The Effect of Systemically Administered Bisphosphonates on Bony Healing After Tooth Extraction and Osseointegration of Dental Implants in the Rabbit Maxilla InSoo Kim, DDS, MSD, PhD1/HyungChun Ki, DDS, MSD2/Won Lee, DDS, MSD, PhD3/ Heesung Kim, BA, MA, PhD4/Jun-Beom Park, DDS, MSD, PhD5 Purpose: To evaluate the effects of bisphosphonates on bone healing after tooth extraction and osseointegration of dental implants in a rabbit model. Materials and Methods: Twenty-four rabbits were divided into four groups; one control and three experimental. The experimental were treated with intravenous zoledronic acid (ZA, 0.1 mg/kg) twice per week starting 4 (Z4 group) and 8 (Z8 group) weeks before surgery until the end of the experiments. The experimental ZD4 group was treated with intravenous ZA (0.01 mg/kg) and intramuscular dexamethasone (1 mg/kg) twice per week starting 4 weeks before surgery until the end of the experiments. The maxillary first premolar was extracted, and an implant with a diameter of 1.5 mm was placed between the incisor and the premolar of each maxilla. Healing of the extraction socket was evaluated and histomorphometric analysis around the implant was performed, using the bone-to-implant contact ratio (BIC) and bone area ratio (BA) 4 and 8 weeks after the surgery. Results: The control group underwent a normal healing process, but all experimental groups showed necrotic bone with hollow lacunae. BIC and BA in the control group increased from the 4- to 8-week evaluations, but decreased in the experimental groups from 4 to 8 weeks. BIC and BA of the Z8 and ZD4 groups were higher than those of the control group at the 4-week evaluation, but were lower than the control at the the 8-week evaluation. Conclusions: This study showed that administration of bisphosphonates interferes with normal bone remodeling after tooth extraction. The experimental groups showed good initial stability, but long-term healing around the implants was impaired. Within the limits of this study, it may be suggested that patients taking bisphosphonates should be treated with caution when performing tooth extraction or placing dental implants. INT J ORAL MAXILLOFAC IMPLANTS 2013; 28:1194–1200. doi: 10.11607/jomi.2685 Key words: bisphosphonates, bisphosphonate-related osteonecrosis of the jaws (BRONJ), dental implant, initial stability, tooth extraction, wound healing isphosphonate-related osteonecrosis of the jaws hypercalcemia caused by malignant tumors, bone B(BRONJ) has generated great interest in the study of metastasis in metastatic prostate cancer or metastatic both dental and bone biology in recent years.1 Bisphos- breast cancer, and Paget’s disease.2 Highly efficient in- phonate (BP) is a strong suppressor of osteoclasts, and travenous BPs have extended their use from treatment it is commonly used to treat diseases that affect bone of malignant bone diseases to prevention of osteo- metabolism including multiple myeloma, secondary porosis.3–5 The Food and Drug Administration (FDA) 1 Associate professor, Division of Oral and Maxillofacial College of Medicine, The Catholic University of Korea, Surgery, Department of Dentistry, Uijeongbu St Mary’s Gyeonggi-do, Korea; Lecturer, Institute of Foreign Language Hospital, College of Medicine, The Catholic University of Studies, Korea University, Seoul, Korea. Korea, Gyeonggi-do, Korea; Adjunct Professor, Department 5 Clinical Assistant Professor, Department of Periodontics, of Dental Implantology, Graduate School of Clinical Dental Seoul St Mary’s Hospital, College of Medicine, The Catholic Science, The Catholic University of Korea, Seoul, Korea. University of Korea, Seoul, Korea. 2 Graduate Student, Department of Dental Implantology, Graduate School of Clinical Dental Science, The Catholic Correspondence to: Dr InSoo Kim, Division of Oral and University of Korea, Seoul, Korea. Maxillofacial Surgery, Department of Dentistry, Uijeongbu 3 Associate Professor, Division of Oral and Maxillofacial Surgery, St Mary’s Hospital, The Catholic University of Korea, #65-1. Department of Dentistry, Uijeongbu St Mary’s Hospital, College of Geumo-dong, Uijeongbu-si, Gyeonggi-do, 480-717, Korea. Medicine, The Catholic University of Korea, Gyeonggi-do, Korea. Fax: +82 31-847-2894. Email: [email protected] 4 Researcher, Division of Oral and Maxillofacial Surgery, Department of Dentistry, Uijeongbu St Mary’s Hospital, ©2013 by Quintessence Publishing Co Inc. 1194 Volume 28, Number 5, 2013 © 2013 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER. Kim et al recently approved the annual injection of zoledronic Fig 1 The implant used in this study (C-implant). It comprised two acid (Reclast, Novartis) for the prevent of osteoporo- parts: a 6.5-mm SLA surface screw 6 sis in menopausal populations. Earlier reports in the part and a 2-mm smooth-surfaced dental field suggested that the use of BPs may be ben- transgingival part. The diameter of eficial in dental implantation and bone transplantation the implant was 1.8 mm. due to their strong inhibitory effects on bone resorp- tion.7,8 However, later reports showed that BPs caused side effects such as acute reactions, gastrointestinal disturbances, and renal disorders.9–11 Moreover, osteo- necrosis of the jaws is one of the most severe adverse effects,12 and BRONJ was first reported in 2003.11 Since then, a number of case reports and studies on BRONJ have been published,13–15 and the American Associa- tion of Oral and Maxillofacial Surgeons defined BRONJ as exposed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks with no histo- ry of radiation therapy to the jaws and with current or previous BP treatment.16 The number of dental patients undergoing long-term administration of BPs is increas- ing, and the incidence of osteonecrosis of the jaws is increasing accordingly.17–19 However, the pathogenesis Experiments of Uijeongbu St Mary’s Hospital Catholic of BRONJ has not been clearly established, although University of Korea (no. UJA2010-04A). various hypotheses have been suggested.1,20,21 The The BP used in this study was ZA (Zometa, Novartis) most supported is that BPs suppress the remodeling and DX was purchased from Sigma-Aldrich. The implants of jaw bones, which may lead to necrosis.1 A direct used in this study had a diameter of 1.8 mm and length cytotoxic effect of BPs on osteocytes, anti-angiogen- of 8.5 mm (C-Implant, Cimplant) (Fig 1). The implant had ic effects, and infection have also been proposed as a sand-blasted, acid-etched (SLA) surface, and 2 mm of causes of BRONJ. Diabetes, smoking, dental extraction, the transgingival part had a smooth surface. and concurrent medications have been thought to be indirectly associated with BRONJ by affecting remodel- Surgical Procedures ing, angiogenesis and infection.1,22,23 Twenty-four rabbits were divided into four groups: A highly efficient BP was recently approved, and one control and three experimental groups. The ex- the use of this drug is gradually increasing as society perimental Z4 group was treated with intravenous is aging.24,25 Therefore, it is necessary to completely administration of ZA (0.1 mg/kg) using the rostral auric- understand and identify the pathogenesis of osteone- ular vein twice a week starting 4 weeks before surgery crosis of the jaws with long-term use of BPs after tooth until the end of the experiments. The experimental Z8 extraction and dental implant installation. This study group was treated with intravenous administration of was performed to evaluate the impact of BPs on bone ZA (0.1 mg/kg) from 8 weeks before surgery to the end healing after tooth extraction and osseointegration of of the experiments. The ZD4 group was treated with dental implants by administration of zoledronic acid intravenous administration of ZA (0.1 mg/kg) and in- (ZA) along with dexamethasone (DX). DX was used si- tramuscular administration of DX (1 mg/kg) from 4 multaneously in some of the experimental groups to weeks before surgery to the end of the study. induce the best resemblance of BRONJ.26,27 General anesthesia was induced by administering a mixture of tiletamine/zolazepam (15 mg/kg) (Zoletil 50, Virbac) and Xylazine (5 mg/kg) (Xylazine 20 Inj, MATERIALS AND METHODS Kepro) into the femoral muscle. Lidocaine (2%) with 1:100,000 epinephrine (Yuhan) was used for local anes- Twenty-four female New Zealand white rabbits weigh- thesia. A crestal incision was made between the incisor ing 2.5 to 3.0 kg were used for the experiments. They and the premolar of the rabbit maxilla. A full-thickness were bred under the same conditions in accordance flap was elevated to expose the alveolar bone. A hole with the regulations of the Clinical Research Institute was made in the implantation site using a guide drill of Uijeongbu St Mary’s Hospital, Catholic University of with a diameter of 1.5 mm. The implant was inserted Korea (Gyeonggi-do, Korea). All animal experiments until the SLA surface was completely submerged in were performed in strict accordance with a proto- the alveolar bone. The flap was repositioned and su- col approved by the Ethics Committee for Animal tured with 4-0 nylon around the smooth surface of The International Journal of Oral & Maxillofacial Implants 1195 © 2013 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER. Kim et al the implant. Extraction of the maxillary first premolar Statistical Methods was performed immediately after implant placement Data are presented as means ± standard deviations. (Fig 2). Gentamycin (4 mg/kg) (Kukje Pharm) and keto- The Mann-Whitney U test was used to test for differ- profen (1 mg/kg) (Bukwang Pharm) were administered ences with commercially available statistical software intramuscularly twice per day for 2 days postoperative- (SPSS version 12 for Windows, IBM).