Short time administration of antirheumatic drugs - methotrexate as a strong inhibitor of osteoblast's proliferation in vitro.
Annussek Tobias,Kleinheinz Johannes,Thomas Szuwart,Joos Ulrich,Wermker Kai
Head & face medicine
INTRODUCTION:Due to increasing use of disease modifying antirheumatic drugs (DMARDs) as first line therapy in rheumatic diseases, dental and maxillofacial practitioner should be aware of drug related adverse events. Especially effects on bone-metabolism and its cells are discussed controversially. Therefore we investigate the in vitro effect of short time administration of low dose methotrexate (MTX) on osteoblasts as essential part of bone remodelling cells. METHODS:Primary bovine osteoblasts (OBs) were incubated with various concentrations of MTX, related to tissue concentrations, over a period of fourteen days by using a previously established standard protocol. The effect on cell proliferation as well as mitochondrial activity was assessed by using 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay, imaging and counting of living cells. Additionally, immunostaining of extracellular matrix proteins was used to survey osteogenic differentiation. RESULTS:All methods indicate a strong inhibition of osteoblast`s proliferation by short time administration of low dose MTX within therapeutically relevant concentrations of 1 to 1000 nM, without affecting cell differentiation of middle-stage differentiated OBs in general. More over a significant decrease of cell numbers and mitochondrial activity was found at these MTX concentrations. The most sensitive method seems to be the MTT-assay. MTX-concentration of 0,01 nM and concentrations below had no inhibitory effects anymore. CONCLUSION:Even low dose methotrexate acts as a potent inhibitor of osteoblast's proliferation and mitochondrial metabolism in vitro, without affecting main differentiation of pre-differentiated osteoblasts. These results suggest possible negative effects of DMARDs concerning bone healing and for example osseointegration of dental implants. Especially the specifics of the jaw bone with its high vascularisation and physiological high tissue metabolism, suggests possible negative effects of DMARD therapy concerning oral and cranio-maxillofacial bone surgery as could be seen in a similar way in bisphosphonate related osteonecrosis of the jaw.
Odontogenic osteomyelitis or bisphosphonate-related osteonecrosis of mandible of patient with autoimmune disease: clinical dilemma.
Tolstunov Len,Cox Darren,Javid Bahram
Compendium of continuing education in dentistry (Jamesburg, N.J. : 1995)
The key to appropriate treatment of odontogenic osteomyelitis or bisphosphonate-related osteonecrosis of the mandible in patients with autoimmune diseases lies in making the correct diagnosis based on meticulous review of signs and symptoms. As this complex case involving a patient with multiple comorbidities illustrates, diagnosis can be difficult, because these conditions may overlap or be mistaken for other conditions. However, prompt treatment is essential to limit the progression, which can be devastating for these medically complex patients. It is, therefore, important to understand local and systemic conditions that can weaken the immune system and predispose patients to chronic bone infection, meticulously go through signs and symptoms, and have a complete medical history, including patient medications.
Methotrexate-related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis.
Horie N,Kawano R,Kaneko T,Shimoyama T
Australian dental journal
Methotrexate (MTX) is the primary drug used in the management of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. MTX is a strong immunosuppressive agent and has been reported to cause iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs). Stomatitis caused by MTX-related cytotoxicity may occur, but gingival MTX-related LPDs are rare. In this article we present a case of gingival MTX-related LPD in a 60-year-old male with RA. The local findings of the gingival ulceration and alveolar bone exposure were similar to those of bisphosphonate-related osteonecrosis of the jaw. However, he had never received bisphosphonate therapy. The biopsy specimen of the gingival lesion was diagnosed as diffuse large B-cell lymphoma with Epstein-Barr virus positivity. Immediate withdrawal of MTX resulted in marked remission of the LPD.
Bisphosphonates and time to osteonecrosis development.
Palaska Pinelopi Kleio,Cartsos Vassiliki,Zavras Athanasios I
Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a complication of long-term bisphosphonate (BP) use. Given the beneficial effects of BP on bone quality in patients with cancer or osteoporosis, it is of great importance to understand the risk as it relates to time to event or cumulative dose until the onset of disease. Because there is no information on the lowest toxic dose from clinical trials, here we report on a review of 71 case series published since 2003. We calculated the weighted mean time to event, as well as the minimum reported time and dose for zoledronate, pamidronate, and oral bisphosphonates. The mean time to BONJ after zoledronate treatment was calculated at 1.8 years and the minimum was 10 months; after pamidronate, the mean time was 2.8 years and the minimum was 1.5 years; and after oral BP therapy, the mean time was 4.6 years and the minimum was 3 years. Zoledronic acid seems to be the most potent among the nitrogen-containing BPs. Factors that seem to affect BONJ and time to event were invasive dental procedures and other comorbid factors such as advanced age, rheumatoid arthritis, diabetes, use of corticosteroids, vitamin D deficiency, and more. Understanding the pathophysiology of the disease requires further research.
BRONJ in patients with rheumatoid arthritis: a multicenter case series.
Di Fede O,Bedogni A,Giancola F,Saia G,Bettini G,Toia F,D'Alessandro N,Firenze A,Matranga D,Fedele S,Campisi G
OBJECTIVE:Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of various medications (bisphosphonates, anti-resorptive, and anti-angiogenic drugs). ONJ pathogenesis is still unclear although some risk factors have been recognized. Of these, rheumatoid arthritis (RA) has been hypothesized as a potential risk factor for developing ONJ. This observational study will describe a multicenter case series of patients affected with RA and ONJ, and it will attempt to evaluate the association between features of ONJ and pharmacological, systemic, and site variables. METHODS:Demographic, pharmacological, and clinical data from 18 RA patients with ONJ were collected and registered from three Italian centers (i.e., Palermo, Verona, and Padua) from 2004 to 2013. RESULTS:Sixteen (88.9%) patients were in therapy for RA: 9 of 18 (50.0%) with systemic steroids, 3 of 18 (16.7%) with methotrexate, and 4 of 18 (22.2%) with both medications. Two patients were not receiving treatment for RA. All patients took NBPs for secondary osteoporosis (average NBP duration of 69 months, range: 20-130): Fifteen (83.3%) patients were treated with single NBPs, while three (16.7%) with different molecules; one patient was also treated with denosumab. Mandible was affected more frequently (66.7%) than maxilla (33.3%); one patient presented multiple ONJ events. CONCLUSIONS:This is the first multicenter case series in the international literature regarding our topic. Focusing on our data, it could be hypothesized that patients with RA may be more susceptible to ONJ than the majority of osteometabolic patients. In our opinion, it could be important to monitor also denosumab or other biological drug side effects.
Is rheumatoid arthritis a risk factor for oral bisphosphonate-induced osteonecrosis of the jaws?
Conte Neto Nicolau,Bastos Alliny de Souza,Chierici-Marcantonio Rosemary Adriana,Marcantonio Elcio
Bisphosphonate-related osteonecrosis of the jaws is a relevant side-effect of these drugs that has been generating a great concern through increasing reports, worldwide, of this bone necrosis. Among several BRONJ hypothetical co-factors that could play a role in BRONJ pathogenesis, rheumatoid arthritis (RA) has been included as a relevant risk factor for BRONJ; however, until now the relationship between these diseases has not been fully explained. Thus, the purpose of this paper is to establish hypothetical factors that could link these two diseases, considering mainly inflammatory components and the organism effects of medicines used to treat RA, particularly steroids and methotrexate (MTX).
Epidemiological aspects of rheumatoid arthritis patients affected by oral bisphosphonate-related osteonecrosis of the jaws.
Conte-Neto Nicolau,Bastos Alliny Souza,Marcantonio Rosemary Adriana Chierici,Junior Elcio Marcantonio
Head & face medicine
This literature review aims to evaluate the epidemiologic profile of patients with rheumatoid arthritis (RA) that developed a bisphosphonate-related osteonecrosis that affect the jaws (BRONJ), including demographic aspects, as well as clinical and therapeutic issues. A search of PUBMED/MEDLINE, Scopus, and Cochrane databases from January 2003 to September 2011 was conducted with the objective of identifying publications that contained case reports regarding oral BRONJ in RA patients. Patients with RA who develop oral BRONJ are usually women above 60 years taking steroids and long-term alendronate. Most of them have osteoporosis, and lesions, triggered by dental procedures, are usually detected at stage II in the mandible. Although there is no accepted treatment protocol, these patients seem to have better outcomes with conservative approaches that include antibiotic therapy, chlorhexidine, and drug discontinuation.
Osteonecrosis of the jaws: a 14-year retrospective survey of hospital admissions.
McGowan K,Ivanovski S,Acton C
Australian dental journal
BACKGROUND:Osteonecrosis of the jaw (ONJ) is a serious complication of both radiation and antiresorptive therapies. This study aimed to determine how many patients have been treated for medication-related osteonecrosis of the jaws (MRONJ) and osteoradionecrosis (ORN), and whether the number of diagnoses has decreased over time with improved awareness and preventative measures. METHODS:Medical records at the Royal Brisbane and Women's Hospital, Gold Coast University Hospital and Robina Hospital were reviewed to identify patients diagnosed with MRONJ and ORN between January 2003 and May 2017. Data on patient demographics, year of admission and primary disease were analysed. RESULTS:Two hundred and thirty-eight patients were diagnosed with ONJ, of which 74.4% were ORN and 25.6% were MRONJ. Tongue (24.6%), floor of mouth (17.3%) and tonsillar (15.1%) squamous cell carcinomas were the most common primary diseases associated with ORN, with a strong male predominance (80%). Of patients diagnosed with MRONJ, 52.5% were taking low-dose antiresorptives for osteoporosis (44.2%), rheumatoid arthritis (4.6%) or Paget's disease (3.3%), while 47.5% were oncology patients receiving high-dose antiresorptives. CONCLUSIONS:The number of patients diagnosed with MRONJ and ORN has trended upwards since 2003. ORN affected three times more patients than MRONJ, and patients on low-dose antiresorptives accounted for over half of the MRONJ cases.
Diseases having an influence on inhibition of angiogenesis as risk factors of osteonecrosis of the jaw.
Paek Seung Jae,Park Won-Jong,Shin Ho-Sung,Choi Moon-Gi,Kwon Kyung-Hwan,Choi Eun Joo
Journal of the Korean Association of Oral and Maxillofacial Surgeons
OBJECTIVES:The objective of this study was to retrospectively investigate the association of diseases having an influence on inhibition of angiogenesis such as hypertension, diabetes mellitus type II, hypercholesterolemia, and rheumatoid arthritis (RA) with the development of osteonecrosis of the jaws. MATERIALS AND METHODS:The 135 patients were allocated into 4 groups of bisphosphonate-related osteonecrosis of the jaw (BRONJ) group (1A); non-BRONJ group (1B); osteonecrosis of the jaw (ONJ) group (2A); and control group (2B), according to histologic results and use of bisphosphonate. This retrospective study was conducted with patients who were treated in one institute from 2012 to 2013. Fisher's exact test and logistic regression analysis were used to analyze the odds ratios of diseases having an influence on inhibition of angiogenesis for development of ONJ. RESULTS:The effects of diabetes and hypertension were not statistically significant on development of ONJ. When not considering bisphosphonate use, RA exhibited a high odds ratio of 3.23 (=0.094), while hyperlipidemia showed an odds ratio of 2.10 (=0.144) for development of ONJ. More than one disease that had an influence on inhibition of angiogenesis showed a statistically significant odds ratio of 2.54 (=0.012) for development of ONJ. CONCLUSION:Patients without diseases having an influence on inhibition of angiogenesis were at less risk for developing ONJ.
Risk of Delayed Healing of Tooth Extraction Wounds and Osteonecrosis of the Jaw among Patients Treated with Potential Immunosuppressive Drugs: A Retrospective Cohort Study.
Hayashi Megumi,Morimoto Yoshinari,Iida Takatoshi,Tanaka Yohei,Sugiyama Shuntaro
The Tohoku journal of experimental medicine
Bone-modifying or antiresorptive agents that target osteoclasts, such as bisphosphonates, are known to cause delayed wound healing and osteonecrosis of the jaw (ONJ) following tooth extraction. However, there are no data on whether such adverse events are also caused by drugs that may suppress the immune system, including corticosteroids, immunosuppressants, biological agents, and disease-modifying anti-rheumatic drugs (DMARDs). The aim of this retrospective study was to examine the incidence of delayed post-extraction wound healing and identify risk factors among patients treated with potential immunosuppressive drugs undergoing tooth extraction. We performed a retrospective cohort study involving 101 patients by reviewing their medical records. The underlying diseases of the enrolled patients included dilated cardiomyopathy, hematological malignancy, sarcoidosis, rheumatoid arthritis, and systemic lupus erythematosus. The sample comprised 131 cases of tooth extraction among the 101 patients; delayed post-extraction wound healing occurred in 10 patients (12 cases, 9.2%), including ONJ in three patients (3 cases, 2.3%). The surgical tooth extraction performed for impacted teeth or a residual root (P = 0.009), the number of surgical tooth extraction (P = 0.012), decreased lymphocyte counts (P = 0.008), and decreased eosinophil counts (P = 0.009) were significantly related to delayed wound healing. Thus, among patients taking corticosteroids, immunosuppressants, biological agents, and/or DMARDs, there is a risk of delayed wound healing and ONJ. Moreover, the significant risk factors are low lymphocyte counts, low eosinophil counts, and surgical extraction. It is of particular importance to prevent surgical site infection, when the high-risk patients undergo tooth extraction.
[Current approaches for early detection and treatment of medication-related osteonecrosis of jaw].
Janovszky Ágnes,Vereb Tamás,Szabó Andrea,Piffkó József
Owing to the increased life expectancy, the incidence of rheumatoid disorders and oncologic cases with bone metastasis has dramatically increased. Despite the beneficial effects of the applied antiresorptive and antiangiogenic drugs (e.g. bisphosphonates), serious side effects such as jaw osteonecrosis may also develop. The aim of the authors was to summarize present knowledge about the possibilities of prevention and treatment in medication-related osteonecrosis of the jaw. Based on literature data, currently used detection methods for medication-related osteonecrosis of the jaw (including their advantages and limitations) are summarized. In addition, novel trends of surgical and adjuvant therapeutic approaches are also reviewed. The authors conclude that possibilities of prevention and efficacy of therapeutic interventions in this disorder are still limited possibly due to an incomplete knowledge of the underlying pathomechanism. An interdisciplinary cooperation for prevention and attentive monitoring in order to decrease the incidence of iatrogenic oral and maxillofacial complications seems to be particularly important.
Surgically treated osteonecrosis and osteomyelitis of the jaw and oral cavity in patients highly adherent to alendronate treatment: a nationwide user-only cohort study including over 60,000 alendronate users.
Eiken P A,Prieto-Alhambra D,Eastell R,Abrahamsen B
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
Osteonecrosis of the jaw (ONJ) is rare (2.53/10,000 person-years) among alendronate users, but long-term and compliant use are associated with an increased risk of surgically treated ONJ. Risk of surgically treated ONJ is higher in patients with rheumatoid diseases and use of proton pump inhibitors. INTRODUCTION:ONJ is a rare event in users of oral bisphosphonates. Our aims were to evaluate if the risk of surgically treated ONJ increases with longer or more compliant treatment with alendronate for osteoporosis and to identify risk factors for surgically treated ONJ. METHODS:Open nationwide register-based cohort study containing one nested case-control study. Patients were treatment-naïve incident users of alendronate 1996-2007 in Denmark, both genders, aged 50-94 at the time of beginning treatment (N = 61,990). Participants were followed to 31 December 2013. RESULTS:Over a mean of 6.8 years, 107 patients received surgery for ONJ or related conditions corresponding to an incidence rate of 2.53 (95% confidence interval (CI) 2.08 to 3.05) per 10,000 patient years. Recent use was associated with an adjusted odds ratio (OR) 4.13 (95% CI 1.94 to 8.79) compared to past use. Similarly, adherent users (medication possession ratio (MPR) >50%) were at two to threefold increased risk of ONJ compared to low adherence (MPR <50%), and long-term (>5 years) use was related with higher risk (adjusted OR 2.31 (95% CI (1.14 to 4.67)) than shorter-term use. History of rheumatoid disorders and use of proton pump inhibitors were independently associated with surgically treated ONJ. CONCLUSIONS:Our data suggest that recent, long-term, and compliant uses of alendronate are associated with an increased risk of surgically treated ONJ. Nevertheless, the rates remain low, even in long-term adherent users. ONJ risk appears higher in patients with conditions likely to indirectly affect the oral mucosa.
Bisphosphonate therapy and osteonecrosis of the jaw complicated with a temporal abscess in an elderly woman with rheumatoid arthritis: a case report.
Manzon Licia,Ettorre Evaristo,Viscogliosi Giovanni,Ippoliti Stefano,Filiaci Fabio,Ungari Claudio,Fratto Giovanni,Agrillo Alessandro
Clinical interventions in aging
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone tissue of the mandible or maxilla, in the course of bisphosphonate therapy. Orally administered bisphosphonates, widely used for the treatment of osteoporosis, are rarely associated with BRONJ. Instead, the risk greatly increases whether the patient is concomitantly taking steroid and/or immunosuppressant agents. The aims of this paper are to briefly discuss the evidence of the associations between bisphosphonate therapy and BRONJ, and the effects of co-occurring factors such as the presence of rheumatoid arthritis, dental surgery, and concomitant corticosteroid therapy. In particular, we present the case of an elderly woman with BRONJ suffering from rheumatoid arthritis, with a recent dental extraction and with a very unusual complication: a temporal abscess, who was successfully treated.
Incidence and risk of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) after tooth extraction in patients with autoimmune disease.
Fujieda Yuichiro,Doi Mototsugu,Asaka Takuya,Ota Masahiro,Hisada Ryo,Ohnishi Naoki,Kono Michihiro,Kameda Hiraku,Nakazawa Daigo,Kato Masaru,Amengual Olga,Takahata Masahiko,Yasuda Shinsuke,Kitagawa Yoshimasa,Atsumi Tatsuya
Journal of bone and mineral metabolism
INTRODUCTION:Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a rare but serious complication in patients receiving antiresorprtive agents (AR). However, the incidence of ARONJ after tooth extraction in patients with autoimmune disease (AID) remains unclear. The present study aimed to clarify the high-risk population of ARONJ in patients with AID. MATERIALS AND METHODS:The study population comprised 232 patients treated with AR, AID or non-AID, who had undergone dental extraction from January 2011 to September 2017. The incidence and risk factors of ARONJ were analysed retrospectively. Additionally, the relationship between ARONJ and osteoporotic fracture (OF) and AR discontinuation during dental procedures was investigated. RESULTS:Of 232 patients, 10 developed ARONJ within 1 year of dental extraction. The incidence of ARONJ in patients with AID was higher than that in non-AID patients (2.0/100 person-year vs 0.5/100 person-year; p = 0.03). Among the AID patients, RA patients had strikingly high incidence of ARONJ (3.6/100 person-year). The incidence of neither ARONJ nor OF significantly differed between patients who continued and discontinued AR in the perioperative period. CONCLUSION:Patients with AID who undergo dental extraction are at high risk of ARONJ. Discontinuation of AR would not significantly contribute to reduce the incidence of ARONJ in those patients.
Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study.
de Molon Rafael Scaf,Hsu Chingyun,Bezouglaia Olga,Dry Sarah M,Pirih Flavia Q,Soundia Akrivoula,Cunha Fernando Queiroz,Cirelli Joni Augusto,Aghaloo Tara L,Tetradis Sotirios
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (µCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by µCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. © 2016 American Society for Bone and Mineral Research.
Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-α) inhibitors: a systematic review.
Sacco R,Shah S,Leeson R,Moraschini V,de Almeida Barros Mourão C F,Akintola O,Lalli A
The British journal of oral & maxillofacial surgery
Tumour necrosis factor-α (TNF-α) inhibitors are increasingly being used as immunomodulators to manage inflammatory conditions such as rheumatoid arthritis and Crohn's disease. Reported serious side effects include an increased incidence of lymphoma and greater susceptibility to infections such as tuberculosis. The aim of this systematic review was to find out whether there is an associated risk of medication-related osteonecrosis of the jaw (MRONJ). Three authors independently searched PubMed, MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials for published reports of oral osteonecrosis (ONJ) or osteomyelitis (OM) in patients who took anti TNF-α drugs and had no history of antiangiogenic agents or antiresorptive treatment. All types of studies on humans treated with TNF-α inhibitors were considered. Only six were eligible for analysis, and all were independently assessed for risk of bias. They included six patients with ONJ or OM that was attributed solely to TNF-α inhibitors. The most common site of ONJ was the posterior mandible (n=5). The mean (SD) duration of anti-TNF-α treatment before the development of bony lesions was 62.5 (47.4) months. Invasive surgery was reported as a precipitating factor in five cases, and the ONJ/OM resolved with conservative management in five. Although all the studies were judged to be at high risk of bias, the limited data suggest that some patients will potentially develop ONJ/OM as a result of treatment with TNF-α inhibitors. Studies of higher quality are now needed to establish the relative risk of MRONJ in patients who take them.
Osteonecrosis of the jaw and nonmalignant disease: is there an association with rheumatoid arthritis?
Lescaille Géraldine,Coudert Amélie E,Baaroun Vanessa,Javelot Marie-José,Cohen-Solal Martine,Berdal Ariane,Goudot Patrick,Azérad Jean,Ruhin Blandine,Descroix Vianney
The Journal of rheumatology
OBJECTIVE:To review cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurring in association with benign disease and to describe and compare the clinical course and outcome for patients with BRONJ and rheumatoid arthritis (RA) or osteoporosis. METHODS:We retrospectively reviewed observations of all patients referred for treatment and followup for BRONJ from January 2007 to December 2011. Only patients with malignant disease were excluded. Demographic data, medical history, maxillofacial findings, BRONJ treatment, and followup were reviewed for each case. RESULTS:Over a 5-year period, we diagnosed 112 patients with BRONJ. Among these patients, 15 received bisphosphonate (BP) treatment for nonmalignant disease (mean age 65.7 ± 19.8 yrs, 80% women). Patients received BP for a variety of reasons: 8 (53%) to prevent osteoporosis in association with underlying RA; 6 (40%) to prevent idiopathic osteoporosis; and 1 (7%) to treat ankle algodystrophy. The mean oral BP exposure period was 48.4 months (median 36 mo). In 13 cases (86.6%), BRONJ was diagnosed following dental extraction. Of the 8 patients with RA, 5 (62.5%) were taking prednisone at the time of the discovery of BRONJ. Major surgery, sequestrectomy, or alveolectomy was performed in 9 patients (60%), all of whom healed within 3 to 36 months (mean 11.5 mo). Comparative analysis of all the variables showed no statistically significant differences between patients with RA and others. CONCLUSION:ONJ is a rare adverse effect of BP therapy, especially when administered orally. Within the limits of our study, we were unable to demonstrate a difference in BRONJ disease spectrum, clinical course, or outcome between patients with and those without RA.
Dental treatments, tooth extractions, and osteonecrosis of the jaw in Japanese patients with rheumatoid arthritis: results from the IORRA cohort study.
Furuya Takefumi,Maeda Shigeru,Momohara Shigeki,Taniguchi Atsuo,Yamanaka Hisashi
Journal of bone and mineral metabolism
This study aimed to evaluate dental treatments, tooth extractions, and osteonecrosis of the jaw (ONJ) in Japanese patients with rheumatoid arthritis (RA). Patients with RA enrolled in our cohort completed self-administered questionnaires, which included questions regarding their dental treatments, tooth extractions by dentists during the past 6 months, and past history of ONJ. The history of ONJ was validated with the patients' medical records. Logistic regression was used to determine the association of variables with dental treatments and tooth extractions during the past 6 months. Among 5695 Japanese patients with RA who responded to the questionnaires (mean age, 61.0 years; 85.6 % female), 2323 patients (40.8 %) and 378 patients (6.6 %) reported having had dental treatments and tooth extractions performed by a dentist within the past 6 months, respectively. In multivariate models, advanced age was significantly (P < 0.0001) associated with both dental treatments and tooth extractions during the prior 6-month period, and ever smoking was significantly (P = 0.023) correlated with tooth extractions during that time. Among patients who reported a history of ONJ, we confirmed five cases of ONJ with patient medical records. The prevalence of ONJ was 0.094 % among all RA patients and 0.26 % among female RA patients ≥65 years of age (n = 1888). Our data suggest that more than a few Japanese patients with RA have dental complications that require care by dentists, and that Japanese rheumatologists and dentists should cooperate to improve dental health in patients with RA.
Duration of treatment with bisphosphonates at the time of osteonecrosis of the jaw onset in patients with rheumatoid arthritis. Review.
Compain H,Berquet A,Loison-Robert L-S,Ahossi V,Zwetyenga N
Journal of stomatology, oral and maxillofacial surgery
INTRODUCTION:Rheumatoid arthritis (RA) is a frequent and co-morbid condition. One of the main complications is induced osteoporosis. Treatments related to this complication significantly modify oral and implant management. Affected patients represent a population at intermediate risk of osteonecrosis of the jaw (ONJ). The objective was to search the literature for durations of treatment with bisphosphonates at the time of ONJ occurrence in patients with RA in order to obtain an average duration. MATERIALS AND METHODS:A bibliographic search in the PubMed/Medline database was carried out using the following equation "(osteonecrosis and jaw) and rheumatoid arthritis" with no time limitation. The primary study endpoint was the duration of treatment with bisphosphonates (BP) at the time of ONJ onset in patients with RA. RESULTS:Twelve articles accounting for 50 patients were included. Patients had had a median of 46.8 months of treatment with BP before ONJ occurred. Mean, minimum and maximum treatment times were 48.68, 6 and 120 months, respectively. The standard deviation was 27.77 months. DISCUSSION:The median treatment duration in our cohort of patients with RA was less than that reported for osteoporosis. We therefore, recommend that practitioners take additional precautions regarding oral surgery or implant procedures, particularly in patients with RA who have been treated with BP for more than 4 years.
Report of a jaw osteonecrosis possibly caused
Saad Daniel,Saad Patrick
European journal of oral implantology
PURPOSE:To report a case of osteonecrosis of the jaw (ONJ) occurring in an implant area possibly related to denosumab, a relatively new antiosteoporotic agent. MATERIALS AND METHODS:Two months following the extraction of both maxillary first molars, a bilateral maxillary sinus floor elevation was performed on a 64-year-old female patient under a biannual
60 mg denosumab antiosteoporotic treatment. Seven months later, two implants were inserted in a single-stage procedure in each of the grafted sinuses. After 3 months, the implants underwent prosthetic rehabilitation at one side, and a series of failures that led to an ONJ instalment at the other side. RESULTS:The ONJ persisted over 7 months and was only resolved by a surgical approach consisting of a piezoelectric osteotomy and platelet-rich fibrin with a tension-free wound closure. CONCLUSIONS:A cumulative effect of denosumab is likely to be associated with a jaw osteonecrosis, which in this case was manageable using a surgical approach with no need to interrupt the appropriate drug treatment course. Conflict of interest statement: The authors certify that they are not affiliated with, or involved in any organisation or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript.
Pharmacogenomics of osteonecrosis of the jaw.
Yang Guang,Singh Sonal,Chen Yiqing,Hamadeh Issam S,Langaee Taimour,McDonough Caitrin W,Holliday L Shannon,Lamba Jatinder K,Moreb Jan S,Katz Joseph,Gong Yan
Osteonecrosis of the jaw (ONJ) is a rare but serious drug induced adverse event, mainly associated with the use of antiresorptive medications, such as intravenous (IV) bisphosphonates (BPs) in cancer patients. In this review, we evaluated all the pharmacogenomic association studies for ONJ published up to December 2018. To date, two SNPs (CYP2C8 rs1934951 and RBMS3 rs17024608) were identified to be associated with ONJ by two genome-wide association studies (GWAS). However, all six subsequent candidate gene studies failed to replicate these results. In addition, six discovery candidate gene studies tried to identify the genetic markers in several genes associated with bone remodeling, bone mineral density, or osteoporosis. After evaluating the results of these 6 studies, none of the SNPs was significantly associated with ONJ. Recently, two whole-exome sequencing (WES) analysis (including one from our group) were performed to identify variants associated with ONJ. So far, only our study successfully replicated discovery result indicating SIRT1 SNP rs7896005 to be associated with ONJ. However, this SNP also did not reach genome-wide significance. The major limitations of these studies include lack of replication phases and limited sample sizes. Even though some studies had larger sample sizes, they recruited healthy individuals as controls, not subjects treated with BPs. We conclude that a GWAS with a larger sample size followed by replication phase will be needed to fully investigate the pharmacogenomic markers of ONJ.
Medication-related osteonecrosis of the jaw associated with implant and regenerative treatments: Systematic review.
Granate-Marques A,Polis-Yanes C,Seminario-Amez M,Jané-Salas E,López-López J
Medicina oral, patologia oral y cirugia bucal
BACKGROUND:The aim of this study was to determine if the treatment with bisphosphonates other anti-resorptive and antiangiogenic agents influences the success of regenerative and / or implant treatments. MATERIAL AND METHODS:We reviewed the literature from the last 5 years in the PubMed database, using the following words: "Sinus Floor Augmentation"[Mesh] OR "Dental Implants"[Mesh]) OR "Guided Tissue Regeneration"[Mesh]) AND "Osteonecrosis"[Mesh]. The articles were selected following the inclusion and exclusion criteria and were evaluated using the 22 items of the STROBE declaration. The following PICO clinical question was applied: Does the treatment with agents associated with drug osteonecrosis influence the success of regenerative and implant treatments? RESULTS:The initial search resulted in a total of 27 articles. After eliminating those that did not refer to the topic, were duplicated or did not meet the inclusion / exclusion criteria, a full reading of the articles was made evaluating their methodological quality, obtaining six studies with high methodological quality and two with moderate. CONCLUSIONS:The literature regarding this topic is scarce, randomized clinical trials would be necessary to establish protocols relative to implant treatment in patients on antiresorptive treatments. The risk of developing an osteonecrosis associated with the regeneration / implant placement in patients with benign bone diseases is scarce, but it exists and it should not be underestimated. Especially, in the posterior areas of the jaw, if the duration of treatment with BP is greater than 3 years, and if the patient is under therapy with systemic corticosteroids.
Incidence of osteonecrosis of the jaw by the use of osteoclast inhibitors in patients with bone metastases: a retrospective cohort study.
Chaurand-Lara Jorge,Pacheco-Ruiz Laura,Trejo-Campos José L,Facio-Umaña José A,Mora-Pérez Josué
Cirugia y cirujanos
Background:The use of osteoclast inhibitors in metastatic bone disease, increase bone mineral density and reduce the risk of fracture, patients with osteonecrosis have been reported after the chronic use of these inhibitors. In our country, the use of osteoclast inhibitors is in the context of osteoporosis and bone metastases, so it is important to describe the incidence of this complication in Mexican population. Objective:To describe the incidence of osteonecrosis of the jaws at the Centro Médico Nacional 20 de Noviembre, during the period from January 1st, 2010 to June 1st, 2016. Methods:This is a retrospective cohort study developed at the Centro Medico Nacional 20 Noviembre, ISSSTE, Mexico. We included all patients who received bisphosphonates or denosumab in the context of metastatic bone disease due to solid tumors and who had osteonecrosis of the jaw. Results:A 802 patients who used bisphosphonates or denosumab in metastatic bone disease (699 bisphosphonates and 103 denosumab). Of these, 28 (3.5%) patients presented osteonecrosis. The median use of zoledronic acid for the presence of osteonecrosis was 25 months (15-49 months) and for Denosumab it was 16 months (11-35 months), without finding significant differences between the use of drugs p = 0.511 and the risk of osteonecrosis. Conclusions:Drug-induced osteonecrosis has a low incidence in Mexican population, denosumab does not show a greater number of cases of osteonecrosis compared to bisphosphonates; no association was found between functional status, number of metastatic bone sites, nor use of antigenic or tyrosine kinase inhibitors as factor associated with osteonecrosis of the jaws.
The Frequency of Medication-related Osteonecrosis of the Jaw and its Associated Risk Factors.
Dodson Thomas B
Oral and maxillofacial surgery clinics of North America
This article provides the best current frequency estimate of medication-related osteonecrosis of the jaws (MRONJ), and identifies factors associated with the risk of developing osteonecrosis of the jaw (ONJ) among patients exposed to relevant medications (ie, antiresorptive or antiangiogenic agents). MRONJ is a rare but serious complication of cancer treatment or osteoporosis management. This review confirms that antiresorptive medications such as oral or intravenous bisphosphonates and denosumab are the most common risk factors for developing ONJ. The risk of MRONJ is greater in patients with cancer than in those receiving antiresorptive treatments for osteoporosis by a factor of 10.
Resolution of a case of denosumab-related osteonecrosis of the jaw after tooth extraction.
Bujaldón-Rodríguez R,Gómez-Moreno G,Leizaola-Cardesa I O,Aguilar-Salvatierra A
European review for medical and pharmacological sciences
Denosumab is an antiresorptive drug that blocks osteoclast maturation, function and survival, improving bone mineral density and reducing the probability of fracture. It has adverse effects and can be the cause of hypocalcemia and osteonecrosis of the jaw. This report describes the case of a 59-year-old woman with hypothyroidism, antecedents of breast cancer, two strokes, and severe bone osteoporosis. Extraction of tooth 3.6 was performed, and within a month she was administered with a denosumab injection. One month later maxillary osteonecrosis appeared in the lingual distal area of the extraction site. Four months later the case was resolved by means of non-surgical treatment.
Drug-induced osteonecrosis of the jaw: the state of the art.
Fassio A,Bertoldo F,Idolazzi L,Viapiana O,Rossini M,Gatti D
Osteonecrosis of the jaw (ONJ) is a rare adverse event of antiresorptive drugs such as bisphosphonates (BP) and denosumab (DMAb). The diagnosis of ONJ is considered in cases where exposed bone in the maxillofacial region does not heal within 8 weeks in a patient previously treated with an antiresorptive agent. In patients with osteoporosis, ONJ is reported as a very rare adverse event while in oncologic patients with bone metastases or malignant hypercalcemia the incidence is significantly higher (up to the 1-10% of the patients). The pathophysiology of ONJ is still not completely understood but it is multi-factorial. ONJ is a condition associated with poor oral health, oral surgery, and use of antiresorptive agents. Prevention is of paramount importance especially in cancer patients, in whom the large majority of cases of ONJ (>90%) are reported, but it should also be considered in osteoporotic patients, especially during dental surgical procedure. Some simple prevention procedures are effective in reducing the risk of its appearance. When ONJ unfortunately occurs, the large majority of patients can be managed conservatively. In conclusion, ONJ is a rare condition associated with antiresorptive drugs. Both osteoporotic and oncologic patients should be well informed about its low absolute risk and regarding the fact that the benefits of antiresorptive therapy far outweigh this potential risk of ONJ.
[Myelodysplastic syndrome, osteoporosis and medication-related osteonecrosis of the jaw: a case report].
Leonardi Nicolás,Garola Federico,Gilligan Gerardo,Piemonte Eduardo,Cappella Fiamma,Panico René
Revista de la Facultad de Ciencias Medicas (Cordoba, Argentina)
Introduction:Medication-related osteonecrosis of the jaw is a frequent collateral effect found in patients under antiresorptive treatments. Malignancies such as multiple myeloma, breast and prostate cancer as well as bone-metabolic disorders such as osteoporosis, lead the indications for these antiresorptive therapies. Even with a low frequency, myelodysplastic syndromes are also entities that have previously been associated with the development of jaw osteonecrosis. Objective:the aim of this study is to present a case of a 78-year-old male patient with myelodysplastic syndrome and secondary osteoporosis, treated with high-dose Zoledronic Acid and who developed a clinical scenario compatible with medication-related osteonecrosis of the jaw during its evolution. Methodology:: the case was recorded and treated in the Oral Medicine Department, Facultad de Odontología, Universidad Nacional de Córdoba, during a two-years period with a partial resolution, which recurred fourteen months later, where finally therapeutic success was achieved through a conservative management. Conclusion:Due to the increasingly use of antiresorptive drugs, the development of jaw osteonecrosis is possible associated with less frequent pathologies, such as myelodysplastic syndrome. Treatment success in these patients depends on interdisciplinary management and a rigorous clinical, medical and dental follow-up.
American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update.
Ruggiero Salvatore L,Dodson Thomas B,Fantasia John,Goodday Reginald,Aghaloo Tara,Mehrotra Bhoomi,O'Ryan Felice,
Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons
Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaw (MRONJ) were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007 and 2009. The position papers were developed by a special committee appointed by the board and composed of clinicians with extensive experience in caring for these patients and basic science researchers. The knowledge base and experience in addressing MRONJ has expanded, necessitating modifications and refinements to the previous position paper. This special committee met in September 2013 to appraise the current literature and revise the guidelines as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis, staging, and management strategies and highlights current research status. The AAOMS considers it vitally important that this information be disseminated to other relevant health care professionals and organizations.
Antiresorptive drug-related osteonecrosis of the jaw.
Uyanne Jettie,Calhoun Colonya C,Le Anh D
Dental clinics of North America
Nitrogen-containing and non-nitrogen-containing bisphosphonates have been implicated in the development of osteonecrosis of the jaw (ONJ), a condition termed bisphosphonate-related OHJ. Other antiresorptive drugs have been implicated in the development of OHJ, hence the new term antiresorptive drug-related ONJ. The underlying pathogenesis remains unclear, and no definite diagnosis or cure has been established for this debilitating condition. This article reviews some of the most common antiresorptive drugs with their associated risks of ONJ and the current understanding of the pathogenesis ONJ, and summarizes current clinical guidelines.
[Drug-induced osteonecrosis of the jaw - not just bisphosphonates].
Finkelshteyn A,Yarom N
Refu'at ha-peh veha-shinayim (1993)
Metastatic bone disease and osteoporosis have a large impact on quality of life and are associated with the development of skeletal-related events (SREs), such as fractures and spinal cord compression. Pharmacologic managing of metastatic bone disease and osteoporosis typically involves antiresorptive agents such as bisphosphonates and RANKL inhibitors. Undesired adverse effects resulting from the use of these drugs include osteonecrosis of the jaw (ONJ). Dentoalveolar surgery, particularly tooth extraction, appears to increase the risk of ONJ. However, spontaneous events were also documented. Therefore, it is of upmost importance for the general practitioner to have updated knowledge in order to prevent and early diagnose ONJ. We present a case of a metastatic breast cancer patient who spontaneously developed ONJ following the use of Denosumab, a monoclonal RANKL antibody.
Osteonecrosis of the jaw in a patient receiving cabozantinib.
Marino R,Orlandi F,Arecco F,Gandolfo S,Pentenero M
Australian dental journal
Since the discovery of bisphosphonate-related osteonecrosis of the jaw, there has been increasing evidence in recent years of osteonecrosis induced by drugs other than bisphosphonates, mainly agents with antiangiogenic and antiosteoclastic activity. Mandibular osteonecrosis was observed in a 51-year-old female with medullary thyroid cancer receiving cabozantinib, a new tyrosine kinase inhibitor having antiangiogenic activity. The bone necrosis appeared after a dental extraction. The clinical, radiographic and histologic picture of a chronic non-healing extraction socket was consistent with drug-induced osteonecrosis of the jaw. Healing was achieved by segmental ostectomy. The osteonecrosis was likely associated with a vascular endothelial growth factor (VEGF) pathway inhibition, implying inhibition of angiogenesis and hampering of the local host defence mechanisms.
Interventions for managing medication-related osteonecrosis of the jaw.
Beth-Tasdogan Natalie H,Mayer Benjamin,Hussein Heba,Zolk Oliver
The Cochrane database of systematic reviews
BACKGROUND:Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of cancer and osteoporosis (e.g. bisphosphonates, denosumab and antiangiogenic agents) and involves the progressive destruction of bone in the mandible or maxilla. Depending on the drug, its dosage, and the duration of exposure, the occurrence of this adverse drug reaction may be rare (e.g. following the oral administration of bisphosphonate or denosumab treatments for osteoporosis, or antiangiogenic agent-targeted cancer treatment) or common (e.g. following intravenous bisphosphonate for cancer treatment). MRONJ is associated with significant morbidity, adversely affects quality of life (QoL), and is challenging to treat. OBJECTIVES:To assess the effects of interventions versus no treatment, placebo, or an active control for the prophylaxis of MRONJ in people exposed to antiresorptive or antiangiogenic drugs.To assess the effects of non-surgical or surgical interventions (either singly or in combination) versus no treatment, placebo, or an active control for the treatment of people with manifest MRONJ. SEARCH METHODS:Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 23 November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 10), MEDLINE Ovid (1946 to 23 November 2016), and Embase Ovid (23 May 2016 to 23 November 2016). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases; however, the search of Embase was restricted to the last six months due to the Cochrane Embase Project to identify all clinical trials and add them to CENTRAL. SELECTION CRITERIA:We included randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. For 'prophylaxis of MRONJ', the primary outcome of interest was the incidence of MRONJ; secondary outcomes were QoL, time-to-event, and rate of complications and side effects of the intervention. For 'treatment of established MRONJ', the primary outcome of interest was healing of MRONJ; secondary outcomes were QoL, recurrence, and rate of complications and side effects of the intervention. DATA COLLECTION AND ANALYSIS:Two review authors independently screened the search results, extracted the data, and assessed the risk of bias in the included studies. For dichotomous outcomes, we reported the risk ratio (RR) (or rate ratio) and 95% confidence intervals (CI). MAIN RESULTS:We included five RCTs (1218 participants) in the review. Three trials focused on the prophylaxis of MRONJ. Two trials investigated options for the treatment of established MRONJ. The RCTs included only participants treated with bisphosphonates and, thus, did not cover the entire spectrum of medications associated with MRONJ. Prophylaxis of MRONJOne trial compared standard care with regular dental examinations in three-month intervals and preventive treatments (including antibiotics before dental extractions and the use of techniques for wound closure that avoid exposure and contamination of bone) in men with metastatic prostate cancer treated with zoledronic acid. The intervention seemed to lower the risk of MRONJ: RR 0.10; 95% CI 0.02 to 0.39 (253 participants; low-quality evidence). Secondary outcomes were not evaluated.As dentoalveolar surgery is considered a common predisposing event for developing MRONJ, one trial investigated the effect of plasma rich in growth factors (PRGF) for preventing MRONJ in people with cancer undergoing dental extractions. There was insufficient evidence to support or refute a benefit of PRGF on MRONJ incidence when compared with standard treatment (RR 0.08, 95% CI 0.00 to 1.51; 176 participants; very low-quality evidence). Secondary outcomes were not reported. In another trial comparing wound closure by primary intention with wound closure by secondary intention after dental extractions in people treated with oral bisphosphonates (700 participants), no cases of intraoperative complications or postoperative MRONJ were observed. QoL was not investigated. Treatment of MRONJOne trial analysed hyperbaric oxygen (HBO) treatment used in addition to standard care (antiseptic rinses, antibiotics, and surgery) compared with standard care alone. HBO in addition to standard care did not significantly improve healing from MRONJ compared with standard care alone (at last follow-up: RR 1.56; 95% CI 0.77 to 3.18; 46 participants included in the analysis; very low-quality evidence). QoL data were presented qualitatively as intragroup comparisons; hence, an effect estimate of treatment on QoL was not possible. Other secondary outcomes were not reported.The other RCT found no significant difference between autofluorescence- and tetracycline fluorescence-guided sequestrectomy for the surgical treatment of MRONJ at any timepoint (at one-year follow-up: RR 1.05; 95% CI 0.86 to 1.30; 34 participants included in the analysis; very low-quality evidence). Secondary outcomes were not reported. AUTHORS' CONCLUSIONS:Prophylaxis of MRONJOne open-label RCT provided some evidence that dental examinations in three-month intervals and preventive treatments may be more effective than standard care for reducing the incidence of MRONJ in individuals taking intravenous bisphosphonates for advanced cancer. We assessed the certainty of the evidence to be low.There is insufficient evidence to either claim or refute a benefit of either of the interventions tested for prophylaxis of MRONJ (i.e. PRGF inserted into the postextraction alveolus during dental extractions, and wound closure by primary or secondary intention after dental extractions). Treatment of MRONJAvailable evidence is insufficient to either claim or refute a benefit for hyperbaric oxygen therapy as an adjunct to conventional therapy. There is also insufficient evidence to draw conclusions about autofluorescence-guided versus tetracycline fluorescence-guided bone surgery.
Medication-related osteonecrosis of the jaw: An update on the memorial sloan kettering cancer center experience and the role of premedication dental evaluation in prevention.
Owosho Adepitan A,Liang See Toh Yoong,Sax Adi Z,Wu Kant,Yom SaeHee K,Huryn Joseph M,Estilo Cherry L
Oral surgery, oral medicine, oral pathology and oral radiology
OBJECTIVE:The aim of this study was to investigate the relationship between type of antiresorptive medication and medication-related osteonecrosis of the jaw (MRONJ) onset and the role of premedication dental evaluation (PMDE) in the prevention of MRONJ. STUDY DESIGN:Our database of patients with MRONJ was reviewed. The Kruskal-Wallis test was used to analyze the onset dose of the 3 frequent medication types associated with MRONJ. To evaluate the role of PMDE in the prevention of MRONJ, all patients on antiresorptive and/or antiangiogenic medications seen in the Dental Service of Memorial Sloan Kettering Cancer Center during a 10-year period were subclassified into 2 groups. Group I comprised patients seen for PMDE before the commencement of A/A and group II patients seen after prior exposure to antiresorptive and/or antiangiogenic medications. Fischer's exact test was used to compare the incidence of MRONJ in both groups. RESULTS:Patients on denosumab developed MRONJ earlier compared with zoledronate and pamidronate (P = .003). Group I had a significantly reduced incidence of MRONJ (0.9%) compared with group II (10.5%) (P < .0001). Dentoalveolar trauma as a precipitating factor between groups I and II was not statistically significant. CONCLUSIONS:Denosumab was associated with an earlier occurrence of MRONJ compared with zoledronate and pamidronate. The role of PMDE may be an effective preventive strategy in reducing the incidence of MRONJ.
Low-dose methotrexate in rheumatoid arthritis: a potential risk factor for bisphosphonate-induced osteonecrosis of the jaw.
Mathai Paul C,Andrade Neelam N,Aggarwal Neha,Nerurkar Shibani,Kapoor Prathmesh
Oral and maxillofacial surgery
Bisphosphonate-induced osteonecrosis of the jaw [BIONJ] is a relatively new pathological condition which was first described in the year 2003. The prevalence of BIONJ in patients on oral formulations is around 0.05% within the first 3 years and increases up to 0.2% after 4 years of consumption. Proven systemic risk factors like anemia, uncontrolled diabetes, corticosteroid therapy, and chemotherapy in neoplastic diseases [e.g., high doses of methotrexate up to 30 mg daily] significantly increase the chances of acquiring BIONJ. We present three patients with osteoporosis and rheumatoid arthritis [RA] who consumed oral bisphosphonates [alendronate] for less than 1 year and developed BIONJ within 2 to 5 months of undergoing a traumatic dental procedure. The patients also gave a history of consuming low doses of methotrexate [disease-modifying anti-rheumatic drugs] up to 20 mg weekly for 4 to 10 years. No history of steroid consumption was given by any of the patients. This case series highlights the possibility of rheumatoid arthritis and low-dose methotrexate being potential risk factors for BIONJ. This may be on account of the synergistic effect of methotrexate and bisphosphonates and the pro-inflammatory state created by RA which increased the risk of acquiring BIONJ.
Osteoporosis therapy in patients with inflammatory rheumatic diseases and osteonecrosis of the jaw.
Schwaneck E C,Streit A,Krone M,Hartmann S,Müller-Richter U,Kübler A C,Gadeholt O,Schmalzing M,Tony H-P,Brands R C
Zeitschrift fur Rheumatologie
BACKGROUND AND OBJECTIVES:The aim of the present study was to assess the prevalence of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients suffering from inflammatory rheumatic diseases, as well as to assess the prevalence of relevant dental, behavioral, and medical risk factors for MRONJ. MATERIALS AND METHODS:A total of 198 patients with inflammatory rheumatic diseases and osteoporosis therapy were recruited from a tertiary rheumatological/immunological referral center between June 2015 and September 2016. They were assessed using a structured interview. A maxillofacial surgeon later examined patients complaining of possible symptoms of osteonecrosis. In cases of osteonecrosis, dental records were obtained and evaluated. Preventive measures taken and dental as well as other clinical risk factors were evaluated. RESULTS:Of the 198 patients, three suffered from osteonecrosis of the jaw, none of whom had any history of malignant disease or radiation therapy, resulting in a prevalence of 1.5%. Of these three patients, only one was given bisphosphonates intravenously (i.v.), whereas all three had been treated orally. All three diagnoses of MRONJ had been previously known to the patients and their maxillofacial surgeons. Two of the patients had rheumatoid arthritis, and one patient suffered from large vessel vasculitis. Long anti-osteoporotic treatment duration, low functional status, and low bone density of the femur were significantly associated with MRONJ development. CONCLUSION:Inflammatory rheumatic diseases constitute a risk factor for MRONJ in patients treated with bisphosphonates for osteoporosis. Patients should be counseled accordingly and should be offered dental screening and regular dental check-ups.
Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology.
Fusco Vittorio,Santini Daniele,Armento Grazia,Tonini Giuseppe,Campisi Giuseppina
Expert opinion on drug safety
INTRODUCTION:Osteonecrosis of the jaw (ONJ) is a clinically important, potentially painful and debilitating condition, which can affect the quality of life of cancer patients. Since 2003, ONJ appeared as a Bisphosphonate(BP)-related class effect, and the term Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) was widespread. AREAS COVERED:Under discussion in this review is the fact that ONJ cases have been reported after treatment including antiangiogenic agents and other "targeted therapy", with and without BPs. Consequently, the comprehensive term Medication-Related Osteonecrosis of the Jaw (MRONJ) has been introduced. The clinical aspects and the prognosis of ONJ associated with these new drugs are still less reported, but basing on their pharmacodynamics, they could be different from the well-known BRONJ. Accordingly, recommendations largely in use for BRONJ should be extended to these new forms, but critically applied and with respect to the individual risk assessment. EXPERT OPINION:There is a high risk of underdiagnoses for ONJ due to a lack of awareness, and too much restrictive or incomplete diagnostic criteria; at the same time, with regard to ONJ associated to the new non -antiresorptive agents, described here, we observe the strong need to improve the defining of any distinguished feature in their diagnosis, prevention and therapy.
[Sunitinib and zoledronic acid induced osteonecrosis of the jaw].
Soós Balázs,Vajta László,Szalma József
The tendency for bisphosphonate and non-bisphosphonate (eg.: antiresorptive or anti-angiogenesis drugs) induced osteonecrosis is increasing. Treatment of these patients is a challenge both for dentists and for oral and maxillofacial surgeons. Cooperation with the drug prescribing general medicine colleagues to prevent osteonecrosis is extremely important. Furthermore, prevention should include dental focus elimination, oral hygienic instructions and education, dental follow-up and, in case of manifest necrosis, referral to maxillofacial departments. Authors outline the difficulties of conservative and surgical treatment of a patient with sunitinib and zoledronic acid induced osteonecrosis. The patient became symptomless and the operated area healed entirely six and twelve months postoperatively. A long term success further follow-up is necessary to verify long-term success.
Spontaneous bone formation after mandible segmental resection in "krokodil" drug-related jaw osteonecrosis patient: case report.
Hakobyan Koryun,Poghosyan Yuri
Oral and maxillofacial surgery
We report a case of a 48-year-old male patient with "krokodil" drug-related osteonecrosis of both jaws. Patient history included 1.5 years of "krokodil" use, with 8-month drug withdrawal prior to surgery. The patient was HCV positive. On the maxilla, sequestrectomy was performed. On the mandible, sequestrectomy was combined with bone resection. From ramus to ramus, segmental defect was formed, which was not reconstructed with any method. Post-operative follow-up period was 3 years and no disease recurrence was noted. On 3-year post-operative orthopantomogram, newly formed mandibular bone was found. This phenomenon shows that spontaneous bone formation is possible after mandible segmental resection in osteonecrosis patients.
[Basic Studies on the Mechanism, Prevention, and Treatment of Osteonecrosis of the Jaw Induced by Bisphosphonates].
Endo Yasuo,Funayama Hiromi,Yamaguchi Kouji,Monma Yuko,Yu Zhiqian,Deng Xue,Oizumi Takefumi,Shikama Yosuke,Tanaka Yukinori,Okada Satoshi,Kim Siyoung,Kiyama Tomomi,Bando Kanan,Shima Kazuhiro,Suzuki Hikari,Takahashi Tetsu
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is common in elderly women, and bisphosphonates (BPs) are typical and widely used anti-osteoporotic or anti-bone-resorptive drugs. BRONJ is now a serious concern in dentistry. As BPs are pyrophosphate analogues and bind strongly to bone hydroxyapatite, and the P-C-P structure of BPs is non-hydrolysable, they accumulate in bones upon repeated administration. During bone-resorption, BPs are taken into osteoclasts and exhibit cytotoxicity, producing a long-lasting anti-bone-resorptive effect. BPs are divided into nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). N-BPs have far stronger anti-bone-resorptive effects than non-N-BPs, and BRONJ is caused by N-BPs. Our murine experiments have revealed the following. N-BPs, but not non-N-BPs, exhibit direct and potent inflammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the inflammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by inflammation. N-BPs are taken into soft-tissue cells via phosphate-transporters, while the non-N-BPs etidronate and clodronate inhibit this transportation. Etidronate, but not clodronate, has the effect of expelling N-BPs that have accumulated in bones. Moreover, etidronate and clodronate each have an analgesic effect, while clodronate has an anti-inflammatory effect via inhibition of phosphate-transporters. These findings suggest that BRONJ may be induced by phosphate-transporter-mediated and infection-promoted mechanisms, and that etidronate and clodronate may be useful for preventing and treating BRONJ. Our clinical trials support etidronate being useful for treating BRONJ, although additional clinical trials of etidronate and clodronate are needed.
Drug induced osteonecrosis of the jaw.
Hamadeh Issam S,Ngwa Bridget A,Gong Yan
Cancer treatment reviews
Despite the widespread use of bisphosphonates and their unequivocal efficacy for the treatment of various disease states, osteonecrosis of the jaw remains one of the most feared complications associated with their use. Current evidence, however, suggests that there is also a relationship between occurrence of osteonecrosis of the jaw and use of other classes of pharmacotherapies namely RANKL inhibitors as well as angiogenesis inhibitors. Although these drugs have different mechanisms of action than bisphosphonates, they all seem to interfere with the bone remodeling process i.e. alter the balance between bone resorption and bone formation which may be the most plausible explanation for pathogenesis of osteonecrosis of the jaw. The main objective of this review is to introduce the readership to a number of relatively new medications that may cause osteonecrosis of the jaw. Accordingly, we will summarize latest findings from clinical studies, meta analyses and case reports published in medical literature on this topic. For some of these medications, the evidence may not appear as robust as that for bisphosphonates; yet, the possibility of this adverse event occurring with these non bisphosphonate drugs should never be precluded unless proven otherwise. Thus, it is imperative that health care providers implement preventive measures so as to circumvent the incidence of osteonecrosis of the jaw. In this day of age where medical care is becoming personalized, we will highlight some of significant findings from studies seeking to identify genetic markers that may potentially play a role in development of osteonecrosis of the jaw.
Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw.
Chang J,Hakam A E,McCauley L K
Current osteoporosis reports
PURPOSE OF REVIEW:Osteonecrosis of the jaw (ONJ) is a rare and severe necrotic bone disease reflecting a compromise in the body's osseous healing mechanisms and unique to the craniofacial region. Antiresorptive and antiangiogenic medications have been suggested to be associated with the occurrence of ONJ; yet, the pathophysiology of this disease has not been fully elucidated. This article raises the current theories underlying the pathophysiology of ONJ. RECENT FINDINGS:The proposed mechanisms highlight the unique localization of ONJ. The evidence-based mechanisms of ONJ pathogenesis include disturbed bone remodeling, inflammation or infection, altered immunity, soft tissue toxicity, and angiogenesis inhibition. The role of dental infections and the oral microbiome is central to ONJ, and systemic conditions such as rheumatoid arthritis and diabetes mellitus contribute through their impact on immune resiliency. Current experimental studies on mechanisms of ONJ are summarized. The definitive pathophysiology is as yet unclear. Recent studies are beginning to clarify the relative importance of the proposed mechanisms. A better understanding of osteoimmunology and the relationship of angiogenesis to the development of ONJ is needed along with detailed studies of the impact of drug holidays on the clinical condition of ONJ.
Emerging therapies with potential risks of medicine-related osteonecrosis of the jaw: a review of the literature.
Kanwar Nupur,Bakr Mahmoud M,Meer Mohammed,Siddiqi Allauddin
British dental journal
In the past, osteonecrosis of the jaw (ONJ) was generally reported with bisphosphonate drugs; hence, the term BRONJ (bisphosphonate-related osteonecrosis of the jaw) was initially proposed. This was followed by the term ARONJ (antiresorptive osteonecrosis of the jaw). More recently, other novel medications such as vascular endothelial growth factor (VEGF) inhibitors, tyrosine kinase inhibitors and humanised antibodies that affect osteoclastic action have been reported to initiate ONJ in several cases. For this reason, in 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) changed the term to MRONJ - medication-related osteonecrosis of the jaw. The review primarily focuses on ONJ associated with emerging therapies for the management of bone disorders. This article sheds some light on the risk factors that predispose dental patients to the development of osteonecrosis, the mechanisms of drug therapies associated with MRONJ, and potential treatment and management regimes for MRONJ patients. The current review noted that the incidence and associated risk of MRONJ is significant with the new therapeutic agents discussed. Therefore, for optimised patient care, pharmacovigilance with the new medications is essential for dental professionals.
Effects of double filtration plasmapheresis, leflunomide, and methotrexate on inflammatory changes found through magnetic resonance imaging in early rheumatoid arthritis.
Yu Xiaoxia,Wang Lixin,Xu Ping,Lu Weiwei,Lan Guobin,Ping Lifeng,Wang Xiaolei,Tian Junge,Liu Junlan
The Journal of rheumatology
OBJECTIVE:To evaluate the effects of double filtration plasmapheresis (DFPP) in combination with leflunomide and methotrexate (MTX) on magnetic resonance imaging (MRI)-detected inflammatory changes (synovitis and bone edema) in patients with early rheumatoid arthritis (RA) with high disease activity. METHODS:Sixty RA patients with highly active disease of 6 months' to 3 years' duration were randomized to receive DFPP in combination with leflunomide and MTX (DFPP group), and leflunomide plus MTX (no-DFPP group). The primary endpoint was the improvement in MRI-detected synovitis from baseline over 6 months. Secondary endpoint variables included DAS28 remission and American College of Rheumatology (ACR) criteria responses for 6 consecutive months. RESULTS:The study achieved significant improvement in synovitis and bone edema, with significantly lower synovitis and bone edema scores in the DFPP group compared with the no-DFPP group (p < 0.001). Synovitis scores in 48.39% of patients (15/31) in the DFPP group were 0 at Month 6. Bone edema scores in 32.26% of patients (10/31) in the DFPP group were 0 at Month 6. We observed significantly greater ACR20, ACR50, ACR70, and ACR90 responses and DAS28 remission rates in the DFPP group than in the no-DFPP group (p < 0.001). Sustained DAS28 remission and ACR90 response for at least 6 months were achieved in 100% of patients receiving DFPP therapy. CONCLUSION:The combination of DFPP and disease-modifying antirheumatic drugs (DMARD) was superior to DMARD alone for reducing MRI-detected signs of synovitis and bone edema in patients with early highly active RA. DFPP therapy enabled rapid and more complete suppression of inflammation in patients with highly active RA. Nearly half the patients (48.39%) who had received DFPP therapy achieved both clinical remission and imaging remission, a state characterized as true remission.