Preventive Protocol for Tooth Extractions in Patients Treated With Zoledronate: A Case Series

J Oral Maxillofac Surg 69:e1-e4, 2011

Preventive Protocol for Tooth Extractions in Patients Treated With Zoledronate: A Case Series Sebastastiano Ferlito, MD, DDS,* Sergio Puzzo, DDS,† and Chiara Liardo, DDS‡ Purpose: We report on an observational longitudinal noncontrolled study of a case series of consecutive

patients treated with zoledronate who underwent tooth extractions. The tooth extractions were performed after a preventive protocol to minimize the risk of bisphosphonate-related osteonecrosis of the jaw. Patients and Methods: A total of 43 patients who had received zoledronate and required single or multiple dental extractions were treated. The preventive protocol provided a surgical approach for dental extractions, characterized by the removal of alveolar bone (alveolectomy), and supported by correct antimicrobial therapy (antibiotics and mouthwash). Results: A total of 102 tooth extractions in 43 patients were performed. The follow-up was 12 months. No signs of inflamed tissue or necrotic exposed bone in any patient were observed. Conclusions: With the limits of the present study, we observed that the removal of the alveolar bone after the tooth extractions and correct antimicrobial prophylaxis (antibiotics and mouthwash) could reduce the risk of occurrence of osteonecrosis in patients taking zoledronate. © 2011 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 69:e1-e4, 2011 Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a relatively rare, but potentially serious, complication of bisphosphonate (BP) treatment, first described by Marx1 and Ruggiero et al2 in 2003 to 2004. BRONJ has been defined as the presence of exposed bone in the oral cavity that has not regressed within 8 weeks in a patient currently or previously exposed to BPs and who had not undergone radiotherapy to the craniofacial region.3

The purpose of BP therapy is to slow the rate of bone resorption. This therapy has mostly been used to treat different types of cancers (eg, multiple myeloma, metastatic breast or prostate cancer), bone disease, and osteoporosis.3,4 Concern has been increasing regarding the risks of oral surgical procedures in patients receiving BPs.5 Confusion surrounding BRONJ exists for several reasons, including a lack of understanding about the mechanism of occurrence and development of this pathologic entity.6,7 According to Allen and Burr,8 remodeling bone suppression, antiangiogenic effects of BPs, despite infection are all possible hypotheses. Furthermore, other conditions, such as diabetes, dental extractions, smoking, and corticosteroid administration could interact. Compromised angiogenesis would most likely be involved in postintervention healing and could contribute to BRONJ.8 Bone remodeling is crucial in the healing process after dental extraction. Therefore, the exposed bone that normally appears in the socket for a short period after extraction does not heal and becomes necrotic and infected.9 One of the preventive recommendations provided in published studies has been to avoid dental extractions in patients treated with BPs. In cases where patients are taking oral BPs, the extractions should be

*Professor of Oral Diseases, and Director of the Postgraduate Master of Dental Science in Complex Oral Rehabilitations, 1st Section of Dentistry, Department of Medical-Surgical Specialties, University of Catania, Catania, Italy. †Postgraduate Master of Dental Science in Complex Oral Rehabilitations, 1st Section of Dentistry, Department of Medical-Surgical Specialties, University of Catania, Catania, Italy. ‡Postgraduate Master of Dental Science in Complex Oral Rehabilitations, 1st Section of Dentistry, Department of Medical-Surgical Specialties, University of Catania, Catania, Italy. Address correspondence and reprint requests to Dr Puzzo: 1st Sezione di Odontoiatria 1. Presidio Ospedaliero “Vittorio Emanuele,” Via Plebiscito, 628, Catania 95127, Italy; e-mail: sergiopu@ libero.it © 2011 American Association of Oral and Maxillofacial Surgeons

0278-2391/11/6906-0012$36.00/0 doi:10.1016/j.joms.2010.10.055

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PREVENTIVE PROTOCOL FOR TOOTH EXTRACTIONS IN ZOLEDRONATE-TREATED PATIENTS

performed with minimal bone damage. Prophylactic antibiotics and suturing of the socket have also been advised.1,10 Regev et al11 have suggested an alternative technique for atraumatic dental extraction that would prevent bone exposure and the associated complications of osteonecrosis. The suggested technique is to perform the extractions using orthodontic elastics, placed around the roots, to cause slow and gradual exfoliation of the teeth. All sockets showed soft tissue secondary healing, without signs of inflammation or exposed bone during the 9 months of follow-up.11 We report on an observational longitudinal noncontrolled study of a group of consecutive patients treated with zoledronate who underwent tooth extractions that were performed after the use of a preventive protocol to minimize the risk of occurrence of BRONJ.

Patients and Methods From January 2007 to December 2008, a total of 114 patients, treated with zoledronate (4-mg intravenous infusion every 3 to 4 weeks), were referred to our Center for Research, Prevention and Care of BRONJ, First Section of Dentistry, University of Catania. The following patient parameters were collected: age, primary systemic pathologic features, duration of zoledronate administration, eventual suspension of zoledronate, and oral pathologic findings. The ethical committee of our university approved the present study, which was performed according to the Helsinki Declaration. PATIENT SELECTION

The inclusion criteria were the administration of zoledronate for at least 9 consecutive months and the presence of teeth and/or residual dental roots, with an indication for extraction according to the American Association of Oral and Maxillofacial Surgeons guidelines on BRONJ.10 These guidelines include high dental mobility, recurrent odontogenic abscesses, recurrent periapical or periradicular lesions, and extraction after endodontic treatment. The exclusion criteria included the suspension of zoledronate for more than 3 months at the first visit, an allergy to amoxicillin/clavulanate, and the presence of radiographic or clinical signs of BRONJ. A total of 43 patients were included in the present study.

DIAGNOSTIC INVESTIGATION

Orthopantomography was used as a routine diagnostic examination before the tooth extractions and 12 months after extraction. No computed tomography was performed, because no clinical or radiographic signs of BRONJ were observed. TREATMENT PROTOCOL

The patients were informed about the possible sequelae of dental extractions during BP treatment. All the patients included in the present study had accepted the proposed treatment and had signed an informed consent form. The following antibiotic prophylaxis was prescribed: oral amoxicillin plus clavulanate 1 g/12 hours, for 2 days before the surgical procedure, and for 5 days postoperatively. The extractive procedure included local anesthesia, the creation of a mucoperiostal flap, tooth extraction, curettage, removal of the adjacent alveolar bone with piezoelectric instruments and/or rongeur, and suture of the flaps using silk 3-0 suture (Figs 1– 4). A rinse with an antimicrobial mouthwash was recommended (chlorhexidine 0.2% or povidone-iodine 10%). The sutures were removed after 7 days. The follow-up was daily for the first week, weekly for the following month, and, subsequently, monthly for 12 months.

Results The average patient age was 56.4 ⫾ 5.8 years. The average duration of zoledronate administration was 16.2 ⫾ 3.2 months (Table 1). A total of 102 dental extractions in 43 patients were performed using the proposed preventive protocol (Table 2). During the

STATISTICAL ANALYSIS

Analysis of variance tests were done to calculate the average patient age and the average duration of zoledronate administration.

FIGURE 1. Preoperative orthopantomogram. Ferlito, Puzzo, and Liardo. Preventive Protocol for Tooth Extractions in Zoledronate-Treated Patients. J Oral Maxillofac Surg 2011.

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FIGURE 2. Orthopantomogram 1 day after dental extraction.

FIGURE 4. Intraoral image 12 months after dental extraction.

Ferlito, Puzzo, and Liardo. Preventive Protocol for Tooth Extractions in Zoledronate-Treated Patients. J Oral Maxillofac Surg 2011.

Ferlito, Puzzo, and Liardo. Preventive Protocol for Tooth Extractions in Zoledronate-Treated Patients. J Oral Maxillofac Surg 2011.

12-month follow-up period, no signs of inflamed tissue or necrotic exposed bone were observed in any patient. No radiographic signs of BRONJ were observed on the orthopantomograms 12 months after the surgical procedures.

Discussion BRONJ, a rare condition characterized by exposed necrotic bone in the maxillofacial region of patients treated with BPs, has received increasing attention since the early reports published in 2003.3,7 Most of the recent publications have suggested that dental treatment of BP-treated patients should be conservative. Restorative dentistry, limited nonoperative periodontics, and endodontics have been the methods

of choice in such patients. According to the American Association of Oral and Maxillofacial Surgeons guidelines, elective dentoalveolar surgery does not appear to be contraindicated in patients taking oral BPs.10 However, in patients treated with intravenous BPs, extractions and all types of surgical interventions involving bone exposure should be avoided.7,10,12 The exact etiologic mechanisms of BRONJ remain unclear but might relate, in part, to altered bone remodeling or local tissue effects in susceptible patients.13 The risk of developing BRONJ also depends on the relative potency of the molecule and on other conditions, such as the use of corticosteroids.10 More than 90% of reported cases to date have occurred after intravenous BP therapy, for which the prevalence has been estimated in the range of 1% to 5%, depending on the treatment duration.13 According to the American Association of Oral and Maxillofacial Surgeons, intravenous BP exposure in the setting of managing malignancy remains the major risk factor for BRONJ, with a cumulative incidence of BRONJ ranging from 0.8% to 12%.10

Table 1. PATIENT PARAMETERS

Variable

FIGURE 3. extraction.

Orthopantomogram

12

months

after

dental

Ferlito, Puzzo, and Liardo. Preventive Protocol for Tooth Extractions in Zoledronate-Treated Patients. J Oral Maxillofac Surg 2011.

Primary systemic pathologic feature Multiple myeloma Breast cancer Prostate cancer Lung cancer Administration of zoledronate at first visit Monthly consecutive administration Drug holiday

Patients (n) 28 8 5 2 26 17

Ferlito, Puzzo, and Liardo. Preventive Protocol for Tooth Extractions in Zoledronate-Treated Patients. J Oral Maxillofac Surg 2011.

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PREVENTIVE PROTOCOL FOR TOOTH EXTRACTIONS IN ZOLEDRONATE-TREATED PATIENTS

Table 2. TOOTH EXTRACTIONS

Location

Extractions (n)

Maxillary Mandibulary

59 (34 teeth and 25 residual dental roots) 43 (26 teeth and 17 residual dental roots)

Ferlito, Puzzo, and Liardo. Preventive Protocol for Tooth Extractions in Zoledronate-Treated Patients. J Oral Maxillofac Surg 2011.

In the present study, we report a case series of patients taking zoledronate who then underwent tooth extractions. The preventive protocol provided antibiotic prophylaxis and the surgical extraction of the intended teeth, accompanied by removal of the adjacent alveolar bone (alveolectomy) to reduce the risk of occurrence of BRONJ. According to Marx et al5 and Sawatari and Marx,14 and Marx,15 BRONJ always begins in the alveolar bone. This event might result from high alveolar bone turnover.14 The vulnerability of any bone to BPs directly relates to its rate of turnover. The rate of alveolar bone turnover is 10 times that of long bones, twice that of the bone about the mandibular canal, and 3 to 5 times that of the bone about the inferior border.15,16 This explains why both osteonecrosis due to intravenous BPs and oral BPs begins in the alveolar bone.5,15 Van Poznak and Estilo17 have suggested that osteoclast inhibition might render the jaw bone vulnerable to osteonecrosis by reducing its ability to repair and remodel in response to damage. Another preventive protocol was proposed in 2010 for tooth extraction in patients treated with zoledronate. The investigators suggested an atraumatic approach to dental extraction and the following pharmacologic prophylaxis: 1 g of amoxicillin 3 days before dental extraction and for the subsequent 17 days.18 Although the results of their study were promising, we do not agree with their approach for 2 reasons. First, the long-term antibiotic administration could result in antibiotic resistance. Second, a tooth extraction, although atraumatic, always induces the physiologic processes of bone remodeling and repairing that, in patients treated with zoledronate, will be suppressed. According to the published data, the nonhealing of the residual alveolar bone could induce BRONJ.9 We are aware of the methodologic limitations of the present study. The sample of patients was not large, and ours was not a controlled study. Therefore, it would rank low in the ideal hierarchy of evidence. We decided not to create a control group for ethical reasons because not providing prevention measures against BRONJ could lead to unwished-for consequences. Within the limits of the present study, the results of our case series have been very promising because BRONJ did not develop in any of our patients. For all

patients taking zoledronate and having untreatable inflammatory dental conditions, the present protocol could be recommended. In conclusion, we have observed that the removal of the alveolar bone and a correct antimicrobial prophylaxis (antibiotics and mouthwash) can reduce the risk of osteonecrosis in patients taking zoledronate.

References 1. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2003 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527, 2004 3. Ruggiero SL, Carlson ER, Assael LA: Comprehensive review of bisphosphonate therapy: Implications for the oral and maxillofacial surgery patient. J Oral Maxillofac Surg 67:1, 2009 4. Schwartz S, Joseph C, Iera D, et al: Bisphosphonates, osteonecrosis, osteogenesis imperfecta and dental extractions: A case series. J Can Dent Assoc 74:537, 2008 5. Marx RE, Cillo JE, Ulloa JJ: Oral bisphosphonates induced osteonecrosis: Risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65: 2397, 2007 6. Khosla S, Burr D, Cauley J, et al: Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479, 2007 7. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369, 2007 8. Allen MR, Burr DB: The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: So many hypotheses, so few data. J Oral Maxillofac Surg 67:61, 2009 9. Cheng A, Mavrokokki A, Carter G, et al: The dental implications of bisphosphonates and bone disease. Aust Dent J 50:S4, 2005 (suppl 5) 10. Ruggiero SL, Dodson TB, Assael LA, et al: Position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 67:2, 2009 (suppl 5) 11. Regev E, Lustmann J, Nashef R: Atraumatic teeth extraction in bisphosphonate treated patients. J Oral Maxillofac Surg 66: 1157, 2008 12. Campisi G, Di Fede O, Musciotto A, et al: Bisphosphonaterelated osteonecrosis of the jaw (BRONJ): Run dental management designs and issues in diagnosis. Ann Oncol 18: vi168, 2007 (suppl 6) 13. Lo JC, O’Ryan FS, Gordon NP, et al: Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. Oral J Maxillofac Surg 68:243, 2010 14. Sawatari Y, Marx RE: Bisphosphonates and bisphosphonate induced osteonecrosis. Oral Maxillofac Surg Clin North Am 19:487, 2007 15. Marx RE: Reconstruction of defects caused by bisphosphonate-induced osteonecrosis of the jaws. J Oral Maxillofac Surg 67:107, 2009 (suppl 5) 16. Dixon RB, Tricker ND, Garetto LP: Bone turnover in elderly canine mandibles and tibia [IADR Abstracts]. J Dent Res 76: 2579, 1997 17. Van Poznak C, Estilo C: Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates. Oncology 20:1053, 2006 18. Lodi G, Sardella A, Salis A, et al. Tooth extraction in patients taking intravenous bisphosphonates: A preventive protocol and case series. J Maxillofac Surg 68:107, 2010