over Figure 16: High magni cation NB forming at the edges into immature NB. and within MSDBA (P) particle. Figure 17: Large amounts of NB formation within a MSDBA core. The Journal of Implant & Advanced Clinical Dentistry • 53

Noumbissi eettaall Figure 19: Low magni cation Core cancellous. Figure 18: High magni cation of gure #17. Figure 20: Cancellous particle repopulated by osteocytes. months. Seven of the twelve MSDBAM cores Histologic and Histomorphometric Analyses were harvested at six (6) months and the other Once in the histology laboratory, the biopsy five at twelve (12) months. Six of the thir- specimens were removed from the trephine teen cancellous (MSDBA) cores were har- drills, fixed in 10% buffered formalin for 4 to 8 vested at six (6) months and the other seven weeks then dehydrated in ascending concentra- cores were harvested at ten (10) months. tions of alcohol and embedded in specialized Biopsy cores were collected at the planned resin (Technovit 7200 VLC, Kulzer, Wehrheim, implantation site in a vertical direction. The Germany). Upon completion of polymerization, 2-mm-diameter biopsy was harvested with a the blocks were mounted onto slides and initial standardized trephine drill from the alveolar midaxial sections of 200 microns were made crest and ended 2 mm short of the most supe- by means of a cutting-grinding system (Exact rior part of the graft. The collected core was Medical Instruments, Oklahoma City, OK). kept in the trephine drill and sent to the labo- These sections were subsequently ground to ratory for processing, and the biopsy site was 40 µm to 50 µm and used unstained for histo- converted to an implantation site by means of morphometric analysis and light fluorescence lateral bone condensation in graduated diam- microscopy. The sections were then ground to eters but stopping 0.6 to 1.2 mm short of the particle sizes ranging from 10 µm to 20 µm and selected implant diameter for the site. The stained with 1% toluidine blue for histologic implants were inserted; the fixture mounts were removed and cover screws installed. The soft tissue was sutured (5-0 Vicryl) over the implants for a two-stage surgical proto- col. The sutures were removed approximately one week later after soft tissue maturation. 54 • Vol. 2, No. 5 • June 2010

Noumbissi et al Figure 21: NB formation within particle. Figure 22: Cancellous particle repopulated by osteocytes. Figure 23: Three levels of bone maturity: 1) Cancellous Figure 24: NB formation within cortical particle of a part, 2) Mature lamellar bone, 3) Immature bone (darker MSDBAM core at12 months: turnover in progress on the red areas). left and ri ght. analysis by means of bright field and polarized images were obtained in field sizes of 2 mm x 2 microscopic evaluation at x20 magnification in mm, digitized as a 256 x 256 array of 8-bit den- a protocol previously described by Donath.28 sity values, and transferred into a microcomputer. The histomorphometric analysis was performed The undecalcified sections were analyzed on a computer (Apple, Cupertino, CA) using the histomorphometrically using backscattered public domain image program developed at the electron image analysis. Before placing the U.S. National Institutes of Health (available on specimens in the scanning electron microscope the Internet at http://rsb.info.nih.gov.nih-image/). chamber, the specimen surfaces were plated with gold palladium. Backscattered electron Volume fractions of the following tissue com- The Journal of Implant & Advanced Clinical Dentistry • 55

Noumbissi et al Table 1: Histomorphometric Findings Analysis MSDBA Graft1 DMBBX/DFDBA Graft2 MSDBAM Graft2 (Cumulative Percentage) % % % Percentage of core 45.61 40.33 45.42 that is bone 79.15 4.67 74.21 ——— ——— Percentage of core that 39.10 is vital bone 42.14 ——— 45.52 ——— ——— Percentage of new bone ——— ——— DMBBX/DFDBA ——— ——— 32.03 (10 months) 54.38 ——— 33.06 54.33 54.63 Percentage of new bone MSDBA1 (6 months) Percentage of new bone MSDBA1 (10 months) Percentage of new bone MSDBAM3 (6 months) Percentage of new bone MSDBAM3 (12 months) Percentage of brous marrow tissue 1. MSDBA Graft = 100% MSDBA Cancellous 2. DMBBX/DFDBA = 50% DMBBX and 50% DFDBA 3. MSDBAM Graft = 50 % MSDBA Cancellous and 50% MSDBA Cortical ponents were computed based on differences (4) percentage of fibrous tissue. These param- in optical density, and the following param- eters were evaluated in all three types of grafts. eters were measured and compared: (1) per- To evaluate the mineralization process in the centage of core that is bone, (2) percentage sinus graft, the grafted region of each speci- of vital bone, (3)percentage of new bone and men was divided into three equally sized areas 56 • Vol. 2, No. 5 • June 2010

Noumbissi et al Figure 25: High magni cation of Fig 24: turnover of Figure 26: Cortical particle of MSDBAM new bone cortical particle at 12 months. formation within particle. Figure 27: More advanced stage of cortical particle Figure 28: High Magni cation of gure 27. turnover in MSDBAM. cortico-cancellous graft. Thirteen sinuses were to determine tissue components at the infe- grafted with cancellous grafts. Four sinuses rior, center and superior levels of the biopsies. were grafted with DMBBX/DFDBA. One of the sinuses that were grafted with MSDBAM RESULTS was perforated and repaired using the Loma Linda pouch technique.31 At 12 months a core Patient and treatment data are summarized in was harvested and the amount of new bone in Table 1. A total of 25 patients with a mean age the core harvested from that particular sinus of 67.5 years were selected for participation in this study. Twelve sinuses were grafted with The Journal of Implant & Advanced Clinical Dentistry • 57

Noumbissi et al amounted to 15.36%, much below the average that of the cancellous particles of MSDBA obtained in the other sinuses during the same (Fig 16, 25, 26). There seems to be albeit time frame. Similar findings were observed in slow, an initial turnover of some of the corti- the MSDBA cores harvested from sinuses that cal particles in MSDBAM, but this appears not were perforated at the time of grafting. These to change in any significant manner. In fact at finding are concurrent with observations made 12 months there were still some mineralized in a previous study by Proussaeffs et al.32 cortical particles in MSDBAM (Fig 24, 25) and the same was observed for the DMBBX/ At six months, the greatest amount of new DFDBA grafts at 10 months (Fig 10, 11). In bone was observed for MSDBA (42.14 %), fol- some cases osteocytes appear to be repopu- lowed by MSDBAM (32.03%). At ten months lating the previous lacunae of the MSDBA the amount of new bone for MSDBA was graft particles (Fig 7, 16, 18, 20 and 22). 45.52% versus 39.19% for DMBBX/DFDBA. At twelve months, the amount of new bone in Histomorphometric findings are summarized MSDBAM specimens was 33.06% which is in Table 1. All grafts successfully achieved new virtually identical to the values observed at six bone formation. The observed percentages of months. One of the main reason there is a the cores which were bone (vital, and non-vital) statistically significant difference in new bone was virtually identical across all graft types. formation between MSDBA and MSDBAM With regards to the percentage of vital bone in is not the time length of bone healing but the the cores, the results were significantly higher perforation of the sinus membrane in one in the MSDBA and MSDBAM grafts. In terms case of MSDBAM that resulted in an unusu- of graft turnover (i.e. resorption and replace- ally low percentage of new bone formation ment by new bone), significant differences (15.36%). Overall, new bone in the MSDBA between the three grafts were found. There cores was higher than the other two grafts were far more DMBBX particles found in the combinations observed in this study. Histol- cores at 10 months and they were large in size ogy findings are presented in Figures 1-28. occupying a great portion of the cores. This All samples exhibited good bone formation explains why in terms of percentage of core that with new bone bridging or growing onto the is bone the DMBBX/DFDBA core show num- surfaces of the residual graft particles (Fig bers very close to that of MSDBA and MSD- 1, 2, 5, 11). DMBBX/DFDBA samples dif- BAM. In contrast, a significant amount of the fered from MSDBA and MSDBAM by gen- cancellous particles had either turned over erally exhibiting a greater number and larger or were surrounded by new bone of different residual graft particles (Fig 5, 6, 10). Residual maturation levels at six and 10 months (Fig 4, MSDBA and MSDBAM graft particles were 5, 6, 11 and 23). Within the cortico-cancellous often so well incorporated that they were dif- cores which were harvested at twelve months, ficult to distinguish from new bone (Fig 7, 8, most of the cortical particles had undergone 9). The turnover of the cortical particles of turnover or were in the advanced stages of the MSDBAM graft material was still slower than process (Fig 27, 28) but the amount of new 58 • Vol. 2, No. 5 • June 2010

Noumbissi et al bone was not statistically different from the local blood vessels and failure to revascular- six-month cores. It is important to note, how- ize the graft.4,28 Graft necrosis and the prolif- ever, that the statistical significance of these eration of inflammatory granulation tissue can histomorphometric differences could not be occur as secondary effects and interfere with a determined because of the small sample size. graft’s incorporation and new bone formation.26 While contemporary tissue processing tech- DISCUSSION niques can attenuate these responses, some may also diminish the mechanical strength of After graft placement, the pattern, rate and the allograft.28 Approximately 12.2% of the quality of new bone formation are directly influ- estimated 40,000 bone allografts placed each enced by complex reactions between the nature year become infected, compared to 3.5% of of the graft material and healing processes of the autografts placed annually.29-30 Such infec- the biological host.4,5,26 Concurrent revascular- tions can arise from a number of recipient fac- ization and substitution of the graft material with tors apart from donor disease or contamination host bone without a significant loss of strength from processing.29 Nonetheless, strict donor or volume are essential for bone grafting to be screening and tissue processing techniques successful.4,5,26 In the present study, graft turn- are crucial. The tissue should be harvested over occurred more rapidly with MSDBA and according to Good Manufacturing Practices by MSDBAM compared to the bovine component a certified tissue bank, and processed for bio- (DMBBX) of the composite grafts. The slower logical safety. All of the graft materials used turnover rate of DMBBX is consistent with the in the present study met these standards. observations of Artzi et al.18 in their comparative canine study. This phenomenon may be attribut- Statistical analysis of clinical data is an able, in part, to structural changes that occur in important standard for determining data integ- the mineral phase of DMBBX during heat-pro- rity, especially when comparing the clinical cessing at 300° C, which reportedly enlarges effectiveness of two products. While the find- the xenograft mineral particles to approximately ings of the present study appeared promis- twice the size of MSDBA mineral particles.27 In ing, they also confirmed the slower turnover comparison, processing does not change the of cortical particles as well as that of the very mineral particle size of cortical or cancellous slow turnover of the DMBBX component of MSDBA. Cancellous MSDBA retains a bone- the Xenograft. The small study population pre- like structure with interconnecting porosity.27 cluded the ability to determine if the faster turn- over of MSDBA cancellous and cortical was Adverse immunologic response by the statistically significant. In a follow up study patient, infection, impaired graft healing and the amount of residual graft material in contact graft failure are some of the complications with new bone and the amount of residual graft associated with allograft placement.2 Host material in the three graft times during the same tissue sensitivity can develop from allograft- timeframes will be investigated and reported. derived antigens and cause lymphoplasma- For this reason, the present study should be cytic infiltration that results in occlusion of The Journal of Implant & Advanced Clinical Dentistry • 59

Noumbissi et al considered a preliminary inquiry and definitive ing and reentry to harvest specimens does conclusions should only be drawn from addi- not seem to have a significant effect on the tional research with a larger study population. amount of new bone formed after six months. CONCLUSIONS Correspondence: Sammy S. Noumbissi, DDS MS Graft turnover (resorption and replacement by 801 Wayne Avenue, Suite G200 new bone) occurred much faster with both cor- Silver Spring, MD 20910 tical and cancellous MSDBA compared to the Tel: 301 588-0768 bovine component (DMBBX) of the composite Fax: 301 588-0873 grafts; the percentage of fibrous or marrow tis- E-Mail: [email protected] sue was virtually identical in all core types, no Web: www.marylandintegrativedentistry.net differences in graft stability or osseointegra- tion were noted. The time between bone graft- Disclosure 11. Bianchi AE, Vinci R, Torti S, Sanfilippo F. 21. Moore TM, Artal R, Arenas M, Gendler E. The author reports no conflicts of interest with Atrophic mandible reconstruction using Influence of postmortem time and temperature anything mentioned in this article. calvarial bone grafts and implant-supported on osteoinductive activity of demineralized overdentures: radiographic assessment of microperforated ethylene oxide-sterilized References autograft healing and adaptation. Int J Periodont syndeneic bone implant in the rat. Clin Orthop 1. LeGall MG. Localized sinus elevation and Rest Dent 2004;24:334-343. Rel Res 1990;259:239-244. osteocompression with single-stage tapered 12. Mazock JB, Schow SR, Triplett RG. Proximal 22. Urist MR, Mikulski A, Boyd SD. A dental implants: technical note. Int J Oral tibia bone harvest: Review of technique, chemosterilized antigen-extracted autodigested Maxillofac Implants 2004;19(3):431-437. complications, and use in maxillofacial surgery. alloimplant for bone banks. Arch Surg 2. Leonetti JD, Koup X. Localized maxillary ridge Int J Oral Maxillofac Implants 2004;19:586-593. 1975;110:416-428. augmentation with a block allograft for dental implant placement: case reports. Implant Dent 13. Matsuura M, Ohno K, Michi K, Egawa K, 23. Günther KP, Scharf H-P, Pesch H-J, Puhl W. 2003;12:217-226. Takiguchi R. Clincoanatomic examination of Osteointegration lösungsmittel-konservierter 3. Keller EE, Tolman DE, Eckert S. Surgical- the fibula: anatomic basis for dental implant Knoche-transplantate im Tiermodell. Osteologie prosthodontic reconstruction of advanced placement. Int J Oral Maxillofac Implants 1995;5(1):4-12 maxillary bone compromise with autogenous 1999;14:879-884. onlay block bone grafts and osseointegrated 24. Pikos MA. Maxillary sinus membrane repair: endosseous implant: A 12-year study of 14. Mehta RP, Deschler DG. Mandibular report of a technique for large perforations. consecutive patients. Int J Oral Maxillofac reconstruction in 2004: an analysis of different Implant Dent 1999;8:29-34. Implants 1999;14:197-209. techniques. Curr Opin Otolaryngol Head Neck 4. Keith JD Jr. Localized ridge augmentation with Surg 2004;12(4):288-293. 25. Rosenlicht JL. Advancement in soft bone implant a block allograft followed by secondary implant stability. West Indian Dent J 2002;6(1):2-7. placement: a case report. Int J Prosthodont Rest 15. Balaji SM. Management of deficient Dent 2004;24:11-17. anterior maxillary alveolus with mandibular 26. Stevenson S, Davy DT, Klein L, Goldberg VM. 5. Noumbissi S, Lozada JL, Boyne P, Rohrer MD, parasymphyseal bone graft for implants. Implant Critical biological determinants of incorporation Clem D, Kim J, Prasad H. Clinical, Histologic Dent 2002;11:363-369. on non-vascularized cortical bone grafts. J Bone and Histomorphometric Study of Mineralized Joint Surg 1997;79-A(1):1-16. Solvent-Dehydrated Bone Allograft (PUROS) 16. Proussaefs P, Lozada J, Kleinman A, Rohrer in Human Maxillary Sinus Grafts. Journal of MD. The use of ramus autogenous grafts for 27. Buser D, Dula K, Belser U, Hirt JP, Berthold H. Oral Implantology 2005; 171-179. vertical alveolar ridge augmentation and implant Localized ridge augmentation using guided bone 6. Nemcovsky CE, Winocur E, Pupkin J, Artzi Z. placement: a pilot study. Int J Oral Maxillofac regeneration. I. Surgical procedure in the maxilla. Sinus floor augmentation through a rotated palatal Implants 2002;17:238-248. Int J Periodont Rest Dent 1993;13:29-45. flap at the time of tooth extraction. Int J Periodont Rest Dent 2004;24:177-183. 17. Gross JS. Bone grafting materials for dental 28. Tadic D, Epple M. A thorough physicochemical 7. Khoury F. Augmentation of the sinus floor applications: A practical guide. Compend Contin characterisation of 14 calcium phosphate-based with mandibular bone block and simultaneous Educ Dent 1997;18:1013-1036. bone substitution materials in comparison to implantation: a 6-year clinical investigation. Int J natural bone. Biomater 2004;25:987-994. Oral Maxillofac Implants 1999;14:557-564. 18. Artzi Z, Weinreb M, Givol N, Rohrer MD, 8. van den Bergh JPA, ten Bruggenkate CM, Nemcovsky CE, Prasad HS, Tal H. Biomaterial 29. American Medical Association. Report 5 of the Krekeler G, Tuinzing DB. Maxillary sinus floor resorptin rate and healing site morphology Council on Scientific Affairs (I-01). Safety of elevation and grafting with human demineralized of inorganic bovine bone and -tricalcium Tissues for Transplantation. Chicago: American freeze dried bone. Clin Oral Impl Res phosphate in the canine: a 24-month longitudinal Medical Association, 2001 (Dec). Available 2000;11:487-493. histologic study and morphometric analysis. Int J online at: http://www.ama-assn.org/ama/pub/ 9. Gross JS. Bone grafting materials for dental Oral Maxillofac Implants 2004;19:357-368. category/13615.html. applications: a practical guide. Compend Contin Educ Dent 1997;18:1013-1036. 19. Urist MR, Strates BS. Bone morphogenetic 30. Proussaefs P, Lozada J The “Loma Linda 10. Schultze-Mosgau S, Nkenke E, Schlegel AK, protein. J Dent Res 1971;50(6):1392-1406. pouch”: a technique for repairing the perforated Hirschfelder U, Wiltfang J. Analysis of bone sinus membrane. Int Journal Periodontics resorption after secondary alveolar cleft bone 20. Schwartz Z, Sopmers A, Mellonig JT, Carnes Restorative Dent 2003;23(6):593-597. grafts before and after canine eruption in DL Jr., Dean DD, Cochran DL, Boyan BD. connection with orthodontic gap closure or Ability of commercial demineralized freeze-dried 31. Sutherland AG, Raafat A, Yates P, Hutchison prosthodontic treatment. J Oral Maxillofac Surg bone allograft to induce new bone formation JD. Infection associated with the use of allograft 2003;61:1245-1248. is dependent on donor age but not gender. J bone from the north east Scotland Bone Bank. Periodontol 1998;69:470-478. Hosp Infect 1997;35:215-222. 32. Proussaefs P, Lozada J, Kim J. Effects of sealing the perforated sinus membrane with a resorbable collagen membrane: a pilot study in humans. J Oral Implantol 2003;29(5):235-41 60 • Vol. 2, No. 5 • June 2010



esthetics enhanced by technology Laser-Lok® Laser-Lok® dental implant at 8 years post-restoration showing superior microchannels crestal bone & tissue maintenance. Case courtesy of Cary A. Shapoff, DDS (Surgical); Jeffrey A. Babushkin, DDS (Restorative) BioHorizons is known for using science and innovation to create unique implants with proven surgical and esthetic results. Laser-Lok microchannels exemplify our dedication to evidence-based research and development. The effectiveness of Laser-Lok has been proven with over 15 years of in vitro, animal, and human studies at leading universities.† This patented precision laser surface treatment is unique within the industry as the only surface treatment shown to inhibit epithelial downgrowth, attract a true, physical connective tissue attachment to a predetermined zone on the implant and preserve the coronal level of bone; long term.‡ Laser-Lok is available on Tapered Internal, Single-stage, and Internal Implants. For more information, contact BioHorizons Customer Care: 1.888.246.8338 or shop online at www.biohorizons.com †Clinical References available. ‡Human Histologic Evidence of a Connective Tissue Attachment to a Dental Implant. M Nevins, ML Nevins, M Camelo, JL Boyesen, DM Kim. The International Journal of Periodontics & Restorative Dentistry. Vol. 28, No. 2, 2008. SPMP09051 REV D JUN 2009

Case of the Month Cóppola et al Acellular Dermal Matrix Allograft Used for Root Coverage and Increased Connective Tissue in Restorative Cases Daniel Melker, DDS1 Abstract Connective tissue as protection to under- mucosal tissue present and uncover underlying lying periodontal support has long been connective tissue. Although acellular dermal recognized. There are multiple ways matrix allograft may not convert to keratinized to increase connective tissue including palatal tissue, it does have characteristics of connec- tissue, tissue from the maxillary tuberosity, as tive tissue which serve as tissue to protect the well as acellular dermal matrix allograft taken periodontium. The cases presented are both from a cadaver. The advantage of allograft for covering root surfaces as well as adding is the lack of the need for a donor site, while connective tissue for protection of the peri- its disadvantage is that it must be covered by odontium from retraction cords during restor- a mucoperiosteal flap. This sometimes cre- ative procedures and cementation procedures ates a need for a second procedure to free any where irritation to the gingiva may take place. KEY WORDS: Acellular dermal matrix, connective tissue, root coverage, periodontal surgery 1. Private practice, Clearwater, Florida, USA The Journal of Implant & Advanced Clinical Dentistry • 63

Melker Case 1 64 • Vol. 2, No. 5 • June 2010

Melker Case 2 The Journal of Implant & Advanced Clinical Dentistry • 65

Melker Case 3 66 • Vol. 2, No. 5 • June 2010

Melker Case 4 The Journal of Implant & Advanced Clinical Dentistry • 67

Melker Case 5 68 • Vol. 2, No. 5 • June 2010

Melker Disclosure The authors report no conflict of interest with anything mentioned in this article Correspondence: Dr. Melker [email protected] Case 5 The Journal of Implant & Advanced Clinical Dentistry • 69

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Osseointegrated Implant in Suphasirioj et al Myasthenia Gravis Patient: A Case Report Wiroj Suphasiriroj DDS, MS1 • Theerathavaj Srithavaj DDS, MS1 Abstract Myasthenia Gravis (MG) is an autoim- generalized MG patient who was treated with mune neuromuscular disease char- dental implant therapy in the maxilla. Dental acterized by muscular weakness and implant delivery was carried out in a conven- fatigability. Dental management of patients tional manner with special considerations to diagnosed with MG present a challenge to prevent complications. As a result, healing and the dental profession. This article describes a restoration of the dental implant were uneventful. KEY WORDS: Myasthenia Gravis, dental implant 1. Maxillofacial Prosthetic Service, Department of Prosthodontics, Faculty of Dentistry, Mahidol University, Rajthevee, Bangkok, Thailand The Journal of Implant & Advanced Clinical Dentistry • 73

Suphasiriroj et al INTRODUCTION finger/wrist extensors are muscles most com- monly affected in the generalized form. Affect- Myasthenia Gravis (MG), an autoimmune neuro- ing 20 to 40% of patients with MG, respiratory muscular disease, is characterized by fluctuat- muscle weakness can be life threatening result- ing weakness of voluntary muscles and abnormal ing in a myasthenic crisis, an acute exacerbation fatigue on exertion.1 The etiology of MG results of symptoms with respiratory failure.1,13 Medical from decreasing acetylcholine receptors at the management of MG is primarily directed toward neuromuscular junction2,3 by three possible mech- generating normal muscle strength in minimal anisms: 1) accelerated endocytosis and degra- time and includes four main treatment modali- dation of the receptors; 2) functional blockade of ties: 1) anticholinesterase agents (pyridostigmine the acetylcholine-binding sites; 3) Complement- bromide: Mestinon® and neostigmine bromide: mediated damage to the acetylcholine recep- Prostigmin®)2,14; 2) immunosuppressive ther- tors. The thymus gland has also been implicated apy (corticosteroids)15-17; 3) thymectomy18,19; in the pathogenesis of MG but it is not known 4) short-term immunotherapy (plasmapheresis whether thymic changes play a primary or sec- and intravenous immunoglobulin: IVIg).14,20,21 ondary role in disease pathogenicity.1 MG has age and gender related peaks.1,2 The first peak Dental implants are an alternative treat- of prevalence, in the second and third decades, ment to restore missing teeth. To the best of affects mostly women, and the second, in the our knowledge, there have been no reports in sixth and seventh decades, affects mostly men. the literature regarding the placement of dental implants in the MG patient. In this case report, Onset of symptoms is often gradual, start- we present a MG patient who was treated with ing with weakness in ocular muscles. Movement dental implant therapy to rehabilitate an edentu- of the eyes and eyelids are initially affected with lous area of the maxilla. Patient considerations, the levator palpebrae, orbicularis oculi, and extra- drug use selection, and the effect of prolonged ocular muscles becoming involved. As a result, immunosuppressive therapy are discussed. patients often experience diplopia, ptosis, and nystagmus.4-5 Approximately one-fourth of diag- CASE REPORT nosed MG patients have bulbar muscle involve- ment, so named for the nerves originating from A 45-year-old Asian woman presented for exami- the brain stem’s bulb like portion.1,6 With bulbar nation in our dental clinic with a 6 month history involvement, muscle weakness causes problems of generalized Myasthenia Gravis. At an earlier with chewing,7 swallowing,8 facial movement,9 presentation in a neurological clinic, the patient’s and articulation.10 Masticatory muscle weak- chief complaints were irritation of eyes and fati- ness occurs in a considerable number of patients gability of lower limbs. Physical examination with myasthenia gravis.6,11-12 In most patients showed drooping of eyelids (ptosis), limiting of with MG, muscle weakness spreads from ocu- eye movement and leading to double vision (dip- lar and oropharyngeal muscles to the upper and lopia), and upper/lower extremity muscle weak- lower extremities, resulting in generalized form ness. Neurophysical findings from the patient of MG.1 Neck flexors, deltoids, hip flexors, and at rest demonstrated power scores of 4 (out of 74 • Vol. 2, No. 5 • June 2010

Suphasiriroj et al Figure 1a: Facial view of site #7 dental implant at time of Figure 1b: Radiograph of site #7 dental implant at time of the 2nd stage surgery. the 2nd stage surgery. a possible 5) for the neck, flexors and extensors fen) was also prescribed to the patient. Neither muscles about 4. The bulbar sign innervated supplemental steroid nor sedation was necessary by cranial nerves V, VII, IX-XII (e.g., dysarthria, in this case after consultation with her neurolo- dysphagia) were not prominent. Difficulties in gist. Vital signs were routinely monitored. Local chewing, swallowing and speech were not pre- anesthesia was administered with 2% lidocaine sented while chest radiographs and computed with epinephrine 1:100,000 and mucoperios- tomography (CT) scans of the mediastinum teal flaps were raised. Subsequently, two-stage were normal. The patient’s clinical degree of implant therapy was performed by installation of MG severity was classified as moderate gener- a 4.3×10.0 mm Replace Select Tapered® implant alized according to the Osserman scale.5 The (Noble Biocare, USA). Buccal bone augmen- patient was treated by using a combination of tation was also performed using the combina- anticholinesterase agents and immunosuppres- tion of bone graft materials (BioOss®, Geistlich, sive therapy. After remission of the disease, the Switzerland) and resorbable collagen membrane patient was referred to the dental clinic for resto- (BioGide®, Geistlich, Switzerland) since buc- ration of the missing maxillary right lateral incisor. cal implant threads (4 threads) were exposed. Implant Placement One hour prior to the morning scheduled sur- gical procedure, the patient took anticholin- esterase agent with 60 mg of pyridostigmine (Mestinon®) and corticosteroid with 5 mg of prednisolone. Antibiotic prophylaxis with 2.0 g of amoxicillin along with presurgical non-steroi- dal anti-inflammatory drugs (400 mg of ibupro- The Journal of Implant & Advanced Clinical Dentistry • 75

Suphasiriroj eettaall Figure 2a: Angled (15º) esthetic abutment connected to Figure 2b: Final prosthesis delivered to implant at site #7. osseointegrated implant. performed 3 weeks later. A 15 esthetic abut- The flaps were closed by suturing with resorb- ment was connected to implant (figure 2a) and able sutures (Vicryl®, Johnson&Johnson, USA). a cement-retained crown was inserted (figure Antibiotic, NSAIDs and chlorhexidine mouth- 2b). A radiograph taken at 1 year post-placement wash were prescribed during the first 2 weeks showed no abnormalities (figure 3). The patient after implant placement. Post-operative care was was both comfortable and satisfied with the result. instructed to the patient. The follow up visits were scheduled at 1, 3, and 6 months after implant DISCUSSION placement. Soft tissue healing around the implant was delayed and completed within 1 month after Myasthenia Gravis is a disease characterized by surgery. Otherwise, healing was uneventful. intermittent muscle weakness, which improves after anticholinesterase and immunosuppressive Abutment Connection and Prosthodontics medications. Patients with this condition may The 2nd stage surgery was carried out 8 months present with problems that necessitate special after implant placement and guided bone regen- consideration when managing their dental treat- eration, providing a longer healing period than ment.1,5 For example, patients should receive in the case of a normal maxilla or guided bone dental treatment at the time of day when cholines- regeneration. The implant had clinically osseo- terase inhibitor medication has maximum effective- integrated and demonstrated adequate sur- ness, typically within 1 and 1½ hours after taking. rounding soft tissue (figure 1a) Radiographic Morning appointment should be scheduled to evaluation showed that the crestal bone was avoid daily added muscle weakness. Basic under- intact at the implant platform level (figure 1b). A standing of the nature of the disease is essential healing abutment of 3.0 mm in height (Noble to avoid complication, such as myasthenia crisis. Biocare, USA) was connected to the implant Infection, surgical procedures, emotional stress and an implant level impression procedure was and drugs may predispose a myasthenia crisis.5,13 76 • Vol. 2, No. 5 • June 2010

Suphasiriroj et al Figure 3: One year post-placement radiograph. the potential to produce complications for MG patients by exacerbating their muscle weakness Effective pain management, soothing music, elimi- or by interfering with breathing.1,4-5,12 Amide-type nation of extraneous noises, aromatherapy, and local anesthetics, such as lidocaine (Xylocaine) anticipatory guidance may promote relaxation or mepivacaine (Carbocaine), can be adminis- and decrease stress during dental treatment. In tered safely in MG patients. Generally, penicillin some situations, use of sedatives may be helpful.5 and its derivatives are not associated with neu- romuscular blocking properties. They can be MG patients on long term corticosteroid safely used, although aggravation of MG follow- involvement need to be medically evaluated for ing administration of those has been reported.25 antibiotic premedication due to immune sup- Some antibiotics (e.g., erythromycin, tetracy- pression.5,22 Patients should be also evaluated cline) demonstrate muscle relaxing properties, for adrenal insufficiency, which would require so their uses in MG patients should be carefully supplemental glucocorticoid medication prior considered since MG patients have increased to treatment.22,23 Additionally, immunosup- sensitivity to the effect of the muscle relaxants. pressant therapy may further predispose MG patients to fungal infections and delayed wound Most MG patients need to use long-term cor- healing.5,24 In this case, the soft tissue around ticosteroids in combination with anticholinester- implant was completely healed within 1 month. ase agents for improving the treatment outcome. From previous studies, the long term systemic use Many common drugs used in dentistry have of corticosteroids is known to induce (second- ary) osteoporosis and it is reported that cortico- steroids can inhibit bone healing and increase the spontaneous fractures.26-28 Thereby, MG patients treated with long term corticosteroids have a chance to be corticosteroid-induced osteoporo- sis. Osteoporosis is considered to be a risk fac- tor for periodontal diseases, temporomandibular disorders, fail implant therapy and denture insta- bility due to alveolar ridge absorption. Neverthe- less, whether osteoporosis is a contraindication or a risk factor for dental implants remains a mat- ter of controversy. A number of reports point to the possibility that osteoporosis or a reduction in bone mass or density could be problematic to the initiation and maintenance of osseointegration of dental implants.29-32 On the contrary, several reports indicate that osteoporosis may not be nec- essarily problematic for dental implant placement The Journal of Implant & Advanced Clinical Dentistry • 77

Suphasiriroj et al or maintenance.33-37 Moreover, there is debate Correspondence: as to whether the diagnosis of skeletal osteopo- Wiroj Suphasiriroj D.D.S., M.S. rosis is in fact manifested in the oral cavity.38-40 Maxillofacial Prosthetic Service, Department of Prosthodontics, Faculty of Dentistry, Mahidol CONCLUSION University, 6 Yothe Road, Rajthevee, Bangkok 10400, Thailand. Tel: 66(81)-644-3022 This case report of a MG patient treated with a E-mail: [email protected] dental implant and GBR was carried out in a con- ventional manner with special considerations to prevent complications. As a result, healing and restoration of the dental implant were uneventful. Disclosure 15. Seybold ME, Drachman DB. Gradually 28. Yao W, Cheng Z, Busse C, Pham A, Nakamura The authors report no conflicts of interest with increasing doses of prednisone in myasthenia MC, Lane NE. Glucocorticoid excess in mice anything mentioned in this article. gravis: reducing the hazards of treatment. N results in early activation of osteoclastogenesis Referrences Engl J Med 1974;290:81-84. and adipogenesis and prolonged suppression 1. Tolle L. Myasthenia gravis: a review for dental of osteogenesis: a longitudinal study of gene 16. Evoli A, Di Schino C, Marsili F, Punzi C. expression in bone tissue from glucocorticoid- hygienists. J Dent Hyg 2007;81:12-12(1). Successful treatment of myasthenia gravis with treated mice. Arthritis Rheum 2008;58:1674- 2. Drachman DB. Myasthenia Gravis. N Engl J Med tracolimus. Muscle Nerve 2002;25:111-114. 1686. 1994;330(25):1797-1810. 17. Chaudhry V, Cornblath DR, Griffin JW, O’Brien 29. Baxter JC, Fattore L. Osteoporosis and 3. Vincent A, Palace J, Hilton-Jones D. Myasthenia R, Drachman DB. Mycophenolate mofetil: osseointegration of implants. J Prosthodont a safe and promising immunosuppressant 1993;2:120-125. Gravis. Lancet 2001;357:2122-2128. in neuromuscular diseases. Neurology 4. Patton LL, Howard JF Jr. Myasthenia gravis: 2001;56:94-96. 30. Garg AK, Winkler S, Bakaeen LG, Mekayarajjananonth T. Dental implants and the dental treatment considerations. Spec Care Dent 18. Seybold ME, Howard FM Jr, Duane DD, Payne geriatric patient. Implant Dent 1997;6:168-173. 1997;17:25-32. WS, Harrison EG Jr. Thymectomy in juvenile 5. Yarom N, Barnea E, Nissan J, Gorsky M. Dental myasthenia gravis. Arch Neurol 1971;25:385- 31. Keller JC, Stewart M, Roehm M, Schneider management of patients with myasthenia 392. GB. Osteoporosis-like bone conditions affect gravis: a literature review. Oral Surg Oral Med osseointegration of implants. Int J Oral Maxillofac Oral Pathol Oral Radiol Endod 2005;100:158- 19. Kuks JB, Oosterhuis HJ, Limburg PC, The TH. Implants 2004;19:687-694. 163. Anti-acetylcholine receptor antibodies decrease 6. Beekman R, Kuks JB, Oosterhuis HJ. Myasthenia after thymectomy in patients with myasthenia 32. Cho P, Schneider GB, Kellogg B, Zaharias gravis; diagnosis and follow up of 100 gravis: clinical correlations. J Autoimmun R, Keller JC. Effect of glucocorticoid- consecutive patients. J Neurol 1997;244:112- 1991;4:197-211. induced osteoporotic-like conditions on 118. osteoblast cell attachment to implant surface 7. Van der Bilt A, Weijnen FG, Bosman F, van der 20. Arsura EL, Bick A, Brunner NG, Namba T, Grob microtopographies. Implant Dent 2006;15:377- Glas HW, Kuks JB. Eur J Oral Sci 2001;109:160 D. High-dose intravenous immunoglobulin in the 385. -164. management of myasthenia gravis. Arch Intern 8. Ertekin C, Yuceyar N, Aydogdu I. Clinical and Med 1986;146:1365-1368. 33. Dao TT, Anderson JD, Zarb GA. Is osteoporosis electrophysiological evaluation of dysphagia in a risk factor for osseointegration of dental myasthenia gravis. J Neurol Neurosurg Psychiatry 21. Fateh-Moghadam A, Wick M, Besinger U, implants? Int J Oral Maxillofac Implants 1998;65:848-856. Geursen RG. High-dose intravenous 1993;8:137-144. 9. Weijnen FG, van der Bilt A, Wokke JH, Kuks JB, gammaglobulin for myasthenia gravis. Lancet. van der Glas HW, Bosman F. What’s in a smile? 1984;1:848-849. 34. Friberg B. Treatment with dental implants Quantification of the vertical smile of patients with in patients with severe osteoporosis: a case myasthenia gravis. J Neurol Sci 2000;173:124- 22. Little JW, Falace DA, Miller CS, Rhodus report. Int J Periodontics Restorative Dent 128. NL. Dental management of the medically 1994;14:348-353. 10. Sellman MS, Mayer RF. Weakness and compromised patient, 6th ed. St.Louis: CV Mosby; 2002:271-282. 35. Fujimoto T, Niimi A, Nakai H, Ueda M. ‘tiredness’: when to suspect myasthenia gravis. Osseointegrated implants in a patient with Geriatrics 1985;40:92-112. 23. Miller CS, Little JW, Falace DA. Supplemental osteoporosis: a case report. Int J Oral Maxillofac 11. Weijnen FG, van der Bilt A, Wokke JH, Kuks JB, corticosteroids for dental patients with adrenal Implants 1996;11:539-542. van der Glas HW, Bosman F. Maximal bite force insufficiency. J Am Dent Assoc 2001;132:1570- and surface EMG in patients with myasthenia 1579. 36. Fujimoto T, Niimi A, Sawai T, Ueda M. gravis. Muscle Nerve 2000;23:1694-1699. Effects of steroid-induced osteoporosis on 12. Weijnen FG, van der Bilt A, Kuks JB, van der 24. Bahn SL. Glucocorticoids in dentistry. J Am osseointegration of titanium. Int J Oral Maxillofac Glas HW, Oudenaarde I, Bosman F. Masticatory Dent Assoc 1982;105:476-481. Implants 1998;13:183-189. performance in patients with myasthenia gravis. Arch Oral Biol 2002;47(5):393-398. 25. Argov Z, Brenner T, Abramsky O. Ampicillin may 37. Mori H, Manabe M, Kurachi Y, Nagumo M. 13. Berrouschot J, Baumann I, Kalischewski P, aggravate clinical and experimental myasthenia Osseointegration of dental implants in rabbit Sterker M, Schneider D. Therapy of myasthenia gravis. Arch Neurol 1986;43:255-256. bone with low mineral density. J Oral Maxillofac gravis. Crit Care Med 1997;25:1228-1235. Surg 1997;55:351-361. 14. Richman D, Agius A. Treatment of autoimmune 26. Aslan M, Simsek G, Yildirim U. Effects of short- myasthenia gravis. Neurology 2004;63:1652- term treatment with systemic prednisolone on 38. Kribbs PJ, Chesnut CH III, Ott SM. Kilcoyne RF. 1661. bone healing: an experimental study in rats. Dent Relationships between mandibular and skeletal Traumatol 2005;21:222-225. bone in an osteoporotic population. J Prosthet Dent 1989;62:703-707. 27. Kozai Y, Kawamata R, Sukurai T, Kanno M, Kashima I. Influence of prednisolone-induced 39. Kribbs PJ. Comparison of mandibular bone in osteoporosis on bone mass and bone quality normal and osteoporotic women. J Prosthet of the mandible in rats. Dentomaxillofac Radiol Dent 1990;63:218-222. 2009;38:34-41. 40. von Wowern N, Storm TL, Olgaard K. Bone mineral content by photon absorptiometry of the mandible compared with that of the forearm and the lumbar spine. Calcif Tissue Int1988;42:157- 161. 78 • Vol. 2, No. 5 • June 2010





Management of a Patient Who Developed Carpenter Uncontrolled Diabetes After Implant Placement: A Case Report John F. Carpenter, DMD, MAGD1 Abstract Background: Diabetes is a serious metabolic Results: The existing implant screw-retained disorder with complications including cardiovas- fixed prosthesis was easily removed provid- cular disease, kidney disease, eye disease, nerve ing access for treatment of the implant fixtures disorders and delayed wound healing. Severe which had developed peri-implantitis. The emer- periodontal disease is another recognized compli- gence profile of the prosthesis was modified cation of diabetes. Diabetes and poor glycemic before re-attaching it to the treated implant fix- control lead to an exaggerated oral tissue response. tures. An improved tissue response was obtained. Method: A case is presented describing a patient Conclusion: Diabetes and periodontal disease who was treated with dental implants to replace have a bidirectional relationship. Just as diabetes her lower incisors. Returning in 20 months, with can worsen periodontitis, studies have shown that an exaggerated tissue response, she was diag- periodontitis has an adverse affect on the glyce- nosed with uncontrolled diabetes with concur- mic control of a diabetic. Diagnosing diabetes is rent severe periodontitis and peri-implantitis. the responsibility of the physician, but a dentist may be the first to notice the signs and symptoms of a poorly controlled or undiagnosed diabetic. KEY WORDS: Dental implants, diabetes, management, prosthetics 1. Private Practice, New Windsor, NY, USA The Journal of Implant & Advanced Clinical Dentistry • 81

Carpenter INTRODUCTION CASE REPORT Diabetes is a metabolic disorder of insulin The patient is a 4’7” 175 pound non-smoking deficiency and/or dysfunction. This leads to a 50 year old female. Twenty months previously, hyperglycemic state and causes a variety of an implant-retained FP-3 restoration to replace metabolic abnormalities involving carbohy- her lower incisors had been inserted. This is drates, fats and proteins. An estimated 17.9 a fixed prosthesis to replace teeth crowns and million people (6%) in the United States have has pink restorative material to replace bone been diagnosed with diabetes and another and soft tissue.8 Tissue colored porcelain pro- 2% are undiagnosed diabetics.1 It is the vides a non-surgical alternative to replace most common cause of blindness (retinopa- tissue and enhance esthetics.9,10 The con- thy) and lower extremity amputation (neuropa- struction of the screw-retained fixed prosthe- thy). Poor wound healing, end stage renal sis had progressed smoothly and the patient disease (nephropathy), myocardial infarc- was very happy. The patient was instructed in tion and stroke are other complications.2-4 oral hygiene including the use of floss thread- ers and a 3 month recare appointment was set. Uncontrolled diabetes compounded with poor oral hygiene can lead to an increased PATIENT DEVELOPS risk of dental caries, xerostomia, taste disor- UNCONTROLLED DIABETES ders, candidiasis, gingivitis and periodontal disease.5,6 About one-third of people with dia- The first sign of trouble was after patient missed betes have severe periodontal disease.7 Dia- her first scheduled recall appointment. After mul- betes is not an absolute contraindication to tiple calls and communication with other fam- implant treatment but most practitioners feel ily members, we were finally able to schedule that a patient’s glycemic levels must be well the patient 20 months after the prosthesis was controlled before undergoing implant treatment. placed. At this appointment, suppuration around several teeth, pyogenic granuloma, and epulis fis- This case report first describes the con- suratum lesions were noted (Figures 1, 2).11 While struction of a well-designed screw retained oral hygiene was poor, the tissue response to fixed implant prosthesis. Approximately two local irritants was excessive, suggesting a pos- years later, the patient returned and presented sible disease-altering systemic complication. with severe periodontal disease and implan- titis. Upon referral to a physician, she was Reviewing medical history with patient, it diagnosed with uncontrolled diabetes. Gradu- was apparent that she had not visited a phy- ally with Phase I periodontal care and medica- sician in the last 3 years. Clinical and radio- tion for her diabetes, we were able to control graphic assessment concluded a relapse and her periodontal and perimplant complications. worsening of periodontal disease and concur- The screw retained prosthesis allowed for rent peri-implantitis (Figure 3). The patient was easy removal, so its design could be modified encouraged to visit her physician immediately. It to allow better patient access for cleansability. took several months of building rapport before the patient could be convinced to visit her physician. 82 • Vol. 2, No. 5 • June 2010

Carpenter Figure 1: Patient returned after 20 months displaying Figure 2: In amed tissue and an epulis ssuratum severe periodontal disease, pyogenic granuloma and epulis alongside the FP-3 pink porcelain. ssuratum. Figure 3: Radiograph displaying peri-implantitis. It was subsequently determined by her physician that she had developed uncontrolled diabetes. Over the next year, her oral health improved slowly, aided by her physician concurrently con- trolling her diabetes. Dental treatment con- sisted of root planing, scaling, curettage, oral hygiene instruction and motivation. The advan- tage of the screw retained prosthesis became quickly apparent. Access to the implant fix- tures and adjacent teeth were easily obtained by unscrewing the prosthetic fixation screws and removing the prosthesis (Figure 4). Upon removal of the prosthesis, the serious- ness of the disease was obvious (Figure 5). To prevent collapse of the inflamed edematous tis- sue, healing collars were immediately placed (Fig- ures 6, 7). Next, the prosthesis was placed in an ultrasonic cleaning solution followed by gentle mechanical debridement of the implant fixtures and teeth. Intrasulcular irrigation was performed with chlorhexidine, the tissue with the epulis The Journal of Implant & Advanced Clinical Dentistry • 83

Carpenter Figure 4: Lingual view of screw-retained prosthesis. Figure 5: View of infected tissue and implant xtures. Chimneys provide for easy removal of prosthesis. Figure 6: Healing collars are placed to prevent collapse of tissue while the tissues are treated and prosthesis is modi ed. appearance was excised and the pink porcelain Figure 7: Radiograph with healing collars in place. thinned in this area, eliminating any ridge lap. At a subsequent appointment, Atridox (Tolmar Inc., Fort Collins, CO, USA) (doxycycline hyclate 10%) was used as a localized chemotherapeutic agent around the implant fixtures after debridement. 84 • Vol. 2, No. 5 • June 2010

Carpenter Figure 8: View of prosthesis before modi cation. Figure 9: View of prosthesis after modi cation. Figure 10: Oral view of slenderized prosthesis to facilitate Figure 11: View with prosthesis o and healing taking oral hygiene. A metal collar is visible in this retracted view. place. After 6 months of monitoring, it was decided bulbous design (Figure 8) was converted to a to remove the prosthesis for the 3rd time and more slender design (Figure 9). This modi- continue to modify its emergence profile12-14 fication sacrificed some esthetics but health to allow for better patient oral hygiene access. improved (Figures 10, 11). This metal collar will This was accomplished by attaching the pros- not be visible in normal function since the lip thesis to an abutment holder with the appropri- functions as a curtain. Eighteen months after ate implant analog. At the lab bench, a more the patient was first diagnosed with uncon- The Journal of Implant & Advanced Clinical Dentistry • 85

Carpenter Figure 12: View of patient 18 months after rst diagnosed physiologic basis for the increase preva- with uncontrollable diabetes. lence and severity of periodontal disease.19 trolled diabetes, in spite of less than ideal home Diagnosing diabetes is the responsibil- care, a healthier state is achieved (Figure 12). ity of the physician, but the dentist plays an important role. The dentist may be the first DISCUSSION to notice the signs and symptoms of a poorly controlled diabetic. Often patients do not It has been estimated that many patients with have a physician or are non-compliant as was diabetes may have the disease at least 10 years the case with this patient. Much time was before it is diagnosed clinically.7 The oral cav- spent on education and encouraging her to ity may exhibit the first signs and symptoms of seek proper medical care. As health care an undiagnosed or poorly controlled diabetic.5 providers, we must often function as psy- This certainly was the case with this patient chologists and listen carefully to our patients. who returned 26 months after initial treatment. Just as diabetes has been shown to worsen Periodontal disease is a recognized and periodontitis, it has been demonstrated that well documented complication of diabe- periodontitis and oral infection may have an tes. This has been determined by epidemio- adverse effect on the glycemic control in logic and animal model studies.15-17 Diabetes diabetic patients. When a diabetic patient is believed to promote periodontitis due to an receives treatment for periodontal disease, exaggerated inflammatory response to a sulcu- resolution of inflammation and improved gly- lar microflora that has been found to be equiv- cemic control may be obtained.20,21 Mealy alent in both periodontal patients with and suggested that many physicians are unaware without diabetes.18 This altered immunity as of the inter-relationship between periodontal a result of hyperglycemia may be the patho- disease and diabetes.5 They are aware that other infections can wreak havoc with glyce- mic control, but may not understand that peri- odontal disease, which dentists treat every day, may have a major impact on glycemic control. Physicians and dentists must better com- municate in order to diagnose and optimize their diabetic patient’s systemic and oral health. It appears obvious that diabetes may cre- ate a less than ideal environment for implant placement.22,23 However, Klokkevold24 per- formed a systematic review of the dental lit- erature and did not find a lower percentage of implant success between patients with and without diabetes. Such optimistic results may 86 • Vol. 2, No. 5 • June 2010

Carpenter have been obtained perhaps because trial Disclosure subjects typically are well-controlled diabet- The author reports no conflicts of interest with anything mentioned in this article. ics with good glycemic levels. Physicians measure diabetic control with HbA1c (gly- References cated hemoglobin) and the American Diabetes 1. National Institute of Diabetes and Digestive and Kidney Diseases. National Association recommends HbA1c level < 7%.25 Diabetes Statistics, 2007. “diabetes.niddk.nih.gov/dm/pubs/statistics” CONCLUSION 2. Wei M, Gaskill SP, Haffner SM, et al. Effects of diabetes and level of glycemia on This case report clearly documents how all-cause and cardiovascular mortality: the San Antonio Heart Study. Diabetes uncontrolled diabetes can worsen a patient’s Care 1998;21:1167-1172. periodontal and perimplant situation. Peri- odontal disease and diabetes seem to have 3. The effect of intensive treatment of diabetes on the development and progression a bi-directional relationship. Periodonti- of long-term complications in insulin-dependent diabetes mellitus: The Diabetes tis is a complication of diabetes and glyce- Control and Complications Trial Research Group. N Engl J Med 1993:977-986. mic control is difficult to obtain if an infection such as periodontal disease is present. 4. Mealey BL, Ocampo GL. Diabetes mellitus and periodontal disease. Periodontol 2000 2007;44:127-153. The easily removable screw retained pros- thesis provided excellent access for peri- 5. Mealey BL. The interactions between physicians and dentists in managing the odontal and perimplant treatment. It also care of patients with diabetes mellitus. J Am Dent Assoc;139(suppl):4S-7S. made possible the modification of the tis- sue side of the prosthesis. By slenderiz- 6. Lamster IB, Lalla E, Borgnakke WS, et al. The relationship between oral health ing the prosthesis’s emergence profile, the and diabetes mellitus. J Am Dent Assoc;139(suppl):19S-24S. patient’s oral hygiene was facilitated. 7. Kidambi S, Patel SB. Diabetes mellitus: considerations for dentistry. J Am Dent Correspondence: Assoc;139(suppl):8S-18S. Dr. John F. Carpenter, DMD, MAGD 272 Quassaick Avenue 8. Misch CE: Prosthetic options in implant dentistry, Int J Oral Implantol 1991; New Windsor, NY 12553 USA 7:17-21. (845) 561-2330 [email protected] 9. Taleghani M, Roshan S, Baker F, et al. Nonsurgical management of interdental papillae loss following extraction of anterior teeth: Gen Dent 2008; 326-331. 10. Hannon SM, Colvin CJ, Zurek DJ, et al. Selective use of gingival-toned ceramics: Case reports, Quintessence Int 1994; 25:233-238. 11. Newland JR, Meiller TF, Wynn R, et al. Oral soft tissue diseases: A reference manual for diagnosis and management, Hudson, OH: Lexi-Comp:2001:96-98. 12. Pissis P. Emergence profile considerations of implant abutments. Pract Periodontics Aesthet Dent 1994; 6:69-76. 13. Davarpanah M, Martinez H, Celletti R, et al. Three-Stage Approach to Aesthetic Implant Restoration: Emergence Profile Concept. Pract Proced Aesthet Dent 2001; 13:761-767. 14. Saba S. Anatomically correct soft tissue profiles using fixed detachable provisional implant restorations. J Can Dent Assoc 1997;63:767-770. 15. Pontes Anderson CC, Flyvbjerg A, Buschard K, et al. Relationship between periodontitis and diabetes: lessons from rodent studies. J Periodontol 2007;78:1264-1275. 16. Graves DT, Liu R, Alikhani M, et al. Diabetes-enhanced inflammation and apoptosis-impact on periodontal pathology. J Dent Res 2006; 85:15-21. 17. Taylor GW. Bidirectional interrelationships between diabetes and periodontal diseases: an epidemiologic perspective. Ann Periodontol 2001; 6:99-112. 18. Lalla E, Kaplan S, Chang SM, et al. Periodontal infection profiles in type 1 diabetes. J Clin Periodontol 2006; 33:855-862. 19. Tyan, ME, Carnu O, Kamer A. The influence of diabetes on the periodontal tissue. J Am Dent Assoc 2003; 134(suppl): 34S-40S. 20. Taylor GW, Burt BA, Becker MP, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol 1996;67(suppl):1085-1093. 21. Mealey BL, Oates TW. American Academy of Periodontology. Diabetes mellitus and periodontal diseases. J Periodontol 2006;77:1289-1303. 22. Hwang D, Wang HL. Medical Contraindications to Implant Therapy: Part II: Relative Contraindications. Implant Dentistry 2007;16:13-20. 23. Fiorellini JP, Nevins ML. Dental implant considerations in the diabetic patient. Periodontol 2000 2000;23:73-77. 24. Klokkevold PR, Han TJ. How do smoking, diabetes, and periodontitis affect outcomes of implant treatment? Int J Oral Maxillofac Implants, 2007; 22(Suppl):173-202. 25. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005;28(suppl 1):S4-S36. The Journal of Implant & Advanced Clinical Dentistry • 87



Preliminary List of Invited Speakers Dr Eduardo Anitua, Spain Dr Ziv Mazor, Israel Dr R. Cancedda, Italy Dr Eitan Mijiritsky, Israel Dr Joseph Choukroun, France Dr Robert Miller, USA Dr Paulo Coelho, USA Dr Stefano Pagnutti, Italy Dr Danilo Di Stefano, Italy Dr G. Papaccio, Italy Dr Matteo Danza, Italy Dr Gabriele Edoardo Pecora, Italy Dr Marco Degidi, Italy Prof Adriano Piatelli, Italy Dr Stefano Fanali, Italy Dr Roberto Pistilli, Italy Dr Pietro Felice, Italy Dr Lorenzo Ravera, Italy Dr Massimo Frosecchi, Italy Dr U. Ripamonti, South Africa Dr Scott Ganz, USA Dr Paul Rosen, USA Dr Dan Holtzclaw, USA Dr Philippe Russe, France Dr Robert Horowitz, USA Dr Gilberto Sammartino, Italy Dr Michelle Jacotti, Italy Dr Marius Steigmann, Germany Dr Adi Lorean, Israel Dr Tiziano Testori, Italy Dr Jack Krauser, USA Dr Nicholas Toscano , USA Dr Carlo Mangano, Italy Secretariat Paragon Conventions 18 Avenue Louis-Casai, 1209 Geneva, Switzerland Tel: +41-(0)-22-5330-948, Fax: +41-(0)-22-5802-953 Email: [email protected]



The E ect of Methotrexate on Bone Healing of aAguiar et al Simulated Fracture Defect in Rat Mandible Leonardo Toledo de Aguiar, DDS, MSc1 Suzana Beatriz Veríssimo de Mello, PhD2 João Gualberto de Cerqueira Luz, DDS, PhD3 Abstract The aim of this study was to verify the effect this time, cartilage formation was increased in of methotrexate (MTX) on bone repair of the saline group (14.08±6.9 %), low-dose MTX mandibular fractures in rats. A 50-µm defect group (12.2±7.8%) and DX group (13.2±8.6%). was created in the mandible of eighty rats subdi- The higher-dose MTX group presented less vided in 4 groups, which received intraperitone- cartilage formation (0.81±0.7%). Thirty days ally: saline; 0.25 and 1.6 mg/Kg of MTX weekly; after surgery, the saline and lower-dose MTX and 0.15 mg/Kg of dexamethasone (DX) after groups had almost complete closure of the surgery. Groups of 5 animals were sacrificed at fracture (5.3±0.01 and 8.07±0.03 µm respec- 1, 7, 15 and 30 days after surgery. Radiographic tively), while animals treated with 1.6 mg/ and histomorphometric evaluations were per- Kg of MTX and DX kept an open bone defect formed to evaluate cartilage and bone formation. (52.86±7.5 and 34.7±3.7 µm respectively). Our Treatments did not alter any parameter at 1 and 7 data show that low-dose MTX did not affect days after surgery. On the 15th day, only saline- bone healing of mandibular fractures. In con- treated animals presented a reduction in the dis- trast, the high-dose here employed impairs car- tance between bony ends (21.8±0.11 µm). At tilage formation that precedes bone healing. KEY WORDS: Mandibular fracture, methotrexate, bone, cartilage, dexamethasone 1. Oral and Maxillofacial Surgeon, Hospital of the Southeast of Pará State, Fellow of Experimental Physiopathology Department, School of Medicine, and Fellow of Oral and Maxillofacial Surgery Department, School of Dentistry, University of Sao Paulo, Brazil. 2. Associate Professor of Rheumatology Division, Department of Internal Medicine, School of Medicine, University of Sao Paulo, Brazil. 3. Associate Professor of Oral and Maxillofacial Surgery, Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Sao Paulo, Brazil. The Journal of Implant & Advanced Clinical Dentistry • 91

Aguiar et al INTRODUCTION alter the repair process after unilateral condy- lectomy in mice.13 In humans, Gester et al14 Mandibular fractures represent the great major- reported two cases of rheumatic patients treated ity of facial trauma in road crashes and other with low-dose MTX (7.5 and 15mg/week) who accidents.1 Moreover, the treatment of maxil- failed to recover from osteotomy. In both cases, lofacial injuries is mainly surgical and patients bone union was observed soon after the MTX that arrive at a hospital are frequently under- was discontinued. Moreover, a protective MTX going treatment with different medications.2 effect on bone resorption has been described in rheumatoid patients.15 Patients with juvenile idio- Immunosuppressive drugs can cause a sig- pathic arthritis showed less temporomandibular nificant delay in the consolidation of fractures destruction while undergoing MTX treatment.3 and bone formation.3 Exogenous Glucocorticoid (GC) promotes bone loss and after a long-term The clinical importance of this issue, the great administration, these drugs frequently promote variability of the previous results with different osteoporosis in humans.4 This group of drugs schedules of MTX treatments and the lack of a includes Methotrexate (MTX), used in high doses controlled study in mandibles led us to develop as chemotherapy agent and as an anti-rheumatic the present protocol to verify the effect of two agent in low doses.5 The literature is conclu- increasing doses of MTX and dexamethasone sive regarding the effect of high doses of MTX. (DX) on bone repair of mandibular fractures in rats. Clinical studies have demonstrated that MTX decreases bone growth and reduces bone min- MATERIALS AND METHODS eral density (BMD), which persists into adult life and may increase bone fracture risk at an older Animals age.6,7 Osteoporosis is verified in growing rats Eighty female Wistar rats weighing 200-250g treated with high doses of MTX and is also asso- at the beginning of the study were employed. ciated with osteopenia in adult animals.8 Short- The animals were allowed a standard pellet term administration of high-dose MTX can have a diet and water ad libitum. During experimen- toxic effect on osteoblasts by reducing their vol- tal procedures, the animals were anaesthetized ume, without altering their number. In addition, this to avoid any stress condition. The Animal Eth- schedule of treatment impairs osteoid thickness.9 ics Committee of COBEA (Brazilian College of Experimental Animals) approved all experimen- Concerning low-dose MTX effect on tal procedures performed on animals in accor- bone, osteoporosis has not been detected in dance with the procedures set by UFAW (The humans.10 Contrarily, it has shown decreased Universities Federation for Animals Welfare). BMD in growing rabbits chronically treated with MTX, which was reverted by concomitant The eighty rats were randomly distributed treatment with folic acid.11 Nilsson et al12 dem- in 4 groups of 20 animals: the control groups onstrated a lower effect of MTX on bone neofor- included a saline-treated group (1 ml after sur- mation during the drug washout period, prior to gery) and a group (DX) intraperitoneally treated surgery. A single report from a Brazilian regional with 1 ml of dexamethasone (0.15 mg/Kg, one journal showed that the MTX treatment did not dose after surgery); this dose has been described 92 • Vol. 2, No. 5 • June 2010

Aguiar et al as increasing bone resorption and decreasing ography panel, the Image Pro Plus program bone formation.5 Groups of animals were intra- was used to evaluate the distance between peritoneally treated with two doses of Methotrex- bony ends, measured in three regions, as ate; 1.6 mg/Kg and 0.25 mg/Kg, both diluted in well as the lesion area. The mean of two 1 ml of saline one hour before surgery and once measurements were expressed in pixels. a week during the post-surgical period. Gain in body weight was indistinguishable between Histomorphometric Analysis groups (p = 0.105). No adverse gastrointesti- Subsequently, the mandibles were paraffin- nal effects (vomiting or diarrhea) were observed embedded and routinely processed. Sequen- as a consequence of treatments. The proto- tial Sections (7mm) were obtained and col consisted in sacrificing groups of five ani- stained by Hematoxylin-Eosin (H&E) and tolu- mals at 1, 7, 15 and 30 days after surgery. idine blue. Images were captured (Leica Qwin Imaging Systems Ltd., Cambridge, Eng- Surgical Procedure land) and digitized in the computer, using an A surgical bone defect with near 50µm of width image analyzer software (Image Pro-plus 6). that simulates a mandibular fracture was pro- duced in rats anaesthetized with 0.4 ml of 1.0 mg/ The H&E-stained bone lesion was semi- kg of xylazine and 0.75 mg/kg of ketamine. After quantitatively evaluated at 100x magnification trichotomy, the skin was cleansed and an inci- for the following parameters: bone callus forma- sion of approximately 15 mm was made exposing tion, bony ends distance, presence of inflamma- mandible bone by blunt dissection. A bicortical tory cells, as well as cartilage amount and bone osteotomy was performed with a multi-laminated neoformation. These observations were made conical carbide bur number 701, from the base by 2 pathologists blinded to the treatment and of the mandible towards the cranium (vertical ori- expressed as the mean of two recorded values. entation) with 10 mm of length. Soft tissues were replaced and sutured. The animals were kept Statistical Analysis in individual cages with food and water ad libi- Results are expressed as the mean of 5 ani- tum and weighed weekly for drug administration. mals ± S.E. The results were analyzed by repeated measure ANOVA and com- Radiographic Analysis pared with Student-Newman Keul’s test. After the animals were sacrificed, the mandi- The chosen level of significance was 0.05. bles were surgically excised and submitted to radiographic examination with a dental X-Ray RESULTS equipment (Spectro II, Dabi Atlante), under 56 kV, 10 mA and 0.4 sec of exposure. Bone Histomorphometric Analysis In order to quantify bone repair, we mea- The radiographic analysis of mandibles sured the distance between the stumps of was performed by two investigators blinded to the bone defect at different times after the the treatment regimen. In each digitized radi- osteotomy. Slices of paraffin including man- dibles stained with hematoxylin-eosin were The Journal of Implant & Advanced Clinical Dentistry • 93

Aguiar et al Figure 1a: E ect of MTX, DX and saline on the distance Figure 1b: Representative picture of the evolution of bone between bony ends of mandibular fractures in rats at 1, 7, callus in saline-treated animals at 1 days after surgery. 15 and 30 days after surgery. Data is expressed as the mean Magni cation of x100, H&E stain. of 5 animals ± SE, ( = control animals, = MTX (1.6 mg/ Kg/week), ∆= MTX (0.25mg/Kg/week) and = DX (0.15mg/ injected animals presented a significant reduc- Kg one dose after surgery). * = p<0.05 vs. control at 7 days; tion in the distance between bony ends when # = p< 0.05 vs. control animals at 30 days and ** = p<0.05 compared to values observed on day 7. It is vs. control animals at 15 days after surgery. possible to observe (figure 1D) a concomitant formation of cartilage tissue (double arrow) and analyzed under a magnification of 100x. In bone neoformation (arrow). Animals treated figures 1A-E, representative pictures of a with DX and 0.25 mg/Kg/week of MTX did saline-treated rat in each experimental period not attain significant change at this time. The are depicted in figures 1B to 1E. The data group treated with 1.6 mg/Kg/week of MTX about the effect of treatments on the distances exhibited an additional increase in the distance between bony ends is summarized in figure 1A. between bony ends. At the end of the experi- mental period (30 days after surgery) bone Data on the animals sacrificed one day repair (figure 1E, arrow) in control animals and after surgery clearly showed that the surgical in those treated with low-dose MTX was still far procedure generated homogenous fractures, from having the gap closed (figure 1, panels A which did not significantly differ among groups and E), with a significant reduction in bony end (p=0.222, ANOVA). At 7 days after the sur- distance (mean 5.3 ± 0.47 and 8.1 ± 0.73 µm gery, a slight, but not significant increase in respectively). In the mandible of animals treated this distance was recorded in all groups, which may reflect retraction of tissues in the fracture region. In figure 1C, we can observe granula- tion tissue (asterisk) in the osteotomy region on the 7th day, without treatment influence. At 15 days (figures 1A, 1D), we verified that saline- 94 • Vol. 2, No. 5 • June 2010

Aguiar et al Figure 1c: Representative picture of the evolution of bone Figure 1d: Representative picture of the evolution of bone callus in saline-treated animals at 7 days after surgery. callus in saline-treated animals at 15 days after surgery. Magni cation of x100, H&E stain. Magni cation of x100, H&E stain. with high-dose MTX and DX, the osteotomy still Figure 1e: Representative picture of the evolution of bone remained open 30 days after surgery (mean callus in saline-treated animals at 30 days after surgery. 52.86 ± 9.3 and 34.7 ± 6.5 µm respectively). Magni cation of x100, H&E stain. Bone Radiographic Analysis The effect of the treatments on bone formation was also evaluated in radiographic panels (figures 2A,2C). Figures 2B and 2D exemplify the extent of the defect and how the distance between the bony ends (figure 2B, arrow) and the total area of osteotomy (figure 2D) were measured. Fig- ures 2A and 2C summarizes the effect of the treatments on these evaluated parameters. The homogeneity of the surgical procedure outcome could be also verified in radiographies of man- dibles taken one day after surgery and no differ- ence was observed among the groups at 7 days after surgery, regarding both parameters. Saline- injected animals and those treated with 0.25mg/ The Journal of Implant & Advanced Clinical Dentistry • 95

Aguiar et al Figure 2a: Radiographic evaluation of mandibular fracture Figure 2b: Representative radiography of normal rat in rats treated with MTX, DX and saline at 1 (white column), mandible 1 day after surgery, the arrow show the 3 7 (black column), 15 (gray column) and 30 days (hatched measurements of bone end distance. column) after surgery. This gure shows the distance between bony ends measured at di erent times after surgery. Figure 2c: Area of the bone defect 1 (white column), 7 Figure 2d: Representative radiography of normal rat (black column), 15 (gray column) and 30 days (hatched mandible 1 day after surgery. In red the measured area of column) after surgery. Data expressed as the mean of 5 bone defect. animals ± SE, * p<0.05 vs. control animals. gery, when compared with saline-injected ani- Kg/week of MTX were indistinguishable through- mals. Although there is a trend of reduction in out all assessed periods. DX and the high that distance at 30 days after surgery, animals dose of MTX promoted a significant increase treated with higher doses of MTX and DX per- in the distance between the bony ends and in sisted with higher values than control animals. the area of the osteotomy 15 days after sur- 96 • Vol. 2, No. 5 • June 2010

Aguiar et al Figure 3a: Percentage of newly formed cartilage amount Figure 3b: Representative image of newly formed in the fracture region 7, 15 and 30 days after surgery. Data cartilage (red) on the 15th day (toluidine blue stained, are expressed as the mean of 5 animals ± s.e.m., black original magni cation ◊ 100) column= seven days, white column= 15 days, hatched column= 30 days after surgery. * = p<0.05 vs. values Figure 3c: Representative image of the replacement of obtained 7 days after surgery # = p<0.05 by comparison cartilage by bone veri ed 30 days after surgery in normal with the control group at 15 days. rat mandible (toluidine blue stained, original magni cation ◊ 100). Cartilage Neoformation Bone repair is accompanied by cartilage neo- in control groups. Animals treated with high-dose formation. The effect of the treatments was also MTX did not present the characteristic upslope in evaluated in slices of fractured mandibles simul- cartilage formation at 15 days after the fracture. taneously stained with toluidine blue. Results are expressed as the percentage of cartilage in DISCUSSION the total area of the bone callus (mm2). Figure 3A summarizes the results, and panels B and C Our study demonstrated that 0.25mg/Kg/ exemplify the appearance of a control slice of the week of MTX did not affect bone healing of bone callus at 15 and 30 days, respectively. Using mandibular fractures in rats. Interestingly, an this software, we can highlight in red all cartilage tissue present in the area. The pattern of carti- lage tissue formation kinetics observed in control animals was an absence of this tissue in the first period (first 7 days), followed by a great increase at 15 days, with subsequent reduction at 30 days after surgery. (figure 3A). Regarding cartilage for- mation, animals treated with low-dose MTX and DX clearly presented the same pattern registered The Journal of Implant & Advanced Clinical Dentistry • 97

Aguiar et al almost six-fold higher MTX dose promoted bone ing this issue, studying newborn rats treated regeneration impairment of the same magni- with much lower doses of MTX, Kameyama et tude of dexamethasone. The above statement al.19 reported that the MTX treatment inhibited was based on the following findings: first, the the formation of cartilage and bone in the grow- chosen model, simulating jaw bone fracture in ing mandibular condyle. At this phase, newborn rats, is a helpful experimental model because it animals present an intense growing process, re-creates fracture in humans and nearly com- so that the administration of a single dose of pletes closure at around 30 days. Eighty per- an immunosuppressive drug such as MTX can cent of mandibular fractures treated by open promote a deleterious effect on the craniofa- or closed reduction with intermaxillary immo- cial skeleton.20 However, adult rats treated with bilization are clinically united in 4 weeks.16,17 MTX, 0.1 mg/kg i.p., administered five times a Additionally, our histological and radiologi- week (cumulative dose of 0.5 mg /week), also cal findings obtained on the first day after exhibited a significant alteration in the strength surgery clearly demonstrates that the bone of the healing osteotomies compared with the defect was homogeneous among the groups. control group.21 Another in vivo study using a cumulative dose of 3.75 mg/Kg/ of MTX dur- The choice of DX as a negative control of ing one week described bone growth defects bone neoformation was appropriate to com- as a consequence of the reduction in chon- pare with a possible deleterious effect of MTX drocyte proliferation.22 The effect of low doses on bone. The histological analysis of mandi- on bone healing can also occur in humans, as bles in osteoporotic (ovariectomized) rats with seen in the report of two cases of bone fracture tooth extraction revealed a significant decrease nonunion in patients taking MTX, which used in the bone volume at 14, 21, and 28 days a therapeutic schedule similar to the one used after the extraction, as well as a decreased by us, about 7.5 and 15 mg/patient/week.14 amount of granulation tissue.18 In accordance with that, our results also revealed a reduc- At the end of the study period, all groups tion in bone and cartilage formation in animals including the one treated with higher-dose MTX treated with a single dose of DX after surgery. presented some degree of bone tissue forma- tion in the fracture region. This finding suggests Seven days after surgery, bone healing that the MTX treatment did not stop or prevent is still occurring in all groups with the forma- the repair, although it probably promoted a delay tion of granulation and cartilage tissues; our in the repair process. In the bone formation pro- assessment showed that in this first phase of cess, newly formed cartilage is followed by the the study, no treatment significantly affected the osteoclastic degradation of the matrix. Osteo- process of bone restoration. On the 15th day of blasts then migrate into the cavities that are the postoperative period, a reduction in the frac- formed by osteoclasts to produce the new bone ture defect was clearly seen in animals treated matrix. As low-dose MTX has been described as with 1.6 mg/Kg/week of MTX, which presented reducing osteoblast cell proliferation along the a retraction of tissues in the fracture region trabecular surface 22,23 a possible mechanism for and almost no cartilage formation. Concern- 98 • Vol. 2, No. 5 • June 2010

Aguiar et al delaying the union is the inhibition of this cell. Correspondence: Together, our results show that low-dose Suzana Beatriz Veríssimo de Mello Departamento de Clínica Médica, Disciplina de MTX did not affect cartilage or bone neoforma- Reumatologia tion in fracture healing. In contrast, the use of Av. Dr. Arnaldo, nº 455, 3º andar, sala 3118 a higher dose of MTX had a worse prognosis Reumatologia. Cerqueira Cesar. in bone regeneration suggesting that, in cases CEP:01246-903 of jaw fracture, there is no need to withdraw São Paulo, SP – Brasil low-dose MTX treatment, whereas patients Phone: (11) 30617200 • Fax: (11) 30617490 undergoing chemotherapy should be the tar- get of greatest concern among surgeons. Disclosure 9. Friedlaender GE, Tross RB, Doganis AC, Kirkwood 20. Karsila S, Salmi TT, Ronning O. Effect of The authors report no conflicts of interest with JM, Baron R. Effects of chemotherapeutic methotrexate alone and in combination with anything mentioned in this article. agents on bone. I. Short-term methotrexate and vincristine on craniofacial morphology in growing doxorubicin (adriamycin) treatment in a rat model. J rats. Acta Odontol Scand 1999; 57: 271-276. Acknowledgments Bone Joint Surg Am 1984; 66: 602-607. The authors are grateful to Dr. Walcy Rosolia Teodoro 21. Pelker RR, Friedlaemder GE, Panjabi MM, for the helpful discussion of histopathological data, 10. Patel S, Patel G, Johnson D, Ogunremi L, Barron Marham T, Hausman M, Doganis AC, Mckay as well as to Viviane R Storto and Lucimar Rodrigues J. Effect of low dose weekly methotrexate on J. Chemotherapy-induced alterations in the for their technical assistance. bone mineral density and bone turnover. Ann biomechanics of rat bone. J Orthop Res 1985; Rheum Dis 2003;62: 186-187. 3: 91-95. References 1. Fasola AO, Obiechina AE, Arotiba JT. Incidence 11. Laurindo IM, Mendes FL, B, Falco V, Jorgetti V. 22. Xian CJ, Cool JC, Scherer MA, Macsai CE, Fan Methotrexate inhibition of bone mineral density C, Covino M, Foster BK. Cellular mechanisms and pattern of maxillofacial fractures in the elderly. increase in growing rabbits: prevention by folinic for methotrexate chemotherapy-induced bone Int J Oral Maxillofac Surg 2003; 32: 206-208. acid. Clin Exp Rheumatol 2003; 21: 581-586. growth defects. Bone 2007; 41: 842-850. 2. Hupp JR, Duddleston DN. Medical Management of the Surgical Patient. In: Miloro M, Ghali GE, Larsen 12. Nilsson OS, Bauer HC, Brostrom LA. 23. Wheller DL, Vander Griend RA, Wronski TJ, Miller PE, Waite PD. Peterson’s Principles of Oral and Methotrexate effects on heterotopic bone in rats. GJ, Keith EE, Graves JE. The short- and long- Maxillofacial surgery (ed 2). London, BC Decker Acta Orthop Scand 1987; 58: 47-53. term effects of methotrexate on the rat skeleton. Inc, 2004: 17. Bone 1995; 16: 215-221. 3. Ince DO, Ince A, Moore TL. Effect of methotrexate 13. Silva LA, Hetem S, Denardin OVP. Efeito on the temporomandibular joint and facial do metotrexato sobre o reparo ósseo após morphology in rheumatoid arthritis patients. Am J condilectomia unilateral em camundongos (Mus Orthod Dentofacial Orthop 2000; 118: 75-83. musculus). Revista de Odontologia Unesp 2006: 4. Sinigaglia L, Mazzochi D, Varenna M. Bone 35: 89. URL: http://rou.hostcentral.com.br/ involvement in exogenous hypercortisolism. J viewpub.php?id=404 [Accessibility verified May Endocrinol Invest 2008; 31: 364-370. 20, 2009] 5. Novaes GS, Mello SBV, Laurindo IMM, Cossermelli W. Low dose methotrexate decreases 14. Gester JC, Bossy R, Dudler J. Bone non- intraarticular Prostaglandin and interleukin 1 levels union after osteotomy in patients treated with in antigen induced arthritis in rabbits. J Rheumatol methotrexate. J Rheumatol 1999; 26(12):2695- 1996; 23: 2092-2097. 2697. 6. Van Leeuwen BL, Kamps WA, Jansen HW, Hoekstra HJ. The effect of chemotherapy on the 15. El Miedany YM, Abubakr IH, El Baddini M. Effect growing skeleton. Cancer Treat Rev 2000; 26: of low dose methotrexate on markers of bone 363-376. metabolism in patients with rheumatoid arthritis. 7. Van Leeuwen BL, Verkerke GJ, Hartel RM, Sluiter J Rheumatol 1998;25: 2083-2087. WJ, Kamps WA, Jansen HW, Hoekstra HJ. Chemotherapy decreases epiphyseal strength and 16. Juniper RP, Awty MD. The immobilization period increases bone fracture risk. Clin Orthop Relat Res for fractures of the mandibular body. Oral Surg 2003; 413: 243-254. Oral Med Oral Pathol 1973; 36: 157-163. 8. Spadaro JA, Damron TA, Horton JA, Margulies BS, Murray GM, Clemente DA, Strauss JA. Density 17. Amaratunga NA. The relation of age to the and structural changes in the bone of growing rats immobilization period required for healing of after weekly alendronate administration with and mandibular fractures. J Oral Maxillofac Surg without a methotrexate challenge. J Orthop Res 1995: 45: 111-113. 2006; 24: 936-944. 18. Pereira MC, Zecchin KG, Campagnoli EB, Jorge J. Ovariectomy delays alveolar wound healing after molar extractions in rats. J Oral Maxillofac Surg 2007; 65: 2248-2253. 19. Kameyama Y, Nakashima T, Sugita Y, Kubo K, Suzumura Y, Kawanishi K, Bessho M, Sato E, Maeda H. Effect of methotrexate on the mandibular condyles of growing rats. Int J Oral and Maxillofacial Surgery 2005; 34: 117. The Journal of Implant & Advanced Clinical Dentistry • 99



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