John R. Kalmar

Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws

Key Summary Points Osteonecrosis of the jaws is strongly associated with the use of aminobisphosphonates, and the mechanism of disease is probably severe suppression of bone turnover. Ninety-four percent of patients are treated with zoledronic acid or pamidronate or both; 85% of affected patients have multiple myeloma or metastatic breast cancer, and 4% have osteoporosis. The prevalence of osteonecrosis in patients with cancer is 6% to 10% and the prevalence in those taking alendronate for osteoporosis is unknown; osteonecrosis seems to be time- and dose-dependent because of the long half-life of aminobisphosphonates. More than half of all cases (60%) occur after dentoalveolar surgery (such as tooth extraction) to treat infections, and the remaining 40% are probably related to infection, denture trauma, or other physical trauma. Preventive strategies include removing all foci of dental infection before starting bisphosphonate therapy. Treatment is directed toward control of pain and infection and careful local dbridement of dead bone, but not wide excision of lesions. Bisphosphonates are used to treat osteoporosis, Paget disease of bone and other metabolic bone diseases, multiple myeloma, and skeletal events associated with metastatic neoplasms. Their primary mechanism of action is inhibition of osteoclastic resorption of bone. Within the past 2 years, an increasing body of literature has suggested that bisphosphonate use, especially intravenous preparations, may be associated with osteonecrosis of the jaws. We briefly review the action of bisphosphonates, outline the clinical manifestations of bisphosphonate-associated osteonecrosis of the jaws, summarize current treatment strategies, discuss possible mechanisms of etiopathogenesis, and suggest avenues of research. Methods We performed MEDLINE and PubMed searches of English- and foreign-language literature (1966 to 31 January 2006) using the following Medical Subject Headings (MeSH) and terms: osteonecrosis, avascular necrosis, phosphorous necrosis, bisphosphonates, and diphosphonates. We then crossed the same terms with the terms jaw diseases, myeloma, breast cancer, and metastatic cancer. Other references were obtained from citations from retrieved articles. Similar terms were used to search abstracts from meetings of the American Society of Clinical Oncology. We specifically reviewed all case reports and case series of patients with bisphosphonate-associated osteonecrosis of the jaws. We included any report that provided acceptable documentation of disease and use of bisphosphonates, regardless of whether it included information on the sex of patients, the site of the lesions, and the bisphosphonate used. Several authors published more than 1 paper describing patients with osteonecrosis. Through direct communication with these authors, we confirmed that some of the same patients were included in multiple reports. When this occurred, we used and cited data only from the larger, more recent publication. No funding was received for this study. Actions of Bisphosphonates Bisphosphonates are powerful inhibitors of osteoclastic activity. They are analogues of inorganic pyrophosphates with low intestinal absorption, are excreted through the kidneys without metabolic alteration, and have a high affinity for hydroxyapatite crystals (1, 2). Because they are incorporated into the skeleton without being degraded, they are remarkably persistent drugs; the estimated half-life for alendronate is up to 12 years (3). Alendronate, risedronate, pamidronate, zoledronic acid, and ibandronate, which are called aminobisphosphonates, have much higher potency because they contain nitrogen in a side chain (Table 1). Table 1. Bisphosphonate Formulations The nonaminobisphosphonates are metabolized by osteoclasts to inactive nonhydrolyzable adenosine triphosphate analogues that are directly cytotoxic to the cell and induce apoptosis (1, 2). The newer aminobisphosphonates have 2 actions (4): induction of another adenosine triphosphate analogue that induces apoptosis, and inhibition of farnesyl diphosphonate synthase, which is part of the mevalonate pathway of cholesterol synthesis. Such inhibition results in dysregulation of intracellular transport, cytoskeletal organization, and cell proliferation, leading to inhibition of osteoclast function. In addition, aminobisphosphonates reduce recruitment of osteoclasts and induce osteoblasts to produce an osteoclast-inhibiting factor (5, 6). Aminobisphosphonates exert several antitumor effects, including induction of tumor cell apoptosis, inhibition of tumor cell adhesion to the extracellular matrix, and inhibition of tumor invasion (4, 7). Bisphosphonates also have antiangiogenesis properties (8, 9) and can activate T cells (10, 11). The use of bisphosphonates in patients with multiple myeloma and metastatic cancer to the bones, such as breast, prostate, lung, and renal cell carcinomas, has resulted in a statistically significant reduction in skeletal complications, including pathologic fractures, spinal cord compression, hypercalcemia of malignant disease, and the need for subsequent radiotherapy or surgery to bone (12-14). Intravenous bisphosphonates have improved bioavailability and do not produce gastrointestinal side effects, resulting in better patient adherence. They have become standard therapy in the management of patients with multiple myeloma and metastatic cancer. Potential Adverse Effects of Bisphosphonate Actions In normal bone homeostasis, osteoclastic resorption is tightly linked to osteoblastic bone deposition and both functions are essential for repair of physiologic microdamage. Prolonged use of bisphosphonates may suppress bone turnover to the point that such microdamage persists and accumulates (15). The result is hypodynamic bone with decreased biomechanical competence. Although osteoblastic function is also reduced during bisphosphonate therapy, continued mineralization yields a hard, brittle bone with an osteopetrotic appearance and an increased risk for fracture (16-18). Thus, some experts caution that the benefits of prolonged use of bisphosphonates must be carefully weighed against the potential negative effects of oversuppression of bone metabolism (1, 19, 20). Other experts argue that although long-term use of bisphosphonates may retard fracture healing or slow callus remodeling, it may not affect bone mineralization or mechanical properties (21, 22). Oral Complications of Bisphosphonate Therapy Although oral bisphosphonates may cause oral mucosal lesions (purportedly arising from direct contact injury) (23, 24), we focus our review on bisphosphonate-associated osteonecrosis of the jaw. Table 2 summarizes 368 reported cases of bisphosphonate-associated osteonecrosis of the jaw (25-54). Reported cases manifested as exposure of portions of the bone of the mandible only (65%), maxilla only (26%), or both (9%). Approximately one third of lesions were painless (27), and there was a slight female predilection in a ratio of 3:2 among all reported cases. Multifocal or bilateral involvement was slightly more common in the maxilla than in the mandible (31% vs. 23%). Most lesions were on the posterior lingual mandible near the mylohyoid ridge. Of importance, 60% of cases occurred after a tooth extraction or other dentoalveolar surgery and the remaining cases occurred spontaneously. The latter cases often involved patients wearing dentures, a possible source of local trauma. Marx and colleagues (27) reported that 39% of cases that occurred spontaneously were located on bony exostoses that were easily traumatized. There is 1 case report of dental implant failure associated with bisphosphonate use (55). Table 2. Reports of Cases of Bisphosphonate-Associated Osteonecrosis of the Jaws Most patients (94%) were treated with intravenous bisphosphonates (primarily pamidronate and zoledronic acid), and most patients (85%) had multiple myeloma or metastatic breast cancer (Table 3). The remaining patients were taking oral bisphosphonates for osteoporosis or Paget disease of bone (25, 27-29, 40, 50, 51). Table 3. Primary Diagnoses and Types of Bisphosphonates in Reported Cases of Osteonecrosis of the Jaws Clinically, intraoral lesions appear as areas of exposed yellow-white, hard bone with smooth or ragged borders (Figures 1 and 2). Extraoral or intraoral sinus tracts may be present (Figure 3). Painful ulcers may develop in soft tissues that impinge on the ragged bony margins. Figure 1. Osteonecrosis of the right mandible after tooth extraction in a patient taking zoledronic acid for metastatic breast cancer. Figure 2. Osteonecrosis of the palatal torus in a patient with osteoporosis taking alendronate. Figure 3. Extraoral fistula in a patient with intraoral osteonecrosis. Results of radiographic evaluation may be negative in early cases. Although some investigators have noted subtle changes, such as widening of the periodontal ligament, these findings are indistinguishable from chronic periodontal infection, a predisposing factor for osteonecrosis (27). Advanced cases show a moth-eaten, poorly defined radiolucency, with or without radio-opaque sequestra. In 1 series, 5 of 63 patients developed pathologic jaw fractures (25). Cultures of exposed bone may identify Actinomyces species, but care must be taken to distinguish between a true suppurative infection and mere surface colonization by Actinomyces, because such organisms are a common component of dental plaque. Patients with bisphosphonate-associated osteonecrosis may present similarly to those with osteoradionecrosis of the jaws. Osteoradionecrosis is a complication of radiotherapy. It is thought to result from osteocyte and microvascular damage after the jaws are exposed to ionizing radiation and also frequently occurs after tooth extraction (56). Osteoradionecrosis, however, infrequently involves the maxilla (<5% of cases) and is more common in men than in women (57, 58). Risk Fac

Oral plasmablastic lymphomas in AIDS patients are associated with human herpesvirus 8.

Human herpes virus type 8 (HHV8) has been strongly associated with Kaposi sarcoma, primary effusion lymphoma (PEL), and Castlemans disease. To our knowledge, infection by this virus has not been strongly associated with other hematopathologic malignancies. We examined five oral cavity lymphomas from men with AIDS for HHV8 and HIV-1 by reverse transcriptase in situ polymerase chain reaction, as well as for Epstein-Barr virus (EBV) (EBER-1, -2) using in situ hybridization and HHV8 protein with immunohistochemistry. Four of these tumors were plasmablastic lymphomas; the final case was diffuse large B-cell lymphoma. Most of the neoplastic cells in these five lymphomas contained HHV8 RNA and protein. Further, the four plasmablastic lymphoma cases had tumor cells that contained EBV. HIV-1 RNA was not detected in the tumor cells but was noted in surrounding benign T cells. In comparison, HHV8 RNA was not detected in any of the five oral cavity lymphomas from people who did not have acquired immunosuppression nor in five lymphomas from AIDS patients that were located at a site other than the oral cavity. It is concluded that oral cavity lymphomas from people with AIDS are strongly associated with infection by HHV8 and EBV. Given the poor prognosis of oral cavity lymphomas in immunocompromised patients, therapy directed against the HHV8 and EBV infection may be of therapeutic value.

FcγRIIa (CD32): A Potential Marker Defining Susceptibility to Localized Juvenile Periodontitis

Epidemiologic studies indicate that blacks are at greater risk for development of localized juvenile periodontitis (LJP) than other ethnic groups. It has also been observed that, despite the relatively uncommon nature of this form of early-onset periodontitis, LJP often tends to cluster within families, which suggests that susceptibility to this disease may be inherited. Immunologic studies of a predominantly black population of LJP subjects have revealed that many of these patients mount a strong IgG response to Actinobacillus actinomycetemcomitans. A substantial proportion of this response is comprised of antibodies of the IgG2 subclass. IgG antibodies are required for efficient phagocytosis and killing of A. actinomycetemcomitans by human neutrophils. Recognition of bacteria coated with IgG antibodies is a process which is mediated by IgG Fc receptors (FcγR) expressed on mononuclear and polymorphonuclear phagocytes. A major class of FcγR found on neutrophils is a transmembrane receptor (FCγRII, or CD32) which binds IgG with low affinity. Recently, a genetically determined biallelic polymorphism has been described for this receptor. One allotype, termed H131, binds human IgG2 efficiently, whereas the alternative form, R131, does not. Neutrophils expressing the H131 allotype of FCγRII readily ingest and destroy IgG2-coated A. actinomycetemcomitans, whereas neutrophils bearing the R131 allotype do not. We hypothesize that the increased risk among blacks for development of LJP may be due to a combination of two factors, which include: 1) a tendency toward preferential synthesis of IgG2 antibodies to A. actinomycetemcomitans; and 2) an increased frequency of the R131 allele of FcγRIIa in this subject population. J Periodontol 1996;67:323-331.

The role of direct visual fluorescent examination (VELscope) in routine screening for potentially malignant oral mucosal lesions

OBJECTIVE Direct visual fluorescent examination (DVFE) is a proposed adjunct to conventional oral examination (COE). We evaluate the benefit of DVFE in screening for potentially malignant mucosal lesions in a general population of patients presenting for dental care. STUDY DESIGN A total of 130 patients were evaluated by COE followed by DVFE. Areas clinically suspicious by COE or with positive DVFE (visual fluorescence loss [VFL]) underwent surgical biopsy. Association between COE and DVFE was assessed and compared with histopathology. RESULTS A total of 42 subjects had one or more areas of VFL, yet histologic evidence of premalignancy/malignancy was only identified in a single individual. Further, one lesion negative by DVFE exhibited epithelial dysplasia. DVFE was statistically different from scalpel biopsy (P = .0001). No difference was found between COE and scalpel biopsy (P = 1.0). CONCLUSIONS Results suggest that COE is more valid than DVFE at discriminating benign mucosal alterations from premalignancy and do not support use of DVFE as an oral cancer screening adjunct.

Allelic imbalance in oral lichen planus and assessment of its classification as a premalignant condition

OLP is a relatively common immune-mediated mucosal condition with a predilection for middle-aged women. Although classified as a premalignant condition, this classification remains controversial. Using stringent diagnostic criteria, some authors have found that OLP patients are not at increased risk for oral SCC. Credible but limited genetic evidence also indicates that epithelial tissues from OLP patients diagnosed using stringent criteria differs from premalignant or malignant oral lesions but is similar to epithelium from benign oral lesions. To further investigate this genetic line of evidence, biopsy specimens diagnosed as fibroma, OLP, low-grade dysplasia, high-grade dysplasia, and SCC were retrieved from the archives of the Oral Pathology Consultants at the Ohio State University. Using laser capture microdissection, tissue of interest was captured from each case and DNA subsequently extracted. Fluorescently labeled PCR primers were used to amplify DNA at 3 tumor suppressor gene loci (3p14.2, 9p21, and 17p13) and evaluated for LOH or microsatellite instability (MSI). OLP was found to be significantly different from low-grade dysplasia, high-grade dysplasia, and SCC when LOH/MSI was found at more than 1 loci (P = .011, P = .032, P = .003), but not different from benign fibromas (P = .395). In agreement with previous studies, well-documented cases of OLP diagnosed using stringent criteria exhibit a genetic profile more similar to a benign or reactive process than a premalignant/malignant one. These findings do not support the classification of OLP as a premalignant condition.

Aggressive Osteoblastoma of the Maxilla: A Case Report and Review of the Literature

Aggressive osteoblastoma is a rare primary bone neoplasm with the potential for local invasion and recurrence. While the vertebrae or long bones are most commonly affected, few well-documented cases have been reported in the jaws. A 25-year-old man presented with a palatal mass of several months’ duration. He reported the lesion had undergone gradual enlargement and, while generally asymptomatic, had recently become increasingly painful. An incisional biopsy was interpreted as “osteoblastic neoplasm” most suggestive of osteoblastoma. However, final diagnosis was deferred until the resection specimen could be evaluated. Following partial maxillectomy, histopathologic examination revealed a proliferation of large epithelioid cells with eccentric nuclei and prominent nucleoli associated with broad, irregular deposits of osteoid and trabeculae of bone. The lesional cells exhibited minimal pleomorphism with infrequent, normal-appearing mitotic figures and numerous osteoclast-like giant cells were observed within an associated loose fibrovascular stroma. Transformation of “blue bone” to more organized eosinophilic trabeculae of woven bone was noted at the periphery of the lesion and there was no evidence of invasion. A diagnosis of aggressive osteoblastoma was made. Previous reports of gnathic aggressive osteoblastoma are reviewed and the features that distinguish this process from conventional osteoblastoma or osteoblastoma-like osteosarcoma are presented.

Trabecular and Psammomatoid Juvenile Ossifying Fibroma of the Skull Base Mimicking Psammomatoid Meningioma

Ossifying fibroma (OF) is a fibro-osseous tumor that usually occurs in young people and arises in the craniofacial bones. We report a case of a 15-year-old boy who developed progressive proptosis and hypertelorism and was found to have a mid-face and skull base tumor, initially diagnosed as psammomatoid meningioma. The tumor recurred and the resected specimen revealed a unique OF having trabecular and psammomatoid features. The clinical, radiographic, histopathologic findings and differential diagnoses of the case are presented.

Oral mucosal melanoma with unusual clinicopathologic features.

Oral mucosal melanoma (OMM) is an extremely rare malignancy, accounting for < 0.5% of all melanomas and all oral malignancies. The rarity of OMM, the heterogeneity in clinical and histopathologic appearances, and the paucity of molecular and genetic studies to date have limited our knowledge of the etiopathogenesis of these cancers. A 39‐year‐old Hispanic male presented for evaluation of a large, pigmented, plaque‐like and nodular growth of the maxillary gingival and palatal mucosa. On presentation, a presumptive clinical diagnosis of mucosal melanoma was made, which was confirmed by incisional biopsy with subsequent histopathologic evaluation. Macroscopically, the morphology and highly pigmented nature of the tumor was suggestive of a rarer subtype of melanoma known as animal‐type melanoma, also referred to as pigmented epithelioid melanocytoma. However, microscopically, the tumor showed histopathologic features consistent with a high‐grade acral (mucosal) lentiginous melanoma with overt cytomorphologic features of malignancy in addition to showing prominent pigment synthesis resembling animal‐type melanoma. A detailed search of the literature did not identify a previous report of OMM with prominent pigment synthesis resembling animal‐type melanoma. Identification of melanoma subtypes has specific implications for therapeutic approach, and thus their recognition is important to successful patient management.

Central odontogenic fibroma with features of central granular cell odontogenic tumor

Much debate exists over the lesions recognized as odontogenic fibromas. In this case report, the authors report 1 lesion that presented with histological features consistent with 2 separate lesions. The findings, histological examination, and recommendations are presented.

Evidence-based clinical practice guideline for the evaluation of potentially malignant disorders in the oral cavity: A report of the American Dental Association

BACKGROUND An expert panel convened by the American Dental Association (ADA) Council on Scientific Affairs and the Center for Evidence-Based Dentistry conducted a systematic review and formulated clinical recommendations to inform primary care clinicians about the potential use of adjuncts as triage tools for the evaluation of lesions, including potentially malignant disorders (PMDs), in the oral cavity. TYPES OF STUDIES REVIEWED This is an update of the ADAs 2010 recommendations on the early diagnosis of PMDs and oral squamous cell carcinoma. The authors conducted a systematic search of the literature in MEDLINE and Embase via Ovid and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials and diagnostic test accuracy studies. The authors used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty in the evidence and to move from the evidence to the decisions. RESULTS The panel formulated 1 good practice statement and 6 clinical recommendations that concluded that no available adjuncts demonstrated sufficient diagnostic test accuracy to support their routine use as triage tools during the evaluation of lesions in the oral cavity. For patients seeking care for suspicious lesions, immediate performance of a biopsy or referral to a specialist remains the single most important recommendation for clinical practice. In exceptional cases, when patients decline a biopsy or live in rural areas with limited access to care, the panel suggested that cytologic testing may be used to initiate the diagnostic process until a biopsy can be performed (conditional recommendation, low-quality evidence). CONCLUSIONS AND PRACTICAL IMPLICATIONS The authors urge clinicians to remain alert and take diligent action when they identify a PMD. The authors emphasize the need for counseling because patients may delay diagnosis because of anxiety and denial.