Salivary Electrostimulation in the Treatment of Radiation Therapy-Induced Xerostomia (LEONIDAS-2): A Multicenter, Randomized, Double-Masked, Sham-Controlled, Phase 3 Trial.

PURPOSE: Radiation therapy-induced xerostomia significantly affects quality of life in head and neck cancer survivors. Neuro-electrostimulation of the salivary glands may safely increase natural salivation and reduce dry mouth symptoms. METHODS AND MATERIALS: This multicenter, double-masked, randomized, sham-controlled clinical trial assessed the long-term effects of a commercially available intraoral neuro-electrostimulating device in lessening xerostomia symptoms, increasing salivary flow, and improving quality of life in individuals with radiation therapy-induced xerostomia. Using a computer-generated randomization list, participants were assigned (1:1) to an active intraoral custom-made removable electrostimulating device or a sham device to be used for 12 months. The primary outcome was the proportion of patients reporting a 30% improvement on the xerostomia visual analog scale at 12 months. A number of secondary and exploratory outcomes were also assessed through validated measurements (sialometry and visual analog scale) and quality-of-life questionnaires (EORTC QLQ-H&N35, OH-QoL16, and SF-36). RESULTS: As per protocol, 86 participants were recruited. Intention-to-treat analyses showed no statistical evidence of a difference between the study groups with respect to the primary outcome or for any of the secondary clinical or quality-of-life outcomes. Exploratory analyses showed a statistically significant difference in the changes over time of the dry mouth subscale score of the EORTC QLQ-H&N35 in favor of the active intervention. CONCLUSIONS: LEONIDAS-2 did not meet the primary and secondary outcomes.

Faculty clinical articles: a regular update for the oral healthcare team.

The Faculty of Dental Surgery of the Royal College of Surgeons of England and British Dental Journal have teamed up to provide a regular series of short articles on different aspects of clinical and academic dentistry. This series will provide concise insight into a diverse range of topics with the aim of providing regular ongoing professional development for all members of the oral healthcare team. We begin here, with a short update on the Faculty and overview of the series' aims.

In vivo evaluation of traumatic and malignant oral ulcers with optical coherence tomography: A comparison between histopathological and ultrastructural findings.

Ulcers in the oral mucosa is a relatively common, although challenging, entity in oral medicine, as it can arise due to a wide range of traumatic, infective, autoimmune, and neoplastic disorders. Although histopathology of lesional and peri­lesional tissues remains the gold standard for persistent oral breaching, optical coherence tomography (OCT) has been recently suggested as a potential ally to enhance the early or non-invasive diagnosis of likely causation. The aim of the present study was to provide an in-vivo OCT analysis and description from a sample of 70 patients affected by traumatic or neoplastic-related ulcers, located on the buccal mucosa, tongue or gingiva, and compare the OCT data with those of 20 patients with healthy oral mucosa. OCT dynamic scans revealed clear distinction of epithelial layer (EP), lamina propria (LP) of healthy buccal mucosa, gingiva, and tongue as well as allowing observation of the keratin layer in gingiva, and the subepithelial vascularization of each site. Traumatic lesions had an EP of reduced in thickness, with an irregular, if not disrupted surface. Interestingly, LP seemed to preserve its reflectiveness and vascularization only in the traumatic lesions. Among neoplastic lesions, regardless their site of onset, both EP integrity/homogeneity, and LP reflectiveness/vascularization were lost and unrecognizable when compared to their healthy counterparts. OCT scanning allowed some differentiation between traumatic and malignant ulcers and thus may a useful and non-invasive means of determining the need and/or urgency of histopathological examination of oral lesions.

Preliminary evaluation of the utility of optical coherence tomography in detecting structural changes during photobiomodulation treatment in patients with atrophic-erosive oral lichen planus.

INTRODUCTION: Oral lichen planus (OLP) is a common oral inflammatory condition. Against symptomatic atrophic-erosive OLP, topical steroids, or photobiomodulation (PBM) are deployed. Optical coherence tomography (OCT) provides a real-time, non-invasive, tissue investigation. Aim of this study was to evaluate modifications of OCT pattern in patients with painful atrophic-erosive OLP, before and after treatment with PBM, comparing those results with patients treated with topical steroid. METHODS: Two groups of 20 OLP patients were evaluated. Group A underwent two daily application of 0.05 % clobetasol propionate for 8 weeks; group B was treated with eight weekly PBM sessions using a 980/645 nm diode laser. OCT scans were performed before and after treatment, and six months after end of the proposed protocol. Changes of width of stratified epithelium (EP) and lamina propria (LP) were quantified. RESULTS: After 8-weeks, both groups experienced a significant increase of EP width (p < 0.05), and a significant decrease of LP width (p < 0.05), with Δ-EP in Group A significantly higher than Group B (p = 0.0015); conversely, Δ-LP was not significantly different (p > 0.05). After six months, significant increase of EP width remained only in group B (p = 0.01), with no significant decrease of LP mean width in both groups (p > 0.05). CONCLUSIONS: Increase of EP and decrease of LP might be explained as consequence of clobetasol and PBM ability to promote epithelial healing, and to reduce interface inflammation. When investigated with OCT, clobetasol appears to provide more significant short-term structural changes, whereas PBM might guarantee long-term alterations.

In-vivo usefulness of optical coherence tomography in atrophic-erosive oral lichen planus: Comparison between histopathological and ultrastructural findings.

Oral lichen planus (OLP) is a common premalignant chronic inflammatory disorder. Optical Coherence Tomography (OCT) provides a real-time, non-invasive, and in-situ optical signature using light of varying wavelengths to examine tissue. Aim of the present study was to assess the possible role of OCT as diagnostic tool for atrophic-erosive OLP by examining OCT scans of healthy buccal mucosa, and comparing their ultrastructural features with those of a buccal mucosa affected by atrophic-erosive OLP, using their histopathological counterparts as the gold standard. Through grayscale (enface scan) and an application in which the vascularization of the tissue is visible (dynamic scan), it was possible to distinguish the healthy from the lichenoid pattern from 20 controls (12 M; 8 F; mean age: 41.32 years) and 20 patients with histologically confirmed atrophic-erosive OLP (7 M; 13 F; mean age: 64.27 years). In detail, mean width of stratified squamous epithelium (EP) and lamina propria (LP) were evaluated. Among controls, EP and LP showed a mean width of 300 (±50) and of 600 (±50) µm respectively; among cases, disruption of membrane basement prevented from any measurement. Furthermore, a differential pattern of EP and LP emerged between the two groups: a light-grayish, hypo-reflective, homogeneous area of EP recurring in controls turned into a hyper-reflective, non-homogeneous area among cases. Dynamic scan showed a differential profile of LP vascularization, varying from a hypo-reflective red area with small blood vessels in the control group, to a hypo/hyper-reflective area, completely overrun by a denser, wider blood flow amid OLP cases. Although histopathological examination remains the gold standard for OLP diagnosis, OCT could be a potentially helpful tool for the clinician and the pathologist, since it allows analysis of the vascularization of the sample without adversely affecting histological processing.

Patient-reported outcome measures in oral lichen planus: A comprehensive review of the literature with focus on psychometric properties and interpretability.

OBJECTIVE: To review the range of patient-reported outcome measures (PROMs) used in clinical studies of patients with oral lichen planus (OLP) and to assess their psychometric properties and interpretability. METHODS: Literature searches were performed on MEDLINE, EMBASE and Web of Science databases (1990-September 2016) to retrieve relevant studies related to the development, psychometric testing and/or use of PROMs assessing oral symptoms, psychosocial status and quality of life in individuals with OLP. The identified PROMs were then categorised by concept measured and assessed for instrument characteristics and evidence for psychometric properties and interpretability. RESULTS: We identified a total of 41 PROMs used in clinical studies for the assessment of patient-reported outcomes in patients with OLP. There were three PROMs of oral symptoms, 30 PROMs of psychosocial status and eight PROMs of quality of life. Six instruments (Visual Analog Scale, Numerical Rating Scale, Change in Symptom Scale, Oral Health Impact Profile-14, Oral Health-related Quality of Life-UK and Chronic Oral Mucosal Disease Questionnaire) demonstrated some evidence of psychometric properties but no evidence for interpretability of their results in the OLP population. CONCLUSION: The range of PROMs used in clinical studies of patients with OLP is wide and include instruments for oral symptoms, psychosocial status and quality of life. The vast majority of these instruments have no evidence of psychometric properties and interpretability for patients with OLP. Further qualitative and validation studies are required to investigate whether these instruments are appropriate for use in this patient population.

Quantitative nanohistological investigation of scleroderma: an atomic force microscopy-based approach to disease characterization.

Scleroderma (or systemic sclerosis, SSc) is a disease caused by excess crosslinking of collagen. The skin stiffens and becomes painful, while internally, organ function can be compromised by the less elastic collagen. Diagnosis of SSc is often only possible in advanced cases by which treatment time is limited. A more detailed analysis of SSc may provide better future treatment options and information of disease progression. Recently, the histological stain picrosirius red showing collagen register has been combined with atomic force microscopy (AFM) to study SSc. Skin from healthy individuals and SSc patients was biopsied, stained and studied using AFM. By investigating the crosslinking of collagen at a smaller hierarchical stage, the effects of SSc were more pronounced. Changes in morphology and Young's elastic modulus were observed and quantified; giving rise to a novel technique, we have termed "quantitative nanohistology". An increase in nanoscale stiffness in the collagen for SSc compared with healthy individuals was seen by a significant increase in the Young's modulus profile for the collagen. These markers of stiffer collagen in SSc are similar to the symptoms experienced by patients, giving additional hope that in the future, nanohistology using AFM can be readily applied as a clinical tool, providing detailed information of the state of collagen.

Oral mucosal manifestations of autoimmune skin diseases.

A group of autoimmune diseases is characterised by autoantibodies against epithelial adhesion structures and/or tissue-tropic lymphocytes driving inflammatory processes resulting in specific pathology at the mucosal surfaces and the skin. The most frequent site of mucosal involvement in autoimmune diseases is the oral cavity. Broadly, these diseases include conditions affecting the cell-cell adhesion causing intra-epithelial blistering and those where autoantibodies or infiltration lymphocytes cause a loss of cell-matrix adhesion or interface inflammation. Clinically, patients present with blistering, erosions and ulcers that may affect the skin as well as further mucosal surfaces of the eyes, nose and genitalia. While the autoimmune disease may be suspected based on clinical manifestations, demonstration of tissue-bound and circulating autoantibodies, or lymphocytic infiltrates, by various methods including histological examination, direct and indirect immunofluorescence microscopy, immunoblotting and quantitative immunoassay is a prerequisite for definitive diagnosis. Given the frequency of oral involvement and the fact that oral mucosa is the initially affected site in many cases, the informed practitioner should be well acquainted with diagnostic and therapeutic aspects of autoimmune dermatosis with oral involvement. This paper reviews the pathogenesis and clinical presentation of these conditions in the oral cavity with a specific emphasis on their differential diagnosis and current management approaches.

Th1 and Th2 polymorphisms in Sjögren's syndrome and rheumatoid arthritis.

BACKGROUND: Sjogren's syndrome is characterized by T-cell infiltration of exocrine glands leading to parenchymal destruction and impaired glandular function. This process is orchestrated by cytokines, whose secretion can be regulated by genetic polymorphisms. MATERIALS AND METHODS: The aim of this study was to investigate the influence of interleukin-6 -174G/C, interleukin-10 -1082G/A, tumor necrosis factor-α -308G/A, interferon-γ +874A/T gene polymorphisms in (RA) and secondary Sjögren's syndrome (sSS). A study sample that comprised of 138 Brazilian patients was divided into three groups: RA (n = 66), sSS (n = 20), and healthy controls - C (n = 52). Patients were subjected to Schirmer's test, unstimulated salivary flow rate, biopsy of minor salivary glands, and serological tests for diagnosing SS. Genomic DNA was obtained from saliva samples and submitted to genotyping. The association between genotypes/alelle frequency and SS susceptibility was tested, as well as their association with clinical features of SS. RESULTS: Tumor necrosis factorα (TNFα)-308GA polymorphisms differed significantly between AR, SS, and C patients (P = 0.008). IL-6 overall G carriers and TNFα A carriers had a higher risk of presenting SS (P = 0.021). IL-6 polymorphism distribution was also distinctive regarding lymphocytic infiltration at the minor salivary glands (P = 0.026) and Schirmer's test (P = 0.035). CONCLUSION: These results suggest that IL-6 -174GC and TNFα-308GA gene polymorphisms are associated with susceptibility to SS. Additionally, IL-6 polymorphism could influence lymphocytic infiltration of salivary glands and diminish lachrymal gland function.

Dental treatment as a risk factor for hepatitis B and C viral infection. A review of the recent literature.

BACKGROUND & AIM: Patients chronically infected either with hepatitis B (HBV) or hepatitis C virus (HCV) are at increased risk of developing cirrhosis, end stage liver disease and hepatocellular carcinoma. Different risk factors were found to be associated with the transmission of these viruses in various settings. HBV and HCV transmission seems to be also acquired by non-parenteral and non-sexual routes. A large number of patients infected with HCV might have non identifiable routes of viral acquisition. Hence, viral hepatitis transmission risk factors identification is the main way to reduce infection. Dental treatment may be one of such risk factors, and this aspect is addressed in the present literature review, drawing information from existing literature. METHODS: An online database search was conducted, limited to publications from January 1999 to February 2012 on specific aspects of HBV and HCV infection, including articles on risk factors, markers of infection, dentistry, epidemiology and transmission. Relevant material was evaluated and reviewed. RESULTS: Overall, 53 studies which met the selection criteria were evaluated. Although these studies were from different geographical regions of varied socioeconomic status and study populations and assessed different dental procedures, using different types of statistical analysis, we found that, although weak, there is an all-time risk of HBV and HCV infection during dental treatment. This is more important in developing countries where the rate of hepatitis infected individuals is higher. There is a need for more studies on this subject, properly planned, controlled and analyzed. CONCLUSION: Dental treatment can be included among the risk factors of HBV and HCV infection. This risk can easily be eliminated using standard precautionary measures.

Intrahost genetic variability of human herpes virus-8.

Studies were conducted to determine whether HHV-8 hyperactivity could be the consequence of the propensity of the host to multiple HHV-8 infection. The aim of the present work was to investigate HHV-8 intrahost genetic variability. HHV-8 subgenomic DNA was amplified by PCR from patients infected with HIV, health care workers (HCW) and bone marrow transplant recipients (BMT), and from oral lesional tissues of AIDS-Kaposi's sarcoma (KS) patients. As controls, blood from HIV-negative health care workers, and the cell lines BC-1, BC-2, and BCP-1 were used. Clones derived from amplicons originating from DNA fragments in open reading frame (ORF) 26 and ORF K1 were isolated. For each ORF, intra-specimen nucleotide sequence differences were determined. The extent of HHV-8 variation in clones derived from blood of patients infected with HIV was significantly higher than in blood from health care workers or post-bone marrow transplantation patients or in AIDS-KS tissue. Among the clones derived from the latter three categories of specimens, sequence variations were not significant. It is concluded that HIV-infected individuals can have multiple of HHV-8, but AIDS-KS lesions are associated with infection by a single HHV-8 variant or a small group of related variants.

Wegener's granulomatosis: a review of clinical features and an update in diagnosis and treatment.

Wegener's granulomatosis (WG) is an idiopathic, systemic inflammatory disease characterized by necrotizing granulomatous inflammation and pauci-immune small-vessel vasculitis of upper and lower respiratory tract and kidneys. The condition affects both genders equally, although some inconsistent gender differences have been observed. The aetiology of WG remains unknown although a number of exogenous factors have been suggested to be of aetiological relevance. Most clinical characteristics of this disease are non-specific, making clinical diagnosis challenging. Histopathological examination of lesional and peritoneal tissue is not pathognomonic, but is an essential investigation to confirm the presence of disease and exclude other disorders. At present, despite the increasingly wide range of potential therapies, cyclophosphamide plus corticosteroids remain the most recognized and effective means of inducing and sustaining remission of WG.

Sarcoidosis - a clinically orientated review.

Sarcoidosis is a multisystem disease of unknown cause. Sarcoidosis can affect all individuals with any race, sex, or age but commonly affects young- and middle-aged adults and usually presents with bilateral hilar lymphadenopathy, pulmonary infiltration, skin and ocular lesions. Other organs can also be affected. Diagnosis is established when clinical and radiological findings are supported by the presence of non-caseating epithelioid cell granulomas, however, local sarcoid reactions and granulomas of known cause should be excluded. The optimal management has not been well defined yet, although corticosteroids remain the mainstay of treatment, there is little evidence on which to base the indications for treatment including dosage and duration of therapy. Certain clinical features are helpful in the prognosis of the condition that can vary from a self-limiting course to progressive life-threatening fibrosis of the vital organs.

Focal epithelial hyperplasia - an update.

Focal epithelial hyperplasia (FEH) is an asymptomatic benign mucosal disease, which is mostly observed in specific groups in certain geographical regions. FEH is usually a disease of childhood and adolescence and is generally associated with people who live in poverty and of low socioeconomic status. Clinically, FEH is typically characterized by multiple, painless, soft, sessile papules, plaques or nodules, which may coalesce to give rise to larger lesions. Human papillomavirus (HPV), especially genotypes 13 and 32, have been associated and detected in the majority of FEH lesions. The clinical examination and social history often allow diagnosis, but histopathological examination of lesional tissue is usually required to confirm the exact diagnosis. FEH sometimes resolves spontaneously however, treatment is often indicated as a consequence of aesthetic effects or any interference with occlusion. There remains no specific therapy for FEH, although surgical removal, laser excision or possibly topical antiviral agents may be of benefit. There remains no evidence that FEH is potentially malignant.

Multiple endocrine neoplasia in an orthodontic patient: Interprofessional diagnostic and treatment implications.

BACKGROUND: Multiple endocrine neoplasia, type 2B (MEN 2B), is an autosomal-dominant condition characterized by the development of multiple endocrine tumors. All affected people develop an aggressive form of medullary thyroid cancer (MTC). Without early prophylactic thyroidectomy, the prognosis for patients with MEN 2B is poor; the average age at death is 21 years. CASE DESCRIPTION: The authors present a case of a 16-year-old girl who had a diagnosis of MEN 2B and was treated successfully for metastatic MTC. CLINICAL IMPLICATIONS: Given the striking orofacial manifestations of MEN 2B (marfanoid habitus; dolichocephaly; everted and thickened lips; mucosal neuromas on lips, tongue, buccal mucosa and eyelids), dental professionals are well positioned to recognize the disorder. Early identification of patients with the condition permits screening for preclinical thyroid disease, molecular genetic testing, counseling and lifesaving thyroid surgery.

Human herpesvirus 8 shedding in the mouth and blood of hemodialysis patients.

In Saudi Arabia, the prevalence of transplantation-associated Kaposi's sarcoma (KS) is high, and there is disparity in the prevalence rates of human herpesvirus 8 (HHV-8) infection between patients with renal disease and the general population. It was hypothesized that oral HHV-8 transmission among patients undergoing hemodialysis treatment contributes to the high prevalence of infection in renal disease patients. The detection rates of anti-HHV8-IgG in plasma and HHV-8-DNA in CD45(+)-peripheral blood cells of 72 hemodialysis patients were compared first with those of 178 blood donors and 60 pregnant women. Between the hemodialysis patients and the apparently healthy people sampled, the detection rate of anti-HHV-8-IgG was 16.7% versus 0.4% (P < 0.001) and that of HHV-8-DNA was 4.2% versus 0.4%, (P < 0.05). HHV-8 DNA was determined in oral samples and the HHV-8 viral load measured in saliva of patients undergoing hemodialysis. The amount of virus shed into saliva ranged between 8,600 and 119,562,500 (mean: 24,009,360) genome-equivalents/ml among the five patients in whom oral HHV-8 DNA was detected. Finally, HHV-8-subgenomic sequencing was conducted which showed that orally shed HHV-8 in four patients belonged to genotype C2, and in one patient to genotypes A1 and C2. HHV-8 shed in the mouth of hemodialysis patients may be extensive and diverse. Oral fluid in addition to blood is thus a likely vehicle for transmission of HHV-8, possibly contributing to the high risk of HHV-8 infection in patients undergoing hemodialysis and to KS following immunosuppression after renal transplantation.

Oral fluid and hepatitis A, B and C: a literature review.

BACKGROUND AND AIMS: Viral hepatitis is a significant global health problem that, depending upon the virus, affects individuals of the developing and/or developed world. In recent years, there has been renewed interest in whether oral fluids can be considered as a source of viral hepatitis transmission and whether oral fluid, in particular, whole saliva, may be a useful source for viral detection as part of the diagnosis and monitoring of viral hepatitis. The aim of this article was to review current data concerning the possible carriage of the hepatitis A, B and C viruses within saliva and gingival crevicular fluid. Such knowledge will indicate if (i) oral fluid is a possible source of infection and (ii) whether oral fluid can be used for diagnosis and monitoring of viral hepatitis. DATA AND SOURCES: A literature search was conducted using PubMed (Medline), EMBASE/Excerpta medica, the Cochrane database and Scopus. The results were limited to published material after 2000. Relevant material was evaluated and reviewed. CONCLUSION: There is some evidence that hepatitis viruses A, B and C are present in oral fluids, particularly whole saliva and gingival crevicular fluid and may thus be possible sources of viral detection in clinical diagnosis and monitoring. However, the data are inconsistent and warrant the need for well-planned longitudinal studies to explore the precise frequency of oral carriage of such viruses and to determine the virological and host factors that may influence the oral presence of hepatitis A, B and C viruses.

Diet and halitosis.

PURPOSE OF REVIEW: The present article reviews the current knowledge of halitosis with particular emphasis upon the interplay of diet and disease of the gastrointestinal tract upon oral malodour. RECENT FINDINGS: Transient-altered breath smell usually reflects the effects of foodstuffs, whereas longstanding halitosis is almost always because of oral disease such as gingivitis or periodontitis. There is, however, increasing evidence that upper gastrointestinal tract disease may give rise to halitosis and that extracts of foodstuffs may be future therapeutic agents for the treatment of halitosis derived from the mouth or upper gastrointestinal tract. SUMMARY: There is some interplay between the halitosis and the gastrointestinal tract, and it is possible that the therapy of halitosis may be aided by investigations of the effects of foodstuffs upon bacteria that give rise to volatile sulphur compounds.

Cisto linfoepitelial em língua: relato de caso / Limphoepithelial cyst on tongue: a case report

O cisto linfoepitelial oral (CLEO) é uma lesão incomum da boca, que se desenvolve do tecido linfoide oral. Clinicamente apresenta-se como uma lesão nodular, que raramente apresenta mais de 1,5 cm em seu maior diâmetro. Possui coloração branco-amarelada, superfície regular, é mole à palpação e assintomático na maioria dos casos, embora possa apresentar tumefação e drenagem, se associado a episódios de trauma. A localização mais freqüente dessa lesão na cavidade oral é o assoalho de boca, seguido da superfície ventral e borda lateral de língua. O CLEO é encontrado em pacientes de várias faixas etárias, porém é mais comum em adultos jovens. Neste artigo, relatamos um caso de CLEO e revisamos a literatura sobre o tema.

The oral lymphoepithelial cyst (CLEO) is an uncommon injury in the oral cavity that develops oral lymphoid tissue. Clinically, it presents as a nodular lesion that rarely has more than 1.5 cm in its largest diameter. It has a whitish-yellow, soft on palpation and asymptomatic in most cases, and although there may be swelling and drainage are associated with episodes of trauma. The most frequent location of this lesion in the oral cavity is the mouth's floor followed by the ventral surface and lateral border of the tongue. The CLEO can be foundbe found in patients of diff erent ages but it is most common in young adults. In this paper, we report a case of oral lymphoepithelial cyst later, discussing the current literature regarding this lesion.

Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series.

PURPOSE: To report a case series of patients with the nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw-a form of jaw osteonecrosis that does not manifest with necrotic bone exposure/mucosal fenestration. METHODS: Among 332 individuals referred to 5 clinical centers in Europe because of development of jawbone abnormalities after or during exposure to bisphosphonates, we identified a total of 96 patients who presented with the nonexposed variant of osteonecrosis. Relevant data were obtained via clinical notes; radiological investigations; patients' history, and referral letters. RESULTS: The most common clinical feature of nonexposed osteonecrosis was jaw bone pain (88/96; 91.6%); followed by sinus tract (51%), bone enlargement (36.4%); and gingival swelling (17.7%). No radiological abnormalities were identified in 29.1% (28/96) of patients. In 53.1% (51/96) of the patients; nonexposed osteonecrosis subsequently evolved into frank bone exposure within 4.6 months (mean; 95% confidence interval; 3.6-5.6). CONCLUSIONS: Clinicians should be highly vigilant to identify individuals with nonexposed osteonecrosis, as the impact on epidemiological data and clinical trial design could be potentially significant. Although the present case series represents approximately 30% of all patients with bisphosphonates-associated osteonecrosis observed at the study centers, further population-based prospective studies are needed to obtain robust epidemiological figures.