John W. Hellstein

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

A Comparison of the Cleaning Efficacy of Short- Term Sonic and Ultrasonic Passive Irrigation after Hand Instrumentation in Molar Root Canals

A total of 100 maxillary molar canals were hand instrumented to a master apical file size #35 and flared to a size #60 file. The canals were randomly divided into 5 groups of 20 each. Group 1 received no further treatment. Groups 2 and 3 received passive sonic irrigation for 30 and 60 s, respectively. Groups 4 and 5 received passive ultrasonic irrigation for 30 and 60 s, respectively. The roots were split longitudinally and photographed with a digital camera. The apical portion of the root was magnified to 100x. A debris score was calculated for the apical 3 and 6 mm. The debris score was calculated as a percentage of the total area of the canal that contained debris as determined by pixels in Adobe Photoshop 5.0. Passive sonic or ultrasonic irrigation, for as little as 30 s, resulted in significantly cleaner canals than hand filing alone. Ultrasonic passive irrigation produced significantly cleaner canals than passive sonic irrigation, when sonic and ultrasonic passive irrigation were compared with only each other.

Oral candidosis: Clinical, historical, and therapeutic features of 100 cases

Oral candidosis is an increasingly important disease that affects a significant percentage of the population. Traditionally known as an opportunistic pathogen, the broader clinical scope of oropharyngeal candidal infections is now being recognized. The clinical and historical features of 100 patients referred for diagnosis and management of candidosis have been reviewed. The age, gender, chief complaint, medical history, medications, and clinical findings have been noted. A wide range of clinical signs and symptoms, and the rationale behind the topical and systemic antifungal therapies provided to this patient population, are discussed.

Prevention of orthopaedic implant infection in patients undergoing dental procedures

&NA; The Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures evidence‐based clinical practice guideline was codeveloped by the American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association. This guideline replaces the previous AAOS Information Statement, “Antibiotic Prophylaxis in Bacteremia in Patients With Joint Replacement,” published in 2009. Based on the best current evidence and a systematic review of published studies, three recommendations have been created to guide clinical practice in the prevention of orthopaedic implant infections in patients undergoing dental procedures. The first recommendation is graded as Limited; this recommendation proposes that the practitioner consider changing the long‐standing practice of routinely prescribing prophylactic antibiotic for patients with orthopaedic implants who undergo dental procedures. The second, graded as Inconclusive, addresses the use of oral topical antimicrobials in the prevention of periprosthetic joint infections. The third recommendation, a Consensus statement, addresses the maintenance of good oral hygiene.

Incidental Findings on Cone Beam Computed Tomography Images

Background. Cone beam computed tomography (CBCT) has gained widespread acceptance in dentistry for a variety of applications. Most dentists who are not radiologists/trained in radiology are generally not familiar with interpretation of anatomical structures and/or pathosis outside their area of primary interest, as often this was not within the scope of their training. Objectives. To assess that the number of incidental findings on a CBCT scan is high both within and outside of the primary area of interest, thereby emphasizing the importance of interpretation of all areas visualized on the scan. Materials and Methods. An oral and maxillofacial radiologist reviewed 1000 CBCT scans (382 males and 618 females) for findings both in- and outside the area of interest. Results. Of the 1000 subjects that were reviewed, 943 scans showed findings in the primary regions of interest and/or outside the regions of interest, and 76 different conditions were visualized in these scans both in and outside the areas of interest. Conclusion. From the wide scope of findings noted on these scans, it can be concluded that it is essential that a person trained in advanced interpretation techniques in radiology interprets cone beam computed tomography scans.

Experimental evaluation of expanded polytetrafluoroethylene for reconstruction of orbital floor defects

OBJECTIVE This study evaluates the efficacy of a medical grade expanded polytetrafluoroethylene (e-PTFE) sheet for reconstruction of the orbital floor. MATERIALS AND METHODS Orbital floor defects were created in 10 domestic sheep and reconstructed with the 1-mm thick e-PTFE sheet. The surgical sites were evaluated for the development of enophthalmos and biocompatibility at 2 weeks, and at 1-, 2-, 4-, and 6-months intervals. RESULTS The results of this indicate that the e-PTFE material has excellent handling characteristics, provides stability to correct surgically created enophthalmos, and causes essentially no foreign body reaction. CONCLUSION Expanded polytetrafluoroethylene proved to be an excellent alloplastic material for the repair of orbital floor defects in this experimental study.

Evaluation of Dental Pulp Sensibility Tests in a Clinical Setting

INTRODUCTION The goal of this project was to evaluate the performance of dental pulp sensibility testing with Endo Ice (1,1,1,2-tetrafluoroethane) and an electric pulp tester (EPT) and to determine the effect of several variables on the reliability of these tests. METHODS Data were collected from 656 patients seen in the University of Iowa College of Dentistry Endodontic graduate clinic. The results of pulpal sensibility tests, along with the tooth number, age, sex, number of restored surfaces, presence or absence of clinical or radiographic caries, and reported recent use of analgesic medications, were recorded. The presence of vital tissue within the pulp chamber was used to verify the diagnosis. RESULTS The Endo Ice results showed accuracy, 0.904; sensitivity, 0.916; specificity, 0.896; positive predictive value, 0.862; and negative predictive value, 0.937. The EPT results showed accuracy, 0.75; sensitivity, 0.84; specificity, 0.74; positive predictive value, 0.58; and negative predictive value, 0.90. Patients aged 21-50 years exhibited a more accurate response to cold testing (P = .0043). Vital teeth with caries responded more accurately to cold testing (P = .0077). There was no statistically significant difference noted with any other variable examined. CONCLUSION Pulpal sensibility testing with Endo Ice and EPT are accurate and reliable methods of determining pulpal vitality. Patients aged 21-50 exhibited a more accurate response to cold. Sex, tooth type, number of restored surfaces, presence of caries, and recent analgesic use did not significantly alter the results of pulpal sensibility testing in this study.

Keratocystic odontogenic tumor: A retrospective analysis of genetic, immunohistochemical and therapeutic features. Proposal of a multicenter clinical survey tool

OBJECTIVE In 2005, the World Health Organization reclassified the parakeratinizing odontogenic keratocyst as a neoplasm. This article reviews the research leading to this reclassification, and validates a new survey tool that can be easily used to pool surgical and recurrence data from multiple offices. STUDY DESIGN All odontogenic lesions accessioned in the Iowa Surgical Oral Pathology Laboratory between 1949 and 2010 were identified from the database. A survey tool to assess treatment and follow-up was created. A total of 46 surgeons agreed to participate. RESULTS A total of 70 keratocystic odontogenic tumors (KOTs) had documented recurrences at follow-up intervals ranging from 6 months to 5 years. Primary tumors that recurred ranged in size as measured by greatest radiographic diameter from 0.7 to 6 cm. CONCLUSIONS This survey tool is recommended as standard allowing treatment of cases by multiple practitioners to be compared retrospectively or prospectively.

Osteochemonecrosis: An Overview

Osteonecrosis of the jaw to a certain extent has been with us for many years. But recently the advent of various medications such as bisphosphonates, VEGF inhibitors, tyrosine kinase inhibitors and humanized antibodies to osteoclastic action have resulted in thousands of cases. While the bisphosphonates continue to be the most common medication associated with osteochemonecrosis antibodies such as denosumab which irreversibly act on osteoclastic action are also being reported. This narrative review will serve as an update with a focus on some of the histopathologic features discussed and reviewed. Perhaps even more uncommonly seen in past reports a discussion of features possibly observed while grossing specimens will be discussed. At the end of this report is hoped that the pathologist will have a better understanding of the historical features, clinical settings, gross examination features as well as histopathologic features associated with osteochemonecrosis.

American Dental Association guidance for utilizing appropriate use criteria in the management of the care of patients with orthopedic implants undergoing dental procedures

American Dental Association– Appointed Members of the Expert Writing and Voting Panels Contributing to the Development of American Academy of Orthopedic Surgeons Appropriate Use Criteria A pproximately 332,000 primary total hip arthroplasties and 719,000 primary total knee arthroplasties were performed in the United States in 2010; 96% of hip replacement and 98% of knee replacement surgeries were performed on patients 45 years and older. Reported infection rates for such operations range from 0.8% to 2.2%. Infections can be caused by introduction of microorganisms at the time of surgery, hematogenous seeding, or contiguous spread of infection from an adjacent site. Infections of total joint replacements can result in failure of the initial surgical procedure and the need for extensive revision, prolonged antibiotic treatment, functional impairment, considerable cost of care, and even death. In 2014, the American Dental Association (ADA) Council on Scientific Affairs (CSA) assembled an expert panel to update and clarify the clinical recommendations found in a 2012 joint ADA and American Academy of Orthopaedic Surgeons (AAOS) evidence report and guideline. In accord with the 2012 ADA/AAOS evidence report, the updated ADA systematic review (published in the January 2015 issue of The Journal of the American Dental Association) found no statistically significant association between dental procedures and prosthetic joint infections (PJI). On the basis of the review of the evidence, the 2015 ADA Clinical Practice Guideline stated, “In general, for patients with prosthetic joint implants, prophylactic antibiotics are not recommended prior to dental procedures to prevent prosthetic joint infection.” The ADA panel found no association between dental procedures and PJIs and no scientifically based efficacy for using antibiotics to prevent PJIs. The panel did acknowledge that there may be special circumstances in which a clinician may consider antibiotic prophylaxis despite the lack