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Seediscussions,stats,andauthorprofilesforthispublicationat:http://www.researchgate.net/publication/273152774 Medication-RelatedOsteonecrosisoftheJaws FromOncePerYearIntravenousZoledronic Acid(Reclast):Reportof4Cases ARTICLEinIMPLANTDENTISTRY·FEBRUARY2015 ImpactFactor:1.18·DOI:10.1097/ID.0000000000000227·Source:PubMed READS 25 2AUTHORS,INCLUDING: CameronYSLee TempleUniversity 32PUBLICATIONS336CITATIONS SEEPROFILE Availablefrom:CameronYSLee Retrievedon:06December2015 IMPLANT DENTISTRY / VOLUME 24, NUMBER 2 2015 227 Medication-Related Osteonecrosis of the Jaws From Once Per Year Intravenous Zoledronic Acid (Reclast): Report of 4 Cases Cameron Y. S. Lee, DMD, MD, PhD,* and Jon B. Suzuki, DDS, PhD, MBA† steonecrosis of the jaws is a commonly reported side effect with patients prescribed oral antiresorptive medications (formerly known as bisphosphonates) to treat osteoporosis and osteopenia.1,2 Oral antiresorptive agents are considered as the standard of care for the prevention and treatment of women with postmenopausal osteoporosis and are the most widely prescribed medications for this skeletal disorder. Unfortunately, the entire dental profession is confronted with this adverse side effect because of established medical therapy in the management of osteoporosis and the complications of skeletal-related events.3,4 Oral medications approved by the United States Food and Drug Administration (FDA) include the following antiresorptive agents: Alendronate sodium (Fosamax; Merck & Co., Inc., Whitehouse Station, NJ)5; Risedronate sodium (Actonel, Warner Chilcot, Dublin, OH)6; and Ibandronate sodium (Boniva, Roche O *Private Practice in Oral, Maxillofacial and Reconstructive Surgery; Professor of Surgery, Department of Periodontology and Oral Implantology, Temple University Kornberg School of Dentistry, Philadelphia, PA. †Professor and Associate Dean, Temple University, Kornberg School of Dentistry, Department of Periodontology and Oral Implantology, School of Medicine; Department of Microbiology and Immunology, Philadelphia, PA. Reprint requests and correspondence to: Cameron Y. S. Lee, DMD, MD, PhD, 98-1247 Kaahumanu Street, Suite 314, Aiea, HI 96701, Phone: 808-484-2288, Fax: 808-484-1181, E-mail: [email protected] ISSN 1056-6163/15/02402-227 Implant Dentistry Volume 24 Number 2 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/ID.0000000000000227 Osteonecrosis of the jaws is a commonly reported side effect with patients prescribed oral antiresorptive medications to treat osteoporosis and osteopenia. Oral antiresorptive agents are considered as the standard of care for the prevention and treatment of women with postmenopausal osteoporosis. Because of patient’s noncompliance of the antiresorptive medications, which may require once-weekly or once-monthly oral ingestion, a new once a year intravenous (IV) infusion of zoledronic acid was recently introduced in the management of osteoporosis. Reports of medication-related osteonecrosis of the jaw (MRONJ) have been reported in patients with cancer treated with multiple doses of IV zoledronic acid. However, there is a paucity of reports occurring with the once-yearly infusion of zoledronic acid (Reclast) for the management of osteoporosis. In this article, we report 4 cases of patients who had a history of longterm oral antiresorptive therapy and now were taking the onceyearly IV zoledronic acid (Reclast) and soon developed MRONJ after completing surgery of the maxilla and mandible. (Implant Dent 2015;24:227–231) Key Words: zoledronic acid (Reclast), osteoporosis, medicationrelated osteonecrosis of the jaws Group, South San Francisco, CA).7 Each of the medications differs in their binding affinity to bone, potency, and duration.8,9 For patient’s convenience and individuals unable to comply with a set dosing schedule of the antiresorptive medications, which may require onceweekly (Fosamax and Actonel) or once-monthly (Boniva) oral ingestion,4 a new once a year intravenous (IV) infusion of zoledronic acid (Reclast, Novartis Pharmaceuticals, East Hanover, NJ; Aclasta, Novartis Pharma) was approved by the FDA in 2007.10 At a dose of 5 mg once per year, it has demonstrated antifracture properties in postmenopausal women and men with osteoporosis.10,11 During a 3-year period, an annual infusion of 5 mg of zoledronic acid significantly reduced the risk of fracture of all major osteoporotic anatomic sites, especially vertebral and hip fractures.2 Once per year infusion of zoledronic acid may be more appealing to the osteoporotic patient, as strict adherence to a weekly or monthly regimen of oral dosing for 12 months can be challenging and lead to patient’s noncompliance.12–14 Medication-related osteonecrosis of the jaw (MRONJ) due to long-term oral antiresorptive therapy has been well documented.1,15–21 This Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 228 INTRAVENOUS ZOLEDRONIC ACID (RECLAST): REPORT OF 4 CASES LEE Table 1. MRONJ Patient Data Patient Sex Age AK JK BS F F F 87 72 70 JS F 89 Time to Event (wk) Stage Complication Maxillary infection Mandible infection Sinusitis of right maxillary sinus Mandible fracture 1 5 2 2 2 2 2 (infection) 4 (fracture) 2 3 Procedure Extraction of teeth Extraction of teeth Sinus lift elevation with bone grafting Extraction of teeth Average age: 79.5 years. Time to Event: From day of surgery to first observed postoperative signs and symptoms of MRONJ based on 2014 AAOMS classification. Stage: Clinical signs and symptoms of MRONJ based on 2014 AAOMS classification. disease entity was formerly known as bisphosphonate-related osteonecrosis of the jaws and antiresorptive-related osteonecrosis of the jaws.1 But, because of the vast amount of recent cases of osteonecrosis of the jaws from other antiresorptive and antiangiogenic treatment strategies, the American Association of Oral and Maxillofacial Surgeons (AAOMS) has recommended the change in nomenclature.15 Since the first reports by Marx16 in 2003 who described 36 patients with ONJ while receiving IV antiresorptive agents and Ruggiero et al17 who presented an additional 63 cases in 2004, multiple reports of MRONJ have appeared in the medical and dental literature.18–20 Development of soft and hard tissue lesions is usually because of an inciting event, such as tooth extraction, bone grafting of the jaws in preparation for dental implants, and implant surgery.16,17,21 MRONJ has been reported in patients with cancer treated with multiple doses of IV zoledronic acid.22,23 The incidence of MRONJ for patients taking the IV form of this medication is estimated at 2% to 18%.24,25 In contrast, Merck et al estimate the risk of developing MRONJ for patients taking the oral form of antiresorptive agents is 0.7 cases per 100,000 person-years of exposure.16 The AAOMS position paper on MRONJ estimate the incidence of ONJ cases for patients taking the oral form as 0.01% to 0.04%.15,26 However, there are very few reports in the English literature of this occurring with the once-yearly infusion of Table 2. MRONJ Staging and Treatment Strategies Stage 0 1 2 3 Description Treatment Nonspecific clinical findings, radiographic findings, and symptoms. No clinical evidence of necrotic bone Asymptomatic, but exposed, necrotic bone or fistulas are present. No evidence of infection Systemic management. Use of analgesics and antibiotics Use of chlorhexidine mouth rinse, close monitoring of patient on quarterly basis. Provide patient education Symptomatic treatment with antibiotics, oral bacterial mouth rinse, pain control, debridement of infected area Exposed necrotic bone or fistulas that probes to bone in area of infection. Clinical signs of infection, such as pain, erythema with or without purulent discharge All of the above treatment with more Exposed necrotic bone or fistulas aggressive surgical intervention, present that probes to bone and such as debridement and resection extends beyond region of alveolar of jaw bone, such as to inferior border of mandible, ramus of mandible, and zygoma in maxilla. Fracture of jaw or osteolysis present in jaws Staging and treatment strategy of MRONJ according to the position paper of the 2014 AAOMS. AND SUZUKI zoledronic acid (Reclast, Novartis Pharmaceuticals; Aclasta, Novartis Pharma) for the management of osteoporosis.27,28 It is estimated that the risk of developing MRONJ from IV zoledronic acid in the management of osteoporosis is approximately 0.017% (1.7 cases per 10,000 patients).28 In this article, we report 4 cases of patients who had a history of long-term oral antiresorptive therapy and now were taking the once-yearly IV zoledronic acid (Reclast) and soon developed MRONJ after completing surgery of the maxilla and mandible. PATIENTS AND METHODS For all clinicians, it is important to obtain a complete health history regarding patient exposure to antiresorptive agents.29 A prospective chart review of 4 patients was completed. Data included gender, age, systemic factors, duration of antiresorptive therapy (oral and IV) prescribed by their physician, jaw location of osteonecrosis, surgical treatment (debridement, sequestrectomy, platelet-rich plasma), and overall outcome. The study group consisted of 4 female patients whose age ranged from 70 years to 89 years. The mean age was 79.5 years (Table 1). We adhere to the classification of the AAOMS15,26 to define MRONJ that consist of 4 stages (0–3) (Table 2). This clinical staging system has been established to define the severity of MRONJ and guide the clinician in the management of this surgical problem. Biopsy specimens were obtained from all 4 patients that were histopathologically diagnosed with actinomyces (Fig. 1). Of the 4 patients, 3 presented with stage 2 disease and 1 (mandible fracture) with stage 3 disease. One patient completed the sinus lift elevation procedure with bone graft augmentation of the right maxillary sinus in preparation for implant placement that became infected 2 weeks after the surgical procedure. Acute sinusitis and fistula formation were present upon initial examination. The other 3 patients had molar teeth extracted from the posterior maxilla and mandible. Oroantral communication was observed in the patient who had teeth extracted from the left Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. IMPLANT DENTISTRY / VOLUME 24, NUMBER 2 2015 Fig. 1. Diffuse purple staining filamentous bacteria identified as actinomyces in nonvital bone specimen. Microbes are not surface contaminants but established deep in the bone that may represent biofilms. Hematoxylin and eosin (3100). Fig. 2. Displaced fracture of left posterior mandible that occurred 4-week postextraction of teeth and surgical debridement in this 89-year-old Asian woman. Mandible fracture due to long-term use of alendronate (greater than 10 years) and recent use of IV zoledronic acid. posterior maxilla as the floor of the maxillary sinus was eroded. The 89-year-old patient sustained a mandible fracture 4 weeks (Fig. 2) after extraction of the teeth and a debridement procedure. All 4 patients (including the patient with the mandible fracture) were treated with surgical debridement that consisted of excision of all necrotic-appearing bone cellular therapy consisting of platelet-rich plasma and long-term oral antibiotic therapy for a period of 4 to 12 months prescribed by an infectious disease specialist. DISCUSSION Antiresorptive agents decrease bone resorption and skeletal fracture by chemically binding to calcium hydroxyapatite in the mineral phase of bone. They are attracted to areas of bone remodeling, where osteoclast activity is high and concentrating in the lacunae of the osteoclast. Therefore, the osteoclastic cell is the main target for antiresorptive agents and prevents osteoclasts from binding to the surfaces of bone, which prevents bone resorption and increases bone mineral density.30–33 229 IV infusion of zoledronic acid (Reclast) 5 mg over a 15-minute interval is used in the management of osteoporosis.2,10,11,34 It is considered as the most potent of the antiresorptive medications with a long half-life.10 In several human and animal studies, yearly IV doses of zoledronic acid had a greater effect on bone remodeling compared with oral antiresorptive medications and may be responsible for one of the many proposed mechanisms of MRONJ.34–36 However, clinical data regarding the incidence of MRONJ from once a year infusion of zoledronic acid (Reclast) is sparse.28,37 Data regarding our case series are presented in Table 1. All 4 patients were Asian women, with an average age of 79.5 years. They all had a positive history of long-term Fosamax (Merck, Whitehouse Station, NJ) use for over 10 years before treatment with IV zoledronic acid. Three of the 4 patients received 2 doses of zoledronic acid. The woman who developed a mandible fracture received only a single dose of zoledronic acid. We hypothesize that all of our patients developed MRONJ while on IV zoledronic acid. Based on past clinical experience, it is the authors’ opinion that compared with the oral form of MRONJ, osteonecrosis of the jaws from the IV form of bisphosphonates presents with greater challenges. Of the 4 patients, 1 developed an infection that progressed to a mandible fracture 4 weeks after the teeth were extracted. The infection was refractory to surgical treatment, which ultimately required application of a reconstruction bone plate to stabilize the fracture segments once the fracture was identified. Currently, it remains unclear if actinomyces is primarily involved in the pathogenesis of osteonecrosis in the patient on antiresorptive therapy.38–42 In Marx’s series of 30 consecutive MRONJ cases, they demonstrated high number of actinomyces species, but the clinical significance of this observation was not addressed.39 In a study by O’Ryan et al,43 actinomyces was present in greater than 75% of histologic specimens. When histopathology was available, Lazarovici et al38 reported that actinomyces colonies were identified Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 230 INTRAVENOUS ZOLEDRONIC ACID (RECLAST): REPORT 93% of the time. In our opinion, recognition of actinomycosis is critical. The reasons for the use of the term “critical” are the facts that in the presence of signs and symptoms of soft tissue edema, erythema, orocutaneous fistulas, and suppuration in the MRONJ patient, actinomycosis should be recognized as a primary diagnosis and specific treatment directed at eradication of this bacterial pathogen. Therefore, our treatment regimen consists of penicillin VK at a dose of 1 g 3 to 4 times per day over a 4- to 12-month duration. If patients are younger than 65 years, probenecid, 500 mg 3 to 4 times per day is added to decrease antibiotic renal clearance. For patients who are allergic to penicillin, an alternative regimen such as doxycycline 100 mg twice daily, erythromycin 500 mg or clindamycin 300 mg 4 times per day is acceptable over 6- to 12-month duration. Based on our surgical experience and that of others,43–52 surgical intervention should be considered early in the course of management of MRONJ. It has been demonstrated that conservative management in many advanced cases (Stage 2 and 3) results in only a 50% resolution defined as closure of the oral mucosa and remains refractory to conservative treatment. Surgical intervention may result in a more definitive treatment and resolution of MRONJ.45–52 CONCLUSION In this report, we describe 4 patients with a medical history of longterm oral antiresorptive therapy who were now taking the once-yearly infusion of IV zoledronic acid who soon developed MRONJ after completing surgery of the jaws. We anticipate that the dental practitioner will increasingly encounter patients not only prescribed the oral form of antiresorptive agents but also the IV form as well and should be able to anticipate the potential complications from this medication. DISCLOSURE The authors claim to have no financial interest, either directly or indirectly, in the products or information listed in the article. OF 4 CASES LEE REFERENCES 1. 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J Oral Maxillofac Surg. 2013;71: 2077–2086. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.