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Identification and Treatment of Bisphosphonate-Associated Actinomycotic Osteonecrosis of the Jaws
Cameron Y. S. Lee, DMD, MD, PHD,* Francis D. Pien, MD, MPH,† and Jon B. Suzuki, DDS, PHD, MBA‡

isphosphonates (BPs) are a pharmacologic class of synthetic analogs of inorganic pyrophosphate that has an affinity for calcium.1 They are used in the treatment of various malignant and benign metabolic conditions, such as hypercalcemia of malignancy; Paget’s disease of bone; multiple myeloma; and metastases from distant sites such as breast, thyroid, prostate glands, and lung. The oral form of BPs is indicated in the management of osteoporosis, fibrous dysplasia, and most recently, osteogenesis imperfecta in the pediatric population.2,3 Currently, there are 5 bisphosphonates in clinical use: alendronate (Fosamax; Merck, Whitehouse Station, NJ), risedronate (Actonel; Proctor & Gamble Pharmaceuticals, Cincinnati, OH), ibandronate (Boniva; Roche Pharmaceuticals, Nutley, NY), zoledronate (Zometa; Novartis Pharmaceuticals, East Hanover, NJ), and pamidronate (Aredia; Novartis Pharmaceuticals). All 5 medications differ in their binding affinity to bone, potency, and duration.2–5

B

Osteonecrosis of the jaws (ONJ) is a condition characterized by necrotic exposed bone in the jaws of patients receiving intravenous or oral bisphosphonate therapy. A review of the medical and dental literature reveals that the pathoetiology of ONJ remains unknown and there is no established link that bisphosphonates are the primary cause of this bone pathology. However, there

is clinical evidence that Actinomyces may play a critical role in the pathogenesis of bisphosphonate-associated ONJ. Identification and a prolonged course of oral antimicrobial therapy may lead to complete resolution of this actinomycotic osteonecrosis. (Implant Dent 2011;20:331–336) Key Words: Actinomyces, actinomycotic osteonecrosis, antibiotic therapy, bisphosphonate therapy

*Private Practice, Oral, Maxillofacial and Reconstructive Surgery, Aiea, Hawaii. †Private Practice, Internal Medicine and Infectious Disease, Honolulu, Hawaii; Clinical Professor of Medicine and Medical Microbiology, John A. Burns School of Medicine, University of Hawaii, Hawaii. ‡Professor and Associate Dean, Department of Periodontology and Oral Implantology and Microbiology and Immunology, Temple University Kornberg School of Dentistry and School of Medicine, Philadelphia, PA.

Reprint requests and correspondence to: Cameron Y. S. Lee, DMD, MD, PHD, Oral, Maxillofacial and Reconstructive Surgery, 98-1247 Kaahumanu Street, Suite 314, Aiea, Hawaii 96701, Phone: 808-484-2288, E-mail: CLee555294@aol.com
ISSN 1056-6163/11/02005-331 Implant Dentistry Volume 20 • Number 5 Copyright © 2011 by Lippincott Williams & Wilkins DOI: 10.1097/ID.0b013e3182310f03

Since the first reports by Marx4 in 2003, who described 36 patients with osteonecrosis of the jaws (ONJ) while receiving intravenous BPs and Ruggiero et al5 who presented an additional 63 cases in 2004, multiple reports of BPassociated ONJ (BPONJ) have appeared in the medical and dental literature, including oral BPONJ.6 –10 Development of BP-associated soft and hard tissue lesions is usually due to an inciting event, such as tooth extraction, bone grafting of the jaws in preparation for dental implants, and implant surgery.4,11 However, spontaneous cases of ONJ have been reported.11 In these instances, thin overlying soft tissues are easily perforated, such as the gingival tissue overlying a palatal torus or the mucosa of the posterior lingual mandible. Several hypotheses have been presented in the literature to explain the pathogenesis of BPONJ. Marx et al8,11 hypothesized that bone turnover is effectively inhibited, because the primary action of BPs is the inhibition of osteoclastic-mediated bone resorption. As nitrogen containing bisphosphonates concentrate in bone hydroxyap-

atite, the major toxic effect is cellular apoptosis of osteoclasts.8 Therefore, coupling of osteoclastic and osteoblastic activity is disrupted, resulting in suppression of bone turnover. A second theory is that ONJ is due to the antiangiogenic effects of bisphosphonates that affects vascularization, inhibits angiogenesis and ultimately, delays wound healing.12 Landesberg et al13 theorize that oral epithelial cells are exposed to localized increased toxic concentrations of BPs after trauma, resulting in compromised epithelial wound healing, jaw exposure, and development of ONJ. The most recent pathogenic hypothesis by Otto et al14 is that local tissue acidosis in the jaw due to bisphosphonates may elicit the onset of osteonecrosis. All of the above theories attempt to explain the pathogenesis of BPONJ. However, they fail to explain why nitrogen containing bisphosphonates result in ONJ, but not other parts of the skeletal bones. To date, there are no studies that demonstrate that bisphosphonates selectively accumulate in the jawbones compared with other parts of the

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skeleton.15 Currently, there is still no direct causal relationship between ONJ and bisphosphonate therapy.11–17 Almost every dental specialty organization has drafted a position paper on BPONJ. The American Association of Oral and Maxillofacial Surgeons published their position paper in 2007,18 which was recently updated in 2009.19 Exposed bone for at least 8 weeks duration with or without pain continues to be the hallmark feature for the diagnosis of BPONJ.18,19 Even though it is well accepted that exposed bone is the primary defining feature of BPONJ,2,4 –19 it is unclear whether Actinomyces plays a critical role or is a secondary infection in the pathogenesis of BPONJ.9,11,20,21 The difficulty is in determining whether Actinomyces represents microbial colonization on the hard and soft tissues or is a true infection. Although this bacterium is a normal inhabitant of the oral cavity, it is the author’s clinical experience, as well of others,21–25 that this microbial pathogen is an opportunistic bacterium directly involved in the pathology of the hard and soft tissues of the maxillofacial region and oral cavity in the BPONJ patient. In every instance, where the diagnosis of Actinomyces was established in our patients, bone exposure was not always observed, corresponding to Stage 0 in the American Association of Oral and Maxillofacial Surgeons position paper.19 Stage 0 describes patients as having nonspecific clinical findings. In our series of 13 patients reported in this publication, one or more of the following clinical features were observed in the presence of Actinomyces: gingival edema, and erythema; pain; fistulous tracts in the gingival and mucosal tissues; and orocutaneous fistulas with suppuration in the maxillofacial region. To our knowledge, the presence and significance of Actinomyces on the soft and hard tissues of the oral cavity in the BPONJ patient has not been thoroughly discussed in the dental literature. A better understanding of this bacteria and its precise role in the pathogenesis of BPONJ is important to possibly identify another pathomechanism of this disease process.20,21,23–25 The goal of this study is to report on 13 patients with a

history of BPONJ involving the mandible and maxilla. In each patient, treatment consisted of surgical debridement with or without sequestrectomy of the jaws and simultaneous soft and hard biopsy to rule-out actinomycosis. Once Actinomyces was identified, treatment focused on a prolonged course of oral antibiotics to eradicate this microbial pathogen. The presence of Actinomyces should not be neglected, as a plausible hypothesis is that Actinomyces plays a critical role in the pathogenesis of BPONJ.20,21,23–25
Review of the Literature

Pathogenesis of Actinomycosis

A review of published cases identified multiple bacterial species in BPONJ patients, especially the genus Actinomyces.8,21,23–27 Other microbial pathogens that have been identified include the following: Streptococcus, Staphylococcus, Treponemes, Bacteroides, Actinobacillus, Moraxella, and Eikenella corrodens.20 –30 It is postulated that these microorganisms exert a synergistic effect in the pathogenesis of disease, secreting bacterial enzymes, such as collagenases and hyaluronidases, that are tissue destructive and promote extension of the lesion to other areas of the head and neck.25,26,29 Currently, it is not known whether the infection of the jaws and overlying soft tissues is a primary or secondary event in BP-associated ONJ.9,11,20,28,30 In 1875, Actinomyces was first discovered by Cohn 29 in lacrimal gland infections, followed by a report of lumpy jaw disease in cattle by Harz in 1877. That same year, Israel isolated the pathogen from the genus, Actinomyces. 29 Currently, there are several recognized species of Actinomyces that normally inhabit the human oral cavity that can cause disease. Actinomyces species are non–spore-forming, filamentous gram-positive, facultative anaerobic bacteria which are normal inhabitants of the oral cavity.29,31–33 These bacteria can be observed on the oral mucosa, gingiva, carious teeth, calculus, periodontal pockets, tonsillar crypts, and in the mucosal tissues of the respiratory tract, gastrointestinal tract, and female genitals.31,33,34

With BPONJ, it is theorized that pathogenicity is due to various bacteria gaining direct entry into the jaw bones from surgical procedures that violate overlying gingival or mucosal tissues of the mandible and maxilla.5,8,11,29 The most common entry site to the jaw bones is the alveolus during extraction of teeth.8,11 Other portals of entry into the jaws may occur during the surgical placement of dental implants, bone grafting procedures, and periodontal and endodontic procedures that require manipulation of the soft tissues of the jaws.5–11,18,19 Actinomyces is a chronic infection characterized by both granulomatous and suppurative infection intra- and extraorally, invading both soft and hard tissues of the oral cavity and maxillofacial region.29,31–33 The infection is capable of advancing across anatomical boundaries, resulting in the formation of pyogenic lesions.29 These lesions are often associated with fistulous tracts that may contain granules, composed of micro colonies of the pathogen embedded in the soft tissues of the jaws.29,31–33 There are 4 clinical types of human actinomycosis that are categorized based on anatomical site of pathology: cervicofacial, cutaneous, thoracic, and abdominal.31,33 For the dentist, the area of interest is the cervicofacial region that may involve the soft tissues of the oral cavity, jaw bones, sinuses, and face.19,29,32 With cervicofacial actinomycosis involving BPONJ, onset can be insidious or slow forming.32 Actinomycosis initially presents as a soft tissue swelling that fails to resolve in the periand submandibular regions of the neck. Often, there is no pain reported by the patient, unless there is a secondary infection. The persistent swelling is firm, and the skin in the affected area is dark red to purple in color. With progression of the cervicofacial variant, the infection becomes fluctuant and does not follow the usual fascial planes of the head and neck.29 With chronic inflammation, the skin is perforated with suppuration of pus from draining orocutaneus fistulas (Fig. 1). The pus from draining fistulas may contain yellow granules, known as “sulfur granules,” that are colonies of filamentous bacteria.29,31–33 With progression of infection, disease may ex-

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tend to other tissues of the maxillofacial region, including the jaw bones and lymph nodes of the head and neck.29 Irrespective of anatomical site, actinomycosis is usually initiated by mechanical trauma that allows these endogenous microbial pathogens entry into the mucosa barrier and ultimately, the jaw bones.

PATIENTS

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METHODS

A prospective chart review of 13 patients was completed that were all histopathologically diagnosed with actinomycosis and BPONJ. Data included gender, age, medical diagnosis, duration of bisphosphonate therapy prescribed by their physician, jaw location of osteonecrosis, surgical treatment (debridement, sequestrectomy, platelet-rich plasma and in some instances, hyperbaric oxygen [HBO] treatment), and overall outcome. The study group consisted of 13 patients (4 men and 9 women) whose ages ranged from 54 to 87 years. The mean age for men was 73.3 years and women 69.6 years. The average age for all patients is 70.7 years. Three patients received intravenous aminobisphosphonates, specifically Zometa. The remaining 9 patients were prescribed oral bisphosphonates for the management of osteoporosis. Based on the disease staging classification of the American Association of Oral and Maxillofacial Surgeons,18,19 4 patients had nonspecific signs and symptoms that corresponded to Stage 0. Five patients presented with Stage 2 disease, as exposed necrotic bone associated with an infection with or without suppuration was documented. There were 3 patients in Stage 3; in this category, 2 patients experienced pathologic mandible fractures, whereas the third patient was diagnosed with an oroantral communication. The last patient in the cohort had exposed necrotic bone, but was asymptomatic and categorized in Stage 1.
Histopathology

Fig. 1. Patient with type 3 bisphosphonateassociated osteonecrosis of mandible. Note the weeping purulent discharge from orocutaneus fistula.

Fig. 3. A, Low power view of purple staining filamentous bacteria identified as Actinomyces (arrows) in nonvital bone specimen. B, High power view of filamentous bacteria, Actinomyces. Note the “sun burst” appearance. Fig. 2. High power view of nonvital bone with empty lacunae lacking osteocytes.

bone with empty lacunae (Fig. 2) was always the primary feature with colonies of filamentous microorganisms consistent with Actinomyces species (Figs. 3, A and B and 4). Colonies of yeast was also a common finding.
Laboratory Diagnosis

Bone specimens of all 13 patients were histopathologically evaluated. Every bone specimen was cut to obtain multiple cross sections. Acute or chronic inflammation was observed in every specimen. Necrotic and nonvital

Diagnosis of this pathogen is accomplished by wound culture or lesion biopsy.31,33 Actinomyces are acid-fast, gram-positive bacilli. The microorganism can easily be detected by Gram stain that will reveal branching filaments, sometimes arranged in a sun burst pattern (Fig. 3, B). Detection of sulfur granules confirms the diagnosis of actinomycosis. These granules are hard in texture and contain filamentous bacteria. Specimens should be incubated both aerobically and anaerobically to differentiate these facultative anaerobes from other pathogens, as polymicrobial infection is common with BPONJ. Bone biopsy demonstrates osteonecrosis, which is a key microscopic feature of infections

Fig. 4. SEM image showing characteristic branching morphology of Actinomyces microorganisms.

involving the maxilla and mandible in the BPONJ patient.
Treatment of Actinomycotic Osteonecrosis

The management of BPONJ remains controversial as the exact pathophysiology remains unknown. There is no consensus as how to best manage the patient who is prescribed bisphosphonate medications.35–37 In our protocol, treatment consists of the use of platelet-rich plasma, surgical intervention in the form of debridement of the jaws with or without sequestrectomy

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and a prolonged course of antibiotic therapy. In cases that have proven difficult to effectively manage, especially the patient on the intravenous formulary, HBO has been used with success.24 With biopsy-proven actinomycosis, it is reasonable to discontinue bisphospohonate therapy (drug holiday) in consultation with the patient’s physician. From past clinical experience, we have observed several cases of exposed jaw bone that did eventually heal without surgical intervention and cessation of bisphosphonate therapy.38 However, as bisphosphonates have a long half life, we do not have a set duration for a “drug holiday.”39 This is despite the fact that the American Association of Oral and Maxillofacial Surgeons position paper recommends a 3-month drug holiday before treatment for patients taking the oral formulation of bisphosphonates for more than 3 years.18,19 There are no controlled trials evaluating the choice or duration of antibiotic therapy for Actinomycosis.21,26 Current recommendations include both high dose and prolonged duration antibiotic therapy.18 –21,30 The “standard” recommendation is for 2 to 6 weeks of daily intravenous antibiotic therapy followed by oral therapy for 3 to 12 months depending on the size and response of jaw osteonecrosis.21,26 In the past 5 years, 1 of the authors (F.D.P.) has treated over 100 patients, referred mainly by oral and
Table 1. Patient Data Patient S.C. W.G. J.W. J.I. M.L. Y.H. M.B. B.Y. A.N.P. B.F. J.I. Y.K. M.K. Age/ Gender 62/M 87/M 54/F 81/F 68/M 75/F 70/F 70/F 57/F 83/F 76/M 74/F 62/F Stage (0–3) 3 2 2 3 1 0 0 0 0 3 2 2 2

maxillofacial surgeons in the community for ONJ related to bisphosphonate therapy ( 95% prescribed to older women for osteoporosis). The majority of these patients had biopsy-proven Actinomycosis. Nearly, all patients were cured with a time period of 12 to 18 months by surgical debridement with or without sequestrectomy and prolonged antibiotic therapy. The only failures were in patients who could not discontinue bisphosphonate use, because of ongoing cancer treatment. For the first 2 years of managing this new pathologic entity, all of the authors’ (F.D.P.) patients were placed on 6 weeks of daily intravenous antibiotics, and then a prolonged course of oral antibiotics. Because acquiring sufficient clinical experience treating this specific type of bone pathology, our standard regimen now consists of high dose oral antibiotics alone for at least 3 to 6 months. This is dependent on the initial size and response of the infection to antibiotic therapy. This exclusive oral regimen was selected primarily for patient convenience, and has proven effective because most patients were older Asian women, usually small in stature with decreased renal clearance of penicillin. For most patients, our current treatment regimen is penicillin VK at a dose of 1 g, 3 to 4 times per day over 3- to 12-month duration. If patients are younger than 65 years, probenicid, 500 mg 3 to 4 times per day is added

to decrease antibiotic renal clearance. For patients that are allergic to penicillin, an alternative regimen such as doxycylcine 100 mg twice daily; erythromycin 500 mg or clindamycin 300 mg 4 times per day is acceptable over 6- to 12-month duration. If intraoral sinus tracts or orocutaneous fistulas are present, we recommend extending antibiotic therapy until complete healing is observed (Table 1).

DISCUSSION
Failure to identify Actinomyces and initiate antibiotic treatment in timely fashion could be responsible for many cases that are difficult to manage and become refractory to treatment.31–34,40–43 Although past published studies reported the presence of Actinomyces in their histopathologic specimens, some clinicians still question the significance of this microbial pathogen in the BPONJ patient.9,11,20,22,24,30,43 In 1983, Marx44 described osteoradionecrosis (ORN) of the jaws as a complication from radiotherapy. The bone pathology of ORN is an osteonecrosis similar to what is clinically observed in BPONJ. When the tissues of the maxillofacial region are radiated, they become hypovascular, hypocellular, and hypoxic.44,45 In ORN, histopathology studies, Actinomyces species were observed in many biopsy specimens. However, Marx44,45 theorized that these microorganisms are surface colonizations and not directly involved in the pathogenesis of ORN. In 2005, Store et al46 and Store and Olsen47 using DNA-DNA hybridization technology observed several different bacterial species, including Actinomyces species in 9 of 14 resected osteonecrotic mandibles from patients diagnosed with ORN. Scanning and transmission electron microscopy also identified other microbial pathogens, such as rods, spirochetes, and cocci deep in the marrow spaces. The presence of pathogenic microorganisms deep in the marrow spaces strongly suggests that Actinomyces could be of great importance in the pathogenesis of ORN and BPONJ. Currently, it remains unclear whether Actinomyces is primarily involved in the pathogenesis of osteonecrosis in the patient on bisphosphonate

Medical Diagnosis MM P-CA NHL OP P-CA OP OP OP NHL OP P-CA OP OP

Bisphosphonate and Route Z/IV Z/IV Z/IV F/PO A/PO B/PO F/PO F/PO A/PO F/PO F/PO F/PO A/PO

Exposed Bone (Y/N) Y* Y N Y* Y N N N N Y† Y Y‡ Y‡

*Mandible fracture; †oroantral communication; ‡late implant failure ( 1 y). MM indicates multiple myeloma; P-CA, prostate cancer; NHL, non-Hodgkin’s lymphoma; OP, osteoporosis; Z, zometa; F, fosamax; A, actonel; B, boniva; IV, intravenous route; PO, oral route.

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therapy.9,11,20,21,30 In Marx’s series of 30 consecutive BPONJ cases, they demonstrated high number of Actinomyces sp, but the clinical significance of this observation was not addressed.11 In a study by O’Ryan et al,48 Actinomyces was present in more than 75% of histologic specimens. When histopathology was available, Lazarovici et al9 reported that Actinomyces colonies were identified 93% of the time. In our opinion, recognition of actinomycosis is critical. In the presence of signs and symptoms of soft tissue edema, erythema, orocutaneous fistulas, and suppuration in the BPONJ patient, actinomycosis should be recognized as a primary diagnosis and specific treatment directed at eradication of this bacterial pathogen. In orthopedic surgery, biofilm theory was introduced to describe the pathoetiology of chronic long bone infections, which cause great treatment difficulty. A biofilm is a microbially derived surface community characterized by a community of microbial cells attached to a surface. Each biofilm is connected to one another and can communicate with each another. Applying biofilm theory to dental medicine, Sedghizadeh et al25 identified the presence of multiple microbial biofilms on both the surface and in the deeper cavities of bone specimens from 4 patients diagnosed with BPONJ. Bone specimens from all patients demonstrated large areas occluded with biofilms that consisted of different bacterial species, especially Actinomyces. There is a paucity of clinical trials and controlled studies in the management of the patient with actinomycosis and BPONJ. It has been our experience that surgical debridement with or without sequestrectomy, platelet-rich plasma, HBO on difficult treatment cases, and a prolonged course of high dose oral antibiotic therapy have proven successful in resolution of this infection of the jaws.

managed with a prolonged course of antibiotics over a 3- to 12-month period.
Disclosure

The authors declare no financial interest in any of the products cited in this manuscript.

REFERENCES
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CONCLUSION
Bisphosphonates are not the only cause of osteonecrosis. The results of this prospective study indicate that Actinomyces directly contributes to the pathogenesis and should be promptly

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clinical significance. Oral Oncol. 2000;36: 294-299. 41. Hansen T, Wagner W, Kirkpatrick CJ, et al. Infected osteoradionecrosis of the mandible: Follow-up study suggests deterioration in outcome for patients with Actinomyces-positive bone biopsies. Int J Oral Maxillofac Surg. 2006;35:10011004. 42. Gaffney RJ, Walsh MA. Cervicofacial actinomycosis: An unusual case of submandibular swelling. J Laryngol Otol. 1993;107:1169-1170. 43. Stanton DC, Balasanian E. Outcome of surgical management of bisphosphonate-related osteonecrosis of the jaws: Review of 33 surgical cases. J Oral Maxillofac Surg. 2009;67:943-950. 44. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg. 1983;41:351-357. 45. Marx RE, Johnson RP. Studies on the radiobiology of osteoradionecrosis and their clinical significance. Oral Surg Oral Med Oral Pathol. 1987;64:379-390. 46. Store G, Eribe ERK, Olsen I. DNADNA hybridization demonstrates multiple bacteria in osteoradionecrosis. Int J Oral Maxillofac Surg. 2005;34:193-196. 47. Store G, Olsen I. Scanning and transmission electron microscopy demonstrates bacteria in osteoradionecrosis. Int J Oral Maxillofac Surg. 2005;34:777781. 48. O’Ryan FS, Khoury S, Liao W, et al. Intravenous bisphosphonate-related osteonecrosis of the jaws: Bone scintigraphy as an early indicator. J Oral Maxillofac Surg. 2009;67:1363-1372.