Article

“Bis-phossy jaws”–High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw

April 2008
Journal of Cranio-Maxillofacial Surgery 36(2):95-103

April 2008
36(2):95-103

DOI:10.1016/j.jcms.2007.06.008

Source
PubMed

Authors:

Mario Abu-Id

Independent Researcher

Patrick H Warnke

Griffith University

Joachim Gottschalk

Asklepios Klinik Nord

Ingo N Springer

Clinic for Oral, Maxillofacial und Plastic Surgery, Sell-Speicher, Kiel Germany

Show all 8 authorsHide

Bisphosphonates (BPs) have transformed our ability to treat certain malignancies, osteoporosis and hypercalcaemia. This class of drug is assumed to be well tolerated by most. There are some important caveats to this assumption, however, one of the significances being the risk of osteonecrosis of the jaw (ONJ). This multi-centre retrospective study examined the role of different BPs on the development of ONJ, its clinical presentation and the efficacy of various treatment modalities, comparing these findings with the available literature. A total of 78 patients from 17 centres were identified with ONJ. A majority of patients identified with ONJ had used Pamidronate or Zoledronate (93.6%) intravenously. 94.9% of patients had received BP in the course of treatment for malignancies and a majority had also received prior chemotherapy or exogenous steroids. 82.1% of patients had received BP for more than 1 year. The mean time from the introduction of BP to the development of ONJ in 24 patients from our department was 31.8 months. The most common intraoral manifestation was exposed necrotic jawbone. Tooth extractions and oral surgical intervention appear to place patients on BP therapy at risk of ONJ, especially after intravenous BP treatments. ONJ proved in this study to be remarkably refractory to treatment, with radical resection being the only curative approach. We recommend that all patients receive necessary dental treatment prior to commencing BP therapy.

Three-dimensional bone evaluation after surgical treatment with plasma rich in growth factors of Medication Related Osteonecrosis of the Jaw (MRONJ): A report of 3 cases

Article

Full-text available

May 2019

Introduction Medication Related Osteonecrosis of the Jaw (MRONJ) is an adverse effect of antiresorptive and antiangiogenic agents that consists of progressive bone destruction in the maxillofacial area. The purpose of this study is to analyze the effect on bone volume of a surgical protocol using plasma rich in growth factors (PRGF) for successfully treating MRONJ. Methods Three patients were treated combining surgical debridement with PRGF. Cone bean computed tomography scans were taken prior to surgery and 12 months after to measure bone volume changes. Biopsies were taken for histology analysis during surgery. Results All patients showed a complete soft tissue and bone healing with pain, discomfort, and neural symptoms resolution for a follow up period of 30 months. A total of 12 to 30% of bone volume gain was found at 12 months after surgery. Conclusions PRGF in combination with surgery may be effective in treating MRONJ. Future trials must be performed to confirm these results, including bone volume analysis.

Osteonecrosis of the Jaw Associated with Bisphosphonates Infusion for Treatment of Plasma Cell Myeloma—A Retrospective Observational Study of Northern Portuguese Population

Article

Full-text available

May 2024

Objectives: To verify medication-related osteonecrosis of the jaw (MRONJ) frequency among patients with plasma cell myeloma (PCM) that had been treated with bisphosphonates, to identify predisposing factors that could influence the development of osteonecrosis. Methods: This observational retrospective study was performed at the Department of Hematology of Hospital Center of Porto (CHUP), Portugal. Results: The study population (n = 112) had a 15.2% (n = 17) prevalence of osteonecrosis. Clinically, bone exposure was the most frequently observed sign, present in 100% (n = 17) of the patients, followed by inflammation in 82.4% (n = 14), orofacial pain in 70.6% (n = 12), suppuration in 47.1% (n = 8), and intra or extra-oral fistula in 17.6% (n = 3) of the cases. The most frequent triggering local factor was dental extraction (82.4%). There was a dependence between the presence of extractions and the development of MRONJ (p < 0.001) but not with the time elapsed from the initiation of infusions with BPs and dental extractions (p = 0.499). In the sample of patients with multiple myeloma (MM), 13.8% were found to be more likely to develop MRONJ after an extraction. Conclusions: The most common local predisposing factor was dental extraction. No dependence was observed between the development of osteonecrosis and the time elapsed from the beginning of treatment with bisphosphonates infusions to surgical procedures.

Role of forest's woody vegetation in the climate change mitigation through carbon sequestration in the northern Pakistan

Chapter

Full-text available

Jan 2024

This chapter documents the role of the woody vegetation of Northern Pakistan in the mitigation of climate change by carbon (C) sequestration. Sequestrating C dioxide by vegetation is a practical approach to mitigate greenhouse gases from the atmosphere. This study investigates the impact of environmental variables and their temporal dynamics on C sequestration. The main objective of this chapter is to determine the role of the woody vegetation of Northern Pakistan in Climate Change reduction and mitigation through C sequestration. For these purposes, 75 plots of 20/20 were laid down following forest inventory. Soil samples were collected following standard laboratory protocols. GPS (Global Positioning System) was used to check the profile location slope angle coordinates. R, sigma, and origin software were used for the statistical analysis of the data through a stepwise regression model, and structural equation modeling. GPS was used to determine the coordinates of the profile location slope angle. The result of the current research work revealed that the woody vegetation of Northern Pakistan plays a significant role in global warming and climate change mitigation through C sequestration. Stand indices (DBH, Height, and BD) reflect a highly significant positive correlation. In contrast, diversity indices (species richness) reflect a significant but negative correlation with C sequestration. C sequestration and storage capacities of various clusters must be explored to trace the efficient composition of plant species with the possible highest capacity.

Assoziation von Entzündungsparametern (CRP und Leukozytenzahl) mit der Rezidivwahrscheinlichkeit der Medikamenten-assoziierten Kiefernekrose nach operativer Sanierung

Thesis

Jan 2021

Celine Schäfer

Die medikamenten-assoziierte Kiefernekrose (MRONJ) tritt als eine mögliche Komplikation bei der Therapie mit Bisphosphonaten, dem Antikörper Denosumab und einigen anderen, vor allem in der Tumortherapie eingesetzten, Medikamenten auf. Klinisch stellt die Nekrose ein ernstzunehmendes Problem dar. Sogar bei der Durchführung einer operativen Therapie kommt es häufig (in circa 11% der Fälle) zu Rezidiven, die die Lebensqualität der Betroffenen und deren Prognose erheblich einschränken. Von einigen Autoren wird eine Rolle entzündlicher Vorgänge bei der Entstehung der MRONJ postuliert. Es soll deshalb mithilfe dieser Arbeit herausgefunden werden, ob es einen Zusammenhang zwischen routinemäßig erhobenen perioperativen Entzündungsparametern, nämlich dem C-reaktivem Protein und der Leukozytenzahl, sowie einem pathohistologischen Nachweis von Bakterien und dem Auftreten eines Rezidivs innerhalb des ersten halben Jahres nach der operativen Sanierung der Knochennekrose gibt. Das Ziel ist es, herauszufinden ob sich ein Screening der Patienten mithilfe der oben genannten Entzündungsmarker präoperativ anbieten würde, um eine langwierige Krankheitsgeschichte in Bezug auf MRONJ-Rezidive zu antizipieren und so möglicherweise verhindern zu können.

Racial Disparities in Intravenous Bisphosphonate Use Among Older Patients With Multiple Myeloma Enrolled in Medicare

Article

Full-text available

Jan 2021

PURPOSE Intravenous (IV) bisphosphonates reduce the risk of skeletal-related events in patients with multiple myeloma (MM). However, data describing racial differences in IV bisphosphonate utilization outside of clinical trial settings are limited. We evaluated population-level IV bisphosphonate initiation and discontinuation among patients of age ≥ 65 years with MM. METHODS We conducted a retrospective cohort study of patients of age ≥ 65 years diagnosed with first primary MM between 2001 and 2011. Patients were identified using the SEER-Medicare linked database and followed through December 2013. Cumulative incidences of IV bisphosphonate initiation and time to discontinuation among users were compared between racial and ethnic groups. In Fine and Gray competing risk models, we estimated subdistribution hazard ratios (SHRs) and 95% CIs for initiation and discontinuation. RESULTS We included 14,231 eligible patients with MM (median age, 76 years; 52% male). Over a median follow-up of 23.1 months, 54% of patients received at least one IV bisphosphonate dose. Our final analytical sample included 10,456 non-Hispanic (NH) Whites, 2,267 NH Blacks, 548 Asian and Pacific islanders, and 815 Hispanic and Latino patients. A higher proportion of White patients (56.1%) newly received IV bisphosphonates after MM diagnosis compared with NH Blacks (45.4%). Compared with White patients, NH Black patients were less likely to initiate IV bisphosphonates (SHR, 0.74; 95% CI, 0.70 to 0.79) and slightly more likely to discontinue treatment (SHR, 1.10; 95% CI, 1.01 to 1.19). CONCLUSION Approximately half of the patients with MM of age ≥ 65 years did not receive IV bisphosphonates, with significant delay among racial minority groups. These findings highlight the need for improvement of IV bisphosphonate uptake in patients with MM of age ≥ 65 years.

Article

Full-text available

Jul 2019

Purpose: To provide guidance regarding best practices in the prevention and management of medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer. Methods: Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. Guideline development involved a systematic review of the literature and a formal consensus process. PubMed and EMBASE were searched for studies of the prevention and management of MRONJ related to bone-modifying agents (BMAs) for oncologic indications published between January 2009 and December 2017. Results from an earlier systematic review (2003 to 2008) were also included. Results: The systematic review identified 132 publications, only 10 of which were randomized controlled trials. Recommendations underwent two rounds of consensus voting. Recommendations: Currently, MRONJ is defined by (1) current or previous treatment with a BMA or angiogenic inhibitor, (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region and that has persisted for longer than 8 weeks, and (3) no history of radiation therapy to the jaws or metastatic disease to the jaws. In patients who initiate a BMA, preventive care includes comprehensive dental assessments, discussion of modifiable risk factors, and avoidance of elective dentoalveolar surgery (ie, surgery that involves the teeth or contiguous alveolar bone) during BMA treatment. It remains uncertain whether BMAs should be discontinued before dentoalveolar surgery. Staging of MRONJ should be performed by a clinician with experience in the management of MRONJ. Conservative measures comprise the initial approach to MRONJ treatment. Ongoing collaboration among the dentist, dental specialist, and oncologist is essential to optimal patient care.

Nasolabial Flap Improves Healing in Medication-Related Osteonecrosis of the Jaw

Article

Oct 2017
J ORAL MAXIL SURG

Purpose: Medication-related osteonecrosis of the jaw (MRONJ) is an adverse side effect of antiresorptive and antiangiogenic therapeutic agents that is difficult to treat owing to its high relapse rate. The aim of the present study was to determine whether patients with MRONJ treated using decortication and a nasolabial flap compared with those who underwent decortication with mucoperiosteal flaps have better outcomes regarding stable wound closure. Materials and methods: Two groups of patients with MRONJ and intraoral exposed bone were evaluated in a cohort clinical study retrospectively. The primary predictor variable was the treatment group. The experimental group used the nasolabial flap for wound closure, and the control group used the mucoperiosteal flap for closure. The outcome variable was successful wound closure defined as a symptomless and closed wound after at least 12 months. Other study variables included factors such as perioperative drug holiday, duration of postoperative oral antibiotic administration, and postoperative use of nasogastric feeding tubes. Cox proportional hazard regression analysis and Kaplan-Meier curves were used to determine the factors independently associated with the dependent variable. The Mann-Whitney U test and χ(2) test were used for analyses regarding group-related data. Results: Both groups showed similar demographics. The 16 study patients receiving nasolabial flaps had a mean age of 69.9 years, and the 16 control patients receiving mucoperiosteal flaps had a mean age of 71.8 years. Both groups included 10 women and 6 men. Of the 16 patients in each group, 15 had received a bisphosphonate and 1, monoclonal antibody therapy. All evaluated patients underwent combined treatment, including decortication and intravenous antibiotics. Of the 16 patients receiving nasolabial flaps, symptomless intact wound closure was achieved in 68.8%. Of the 16 patients with mucoperiosteal closure, 18.7% achieved wound closure, with 81.2% developing a relapse of MRONJ, a statistically significant difference (P < .001). No statistically significant differences were found between the 2 groups in the demographic variables. The mean interval to relapse for the experimental and control groups was 13.6 ± 7.8 and 8.2 ± 7.9 months, respectively (P = .017). Conclusions: MRONJ is a complication of antiosteoclastic treatment of mostly oncologic, palliative patients, which requires a very methodical approach to surgical treatment. A variety of different methods have been reported. The use of nasolabial flaps can be considered as a highly reliable option for coverage the bone wound with less morbidity than microvascular free flaps and better long-term results compared with mucoperiosteal flaps.

Role of Actinomyces spp. and related organisms in the development of medication-related osteonecrosis of the jaw (MRONJ): Clinical evidence based on a case series

Article

Full-text available

Dec 2023

Medication-related osteonecrosis of the jaw (MRONJ) is an increasingly common consequence of antiresorptive treatment, which often leads to the development of necrotic exposed bone surfaces with inflammatory processes affecting the jawbone. Although the development of MRONJ is often associated with the inflammatory response or infections caused by the colonizing members of the oral microbiota, the exact pathogenesis of MRONJ is still not fully understood. In the present paper, we aimed to provide additional, microbiological culture-supported evidence, supporting the “infection hypothesis” that Actinomyces spp. and related organisms may play an important pathogenic role in the development of MRONJ and the resulting bone necrosis. In our case series, all patients presented with similar underlying conditions and anamnestic data, and have received antiresorptive medications (bisphosphonates or a RANK ligand (RANKL) inhibitor) to prevent the occurrence or progression of bone metastases, secondary to prostate cancer. Nevertheless, a few years into antiresorptive drug therapy, varying stages of MRONJ was identified in the mentioned patients. In all three cases, quantitative microbiological culture of the necrotic bone samples yielded a complex microbiota, dominated by Actinomyces and Schaalia spp. with high colony counts. Additionally, our followed-up case series document the treatment of these patients with a combination of surgical intervention and long-term antibiotic therapy, where favourable clinical responses were seen is all cases. If the “infection hypothesis” is valid, it may have significant consequences in the preventative and therapeutic strategies associated with this disease.

Spontaneous Recovery of Pathological Fracture Caused by Medication-Related Osteonecrosis of the Jaw

Article

Aug 2023
J CRANIOFAC SURG

Pathological fracture is one of the most serious complications in medication-related osteonecrosis of the jaw (MRONJ). This case is a report of an 87-year-old woman who had been diagnosed with pathological fracture due to MRONJ. The authors performed minimally invasive and conservative treatment, such as intraoral dressing, antibiotic therapy, and simple debridement, for patients with pathologic fractures due to MRONJ. After 1 year, the inflammatory symptoms disappeared and pathological fractures spontaneously recovered.

Bisfosfonatos e osteonecrose maxilar: uma revisão narrativa da literatura

Article

Full-text available

Apr 2023

Os bisfosfonatos são uma classe medicamentosa utilizada no tratamento de doenças que causam reabsorção óssea, incluindo osteoporose, doença óssea de Paget, como também doenças ligadas a malignidade como mieloma múltiplo. Um de seus mecanismos de ação é a inibição da atividade dos osteoclastos. Desde o ano de 2003 estudos relatam a associação da osteonecrose avasculares dos ossos maxilares ao uso de bisfosfonato sendo um exemplo de reação adversa. Vários sinais e sintomas resultam em suas manifestações clínicas, por complicações na terapia dos bisfosfonatos, podendo ser assintomática ou em alguns casos apresentar dor e necrose quando houver exposição do osso mandibular ou maxilar. Desta maneira, o objetivo deste trabalho foi realizar uma revisão de literatura acerca da relação da osteonecrose dos maxilares e o uso de bisfosfonato. Para a realização desta revisão de literatura, foram avaliados artigos científicos pesquisados na língua inglesa e portuguesa sem limite de ano de publicação nas seguintes bases de dados: PubMed, SciELO (Scientific Electronic Library Online, Scopus Elsevier, BVS (Biblioteca Virtual em Saúde) e Google acadêmico. Usando os descritores: “Bisphosphonate, Osteonecrosis, Jaws, Dentistry”. Conclui-se que a osteonecrose de maxilares é uma doença que pode ser relacionada ao uso de bisfosfonatos, e que ainda não existe um tratamento padrão para esta patologia, o ideal é que o paciente antes de iniciar o tratamento com bisfosfonato, passe por uma consulta odontológica para realizar possíveis tratamentos invasivos e alcançar uma boa saúde bucal.

Clinical and Radiographic Outcomes of Dental Implants in Patients Treated With Antiresorptive Drugs: A Consecutive Case Series

Article

Full-text available

Apr 2022

Medication-related osteonecrosis of the jaw (MRONJ) is a serious concern for dentists as well as maxillofacial surgeons. Therefore, the safety of dental implant placement in patient receiving antiresorptive drugs (ARDs) has been the subject of controversial debate for several years and remains a source of uncertainty for surgeons and patients. This consecutive case series assessed the clinical and radiographic outcomes of dental implants placed in patients under antiresorptive therapy. Patients who received at least one dental implant at the Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians-University (LMU), Munich, Germany between 2010 and 2019 with a history of current or past antiresorptive medication were included the study. The main outcomes were occurrence of MRONJ, implant success and survival rate. A total of 16 patients were treated with 39 implants. No implant loss or MRONJ occurred in the respective patients. The reasons for antiresorptives intake were osteoporosis, malignancy, edema of bone marrow or diffuse sclerosing osteomyelitis (DSO). MRONJ occurred neither around implants nor in other locations. Cumulative implant success was 92.6% (25 of 27). No subjective complaints or postoperative complications were documented. Mean bone loss was 0.60±0.98mm. The prevalence of peri-implantitis was 30% on patient level and 29.6% on implant level. None of the patients had failed implants. No major complications after implant placement under antiresorptives could be detected. As long as implant surgery follows a specific protocol, implant placement in patients treated with antiresorptive therapy seems to be safe and predictable.

Causes of and Molecular Targets for the Treatment of Intervertebral Disc Degeneration: A Review

Article

Full-text available

Jan 2022

Intervertebral disc degeneration (IVDD) is a pathological condition that can lead to intractable back pain or secondary neurological deficits. There is no fundamental cure for this condition, and current treatments focus on alleviating symptoms indirectly. Numerous studies have been performed to date, and the major strategy for all treatments of IVDD is to prevent cell loss due to programmed or regulated cell death. Accumulating evidence suggests that several types of cell death other than apoptosis, including necroptosis, pyroptosis, and ferroptosis, are also involved in IVDD. In this study, we discuss the molecular pathway of each type of cell death and review the literature that has identified their role in IVDD. We also summarize the recent advances in targeted therapy at the RNA level, including RNA modulations through RNA interference and regulation of non-coding RNAs, for preventing cell death and subsequent IVDD. Therefore, we review the causes and possible therapeutic targets for RNA intervention and discuss the future direction of this research field.

Article

Full-text available

Jan 2022

Medication-related osteonecrosis of the jaw (MRONJ) is a major problem that can occur in people taking certain medications such bisphosphonates and denosumab. It can be used to treat osteoporosis or cancer. Bisphosphonate exposure, dental diseases and procedures, age, sex, anatomical factors, medical issues, and hereditary factors are all variables that enhance the risk of MRONJ. Even though MRONJ and antiresorptive medications have a close association, the pathophysiology of MRONJ is unknown. Careful dental preparation and oral hygiene instructions significantly minimize the risk of osteonecrosis of the jaw (ONJ). It is ideal to start antiresorptive treatment after the completion of required dental treatment; it is not contraindicated and carries low risk in patients who are on oral antiresorptive medications for less than three years. Drug holidays are one proposed solution to address MRONJ. However, there is still inadequate evidence to support their effectiveness. The objectives of this literature review are to recognize the main diagnostic principles and risk factors and to review the pathophysiology, protective procedures and treatment modalities related to MRONJ. The following topics are covered in the review: epidemiology, diagnostic criteria, risk factors, pathogenesis and mechanism, MRONJ staging and symptoms, clinical and radiographic findings, treatment strategies, prevention and drug holiday.

F-Fluoride PET/CT Imaging of Medication-Related Osteonecrosis of the Jaw in Conservative Treatment—A Case Report

Article

Full-text available

Jul 2021

Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect in antiresorptive treatment. Treatment of MRONJ is considered primarily conservative with oral mouth rinses and antibiotics but may demand surgery, depending on the complaints and general condition of the patient, the extent of the necrosis, and the overall prognosis with respect to the underlying disease. A 77 year old female patient with invasive ductal breast cancer and bone metastases was treated with intravenous bisphosphonate (BP) zoledronic acid. During therapy, she developed MRONJ in the mandible with severe pain. Clinical examination revealed confluent exposed bone of the lower left jaw and a fistula at the right molar region. The panoramic radiograph revealed a mandibular osseous involvement with diffuse radiopaque areas between radiolucent areas. For preoperative planning, ¹⁸F-fluoride positron emission tomography/computed tomography (PET/CT) of the jaw was performed, showing substantially increased ¹⁸F-fluoride uptake in regions 38 to 47 of the mandible with a focal gap in region 36 (area of clinically exposed bone). CT revealed medullary sclerosis and cortical thickening with confluent periosteal reaction and focal cortical erosion in the regions 37 to 42, whereas the regions 43 to 47 were only subtly sclerotic without cortical thickening. After systemic antibiotic therapy with sultamicillin following significant symptom and pain relief, ¹⁸F-fluoride PET/CT imaging was performed again after 5 months. No changes in either CT and PET were observed in regions 38 to 42, whereas the bony sclerosis was slightly increased in regions 43 to 47 with a slight reduction of ¹⁸F-fluoride uptake. ¹⁸F-fluoride PET/CT showed no significant changes assessing the extent of MRONJ prior and after systemic antibiotic therapy, providing no evidence that conservative treatment reduced the extent of the MRONJ-affected jawbone. The additional information of ¹⁸F-fluoride PET enables to identify the true extent of MRONJ which may be underestimated by CT imaging alone. Patients with MRONJ undergoing conservative treatment could benefit because additional imaging may be avoided as the pre-therapeutic ¹⁸F-fluoride PET/CT delivers all information needed for further treatment. Our findings support the recommendation of a surgical approach as long-term antibiotics cannot downsize the extent of MRONJ.

Is Dental Implant Placement Compatible in Patients Treated with Bisphosphonates? A Literature Review

Article

Full-text available

Jul 2019

Background: Bisphosphonates (BP) are a group of drugs used in treatment and prevention of alterated turn-over of bone diseases. Since 2003, it is known That BP are able to develop osteonecrosis of the jaw (BRONJ: Bisphosphonate-Related Osteonecrosis of the Jaw) when they are associated to any surgical trauma, even dental implant therapy. Materials and Methods: Comprehensive research of scientific articles from ten years ago to our days in Medline (Pubmed). Results and Discussion: 1090 dental implants placed patients treated with BP and 3472 dental implants placed in healthy patients had successfully rates of 97.6% and 97.9%, respectively. Therefore, implant placement in patients in treatment with BP does not reduce implant success rates. Besides, BRONJ appears before with intravenous vs oral administration of BP. Conclusion: Further well-designed long-term studies are necessary to evaluate correctly the relationship between BP and dental implants. Keywords: Dental implant; Osteonecrosis; Bisphosphonate; Bisphosphonate-related osteonecrosis of the jaw Abbreviations: BP: Bisphosphonates; BRONJ: Bisphosphonate Related Osteonecrosis of the Jaw; CTX: C Terminal Telopeptide, TCT; AAOMS: The American Association of Oral and Maxillofacial Surgeons

Molecular Targeted Therapy for the Bone Loss Secondary to Pyogenic Spondylodiscitis Using Medications for Osteoporosis: A Literature Review

Article

Full-text available

Apr 2021
INT J MOL SCI

Pyogenic spondylodiscitis can cause severe osteolytic and destructive lesions in the spine. Elderly or immunocompromised individuals are particularly susceptible to infectious diseases; specifically, infections in the spine can impair the ability of the spine to support the trunk, causing patients to be bedridden, which can also severely affect the physical condition of patients. Although treatments for osteoporosis have been well studied, treatments for bone loss secondary to infection remain to be elucidated because they have pathological manifestations that are similar to but distinct from those of osteoporosis. Recently, we encountered a patient with severely osteolytic pyogenic spondylodiscitis who was treated with romosozumab and exhibited enhanced bone formation. Romosozumab stimulated canonical Wnt/β-catenin signaling, causing robust bone formation and the inhibition of bone resorption, which exceeded the bone loss secondary to infection. Bone loss due to infections involves the suppression of osteoblastogenesis by osteoblast apoptosis, which is induced by the nuclear factor-κB and mitogen-activated protein kinase pathways, and osteoclastogenesis with the receptor activator of the nuclear factor-κB ligand-receptor combination and subsequent activation of the nuclear factor of activated T cells cytoplasmic 1 and c-Fos. In this study, we review and discuss the molecular mechanisms of bone loss secondary to infection and analyze the efficacy of the medications for osteoporosis, focusing on romosozumab, teriparatide, denosumab, and bisphosphonates, in treating this pathological condition.

Quantitative Segmentation Analysis of the Radiological Changes by Using ITK-SNAP: Risk Assessment of the Severity and Recurrence of Medication-related Osteonecrosis of the Jaw

Article

Full-text available

Mar 2021
Int J Med Sci

Background and purpose: Medication-related osteonecrosis of the jaw (MRONJ) severely impairs patients' quality of life and is remarkably refractory to treatment. There are lots of studies about identification of the radiographic features of MRONJ, yet reports about quantitative radiographic analysis for the risk assessment of the severity and recurrence of MRONJ are rarely heard. The aim of this study was to investigate the volumes of osteolytic lesions and radiodensity values of osteosclerotic lesions in MRONJ patients by using ITK-SNAP for severity prediction and prognosis evaluation. Materials and methods: Of 78 MRONJ patients (78 lesions) involved in this retrospective study, 53 were presented as osteolytic lesions and 25 were presented as osteosclerotic changes alone. Comprehensive CBCT images, demographics and clinical data of patients were investigated. The volumetric analysis and radiodensity measurement were performed by ITK-SNAP. SPSS 25.0 were used for statistical analysis. Results: The osteolytic lesion volumes in MRONJ patients receiving intravenous bisphosphonates (P=0.004) and patients without osteoporosis (P=0.027) were significantly large. No significant correlation between the volumes and bisphosphonates duration was found (P=0.094). The radiodensity values of osteosclerotic lesions was significantly correlated with bisphosphonates duration (P=0.040). The surrounding area of post-surgical lesions in MRONJ patients with recurrence showed significantly great radiodensity values (P=0.025). No significant correlation between the radiodensity values and the transformation from osteosclerotic lesions to osteolytic lesions was observed (P=0.507). Conclusion: MRONJ patients receiving intravenous bisphosphonates develop into large volumes of osteolytic lesions more easily. Long-term bisphosphonates duration is possibly related with higher bone density of osteosclerotic lesions, while higher density is not associated with the transformation from osteosclerotic lesions to osteolytic lesions. A rise of bone mineral density nearby post-surgical lesions is probably a predictor for MRONJ recurrence.

“MRONJ: Dentistry and Physician Events under Bisphosphonates, Denosumab and Antiangiogenic Drugs”

Article

Jan 2020

Associated characteristics and treatment outcomes of medication-related osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases

Article

Full-text available

Aug 2021
SUPPORT CARE CANCER

Purpose This study aimed to evaluate the association between clinical characteristics and development of medication-related osteonecrosis of the jaw (MRONJ) in patients who underwent dental examinations before the initiation of treatment with denosumab or zoledronic acid, which are bone-modifying agents (BMAs), for bone metastases. Additionally, the clinical outcomes of patients who developed MRONJ were evaluated along with the time to resolution of MRONJ. Methods The medical charts of patients with cancer who received denosumab or zoledronic acid for bone metastases between January 2012 and September 2016 were retrospectively reviewed. Patients were excluded if they did not undergo a dental examination at baseline. Results Among the 374 included patients, 34 (9.1%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the zoledronic acid (27/215 [12.6%] vs 7/159 [4.4%], P = 0.006) group. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment, older age, and tooth extraction before and after starting BMA treatments were significantly associated with developing MRONJ. The time to resolution of MRONJ was significantly shorter for patients who received denosumab (median 26.8 months) than for those who received zoledronic acid (median not reached; P = 0.024). Conclusion The results of this study suggest that treatment with denosumab, age > 65 years, and tooth extraction before and after starting BMA treatments are significantly associated with developing MRONJ in patients undergoing treatment for bone metastases. However, MRONJ caused by denosumab resolves faster than that caused by zoledronic acid.

Is Dental Implant Placement Compatible in Patients Treated with Bisphosphonates? A Literature Review

Article

Full-text available

Jul 2019

Cristina Meniz-García

Does inflammatory dental disease affect the development of medication-related osteonecrosis of the jaw in patients using high-dose bone-modifying agents?

Article

Full-text available

May 2021
CLIN ORAL INVEST

Objectives High-dose bone–modifying agents (BMAs), such as bisphosphonates and denosumab, are essential for the treatment of cancer patients with bone metastases. The incidence of medication-related osteonecrosis of the jaw (MRONJ) is increasing. Inflammatory dental diseases could lead to MRONJ, and hence, they should be managed appropriately. Tooth extractions are commonly advised to prevent dental inflammation; however, the accurate indications for tooth extractions before starting BMA therapy have not been established. Hence, we assessed teeth with inflammatory dental diseases to identify indicators for prophylactic extraction before starting BMA therapy. Materials and methods We included 745 teeth with inflammatory dental diseases of 212 cancer patients on high-dose BMA therapy. We assessed the relationship between inflammatory dental disease and risk of MRONJ development. Multivariate Cox regression analysis was used for statistical analysis. The cumulative occurrence rate of MRONJ was calculated using the Kaplan–Meier method. Results MRONJ occurred in 43 of 745 teeth. Teeth characteristics significantly correlated with MRONJ occurrence were mandible (p = 0.009), molar region (p = 0.005), radiopaque changes in bone surrounding the root on orthopantograms obtained at patients’ first visits (p < 0.001), and tooth extractions after starting BMA therapy (p < 0.001). Conclusions Radiopaque changes in bone surrounding the root are an important radiographic finding that indicates the need for prophylactic tooth extractions before starting BMA therapy. Clinical relevance Our results suggest that the prophylactic extraction of teeth with radiopaque changes in bone surrounding the root before starting BMA therapy could prevent the onset of MRONJ.

Therapeutic Dimensions of Bisphosphonates: A Clinical Update

Article

Full-text available

Oct 2020

Bisphosphonates (BPs) are a commonly used class of drugs for the treatment of bone disorders. An extensive review of BPs with their clinical efficacy and safety profile is unavailable. This study aimed to review the available literature on BPs, summarize their role in clinical therapy, and emphasize their safety profile. Authors reviewed the existing literature using the Google Scholar, PubMed, and Micromedex databases and analyzed the collected articles. BPs are the preferred medication for osteoporosis and other similar conditions owing to their efficient antiosteoclastic activity. Few of them are available in oral dosage forms; hence, they are patient‑friendly. The mechanism of action, common adverse effects and their clinical applications, precautions and warnings pertaining to the route of administration, and safety profiles have been discussed in this manuscript. The common adverse effects are majorly related to the gastrointestinal, cardiovascular, and endocrine system. Upon chronic usage, patients may experience serious problems like osteonecrosis of the jaw and atypical bone fractures. Although BPs are effective and safe, they may cause GI adverse effects and rare cases of osteonecrosis. Patient counseling could prove beneficial in early identification and prevention of the adverse effects associated with BPs.

Risk Factors of Bisphosphonate-Associated Osteonecrosis of the Jaws: Review of the Literature

Article

Full-text available

Jan 2018

Meri Hristamyan

Bisphosphonates (BP) are synthetic analogs of naturally occurring pyrophosphate compounds with high affinity to calcium crystals, which allows them to bind to bone hydroxyapatite and inhibit osteoclastmediated cross-resorption. In the clinical practice BP have been used for several decades for the treatment of multiple myeloma, bone metastases, osteoporosis, Paget disease and others. In recent years, reports of Bisphosphonate-associated osteonecrosis of the jaws (BAONJ) have increased. Epidemiological and clinical studies on this topic summarize discussions and controversies of different expert groups on various aspects of the problem, one of which are the risk factors of its occurrence. The risk factor are link to the BP and the specifics of the treatment with these drugs, to anatomical specifics of the dento-alveolar area, dental diseases and their related dental procedures and treatments, and other risk factors such as different medications, comorbidities, risky health behavior, genetics and more. This suggests that BAONJ is an extremely complex and multifactorial process requiring careful monitoring and individual approach to each patient. BAONJ is considered an irreversible condition, and therefore efforts should be directed to its prevention both before and after the onset of BP therapy. The level of knowledge of dental practitioners, and medical specialist in general, about the risk factors of BAONJ, is crucial for the prevention of this complication.

A Drug Holiday Reduces the Frequency and Severity of Medication-Related Osteonecrosis of the Jaw in a Minipig Model

Article

Full-text available

Jun 2020

Treatment of medication related osteonecrosis of the jaw (MRONJ) is challenging and no clear consensus has been achieved. This study investigated preventive measures recommended for tooth extractions under antiresorptive treatment and the role of discontinuation of antiresorptive therapy to avoid the onset of MRONJ in a minipig model. Thirty‐six Göttingen minipigs were divided into four groups. Group 1 (negative control): tooth extractions but no zoledronate. Group 2 (positive control): weekly zoledronate infusions for 12 weeks followed by tooth extractions without wound management followed by eight weeks of zoledronate treatment. Group 3: weekly zoledronate infusions for 12 weeks followed by tooth extractions. Surgical wound management (resection of sharp bone edges, mucoperiosteal coverage). Continuation of zoledronate infusions for 8 weeks plus antibiotic treatment. . Group 4: 12 weeks of zoledronate infusions followed by a drug holiday for 6 weeks. Tooth extrations with preventive wound management followed by antibiotic treatment for 8 weeks but no zoledronate infusions. Jawbones were subjected to macroscopic, radiological (CT and μCT) and histopathological investigations. No clinical cases of MRONJ were observed in the negative group, in the positive control all animals developed MRONJ. Group 3 developed MRONJ in 83% of cases. With a drug holiday, 40% developed MRONJ in areas of tooth extraction. This is the first large animal model that reduces the occurrence of MRONJ following tooth extraction by the implementation of a drug holiday combined with antibiotic prophylaxis and smoothening of sharp bony edges. This article is protected by copyright. All rights reserved.

Calcium Phosphate Ceramics Can Prevent Bisphosphonate-Related Osteonecrosis of the Jaw

Article

Full-text available

Apr 2020

Bisphosphonate-associated osteonecrosis of the jaw (BRONJ), a post-surgical non-healing wound condition, is one of the most common side effects in patients treated with nitrogen-containing bisphosphonates. Its physiopathology has been related with suppression of bone turnover, of soft tissue healing and infection. Biphasic calcium phosphates (BCP) are used as a drug delivery vehicle and as a bone substitute in surgical wounds. Due to their capacity to adsorb zoledronate, it was hypothesized these compounds might have a protective effect on the soft tissues in BRONJ wounds. To address this hypothesis, a reproducible in vivo model of BRONJ in Wistar rats was used. This model directly relates chronic bisphosphonate administration with the development of osteonecrosis of the jaw after tooth extraction. BCP granules were placed in the alveolus immediately after tooth extraction in the test group. The animals were evaluated through nuclear medicine, radiology, macroscopic observation, and histologic analysis. Encouragingly, calcium phosphate ceramics were able to limit zoledronate toxicity in vivo and to favor healing, which was evidenced by medical imaging (nuclear medicine and radiology), macroscopically, and through histology. The studied therapeutic option presented itself as a potential solution to prevent the development of maxillary osteonecrosis.

Mesenchymal stromal cells administration for osteonecrosis of the jaw caused by bisphosphonate: report of two cases

Article

Feb 2020

Cloud-Based Multicenter Data Collection and Epidemiologic Analysis of Bisphosphonate-Related Osteonecrosis of the Jaws in a Central European Population

Article

Full-text available

Feb 2020

Objective: Bisphosphonate-related osteonecrosis of the jaws is considered to be a rare but severe complication of bisphosphonate therapy. To understand this condition better, data collection is essential. Although the number of scientific papers about this subject is large, to date only a few multicenter reports have been published. Study design: We present a novel cloud-based data collection system for the evaluation of the risk factors of bisphosphonate-related osteonecrosis of the jaws. Web-based questionnaire and database have been set up and made available to voluntary researchers and clinicians in oral and maxillofacial surgery in Hungary and Slovakia. Results: To date, fifteen colleagues from eight maxillofacial units have joined the study. Data of 180 patients have been recorded. Collected data were statistically analysed and evaluated from an epidemiological point of view. Conclusions: Authors consider cloud-based multicenter data collection a useful tool that allows for real-time collaboration between users, facilitates fast data entry and analysis, and thus considerably contributes to widening our knowledge of bisphosphonate-related osteonecrosis of the jaws.

The effects of mechanically loaded osteocytes and inflammation on bone remodeling in a bisphosphonate-induced environment

Article

Jul 2019

Bisphosphonate-related osteonecrosis of the jaw is a disease appearing after tooth removal in patients undergoing bisphosphonate treatment for metastasizing cancers and osteoporosis. The complexity of the condition requires a multicellular model to address the net effects of two key risk factors: mechanical trauma (pathologic overload) and inflammation. In this work, a system comprised of a polydimethylsiloxane chip and mechanical loading device is used to expose bisphosphonate-treated osteocytes to mechanical trauma. Specifically, osteocytes are treated with the potent nitrogen-containing bisphosphonate, zoledronic acid, and exposed to short-term pathologic overload via substrate stretch. During bone remodeling, osteocyte apoptosis plays a role in attracting pre-osteoclasts to sites of damage; as such, lactate dehydrogenase activity, cell death and protein expression are evaluated as functions of load. Additionally, the effects of osteocyte soluble factors on osteoclast and osteoblast functional activity are quantified. Osteoclast activity and bone resorption are quantified in the presence and absence of inflammatory components, lipopolysaccharide and interferon gamma. Results suggest that inflammation associated with bacterial infection may hinder bone resorption by osteoclasts. In addition, osteocytes may respond to overload by altering expression of soluble signals that act on osteoblasts to attenuate bone formation. These findings give insight into the multicellular interactions implicated in bisphosphonate-related osteonecrosis of the jaw.

Treatment outcomes and prognostic factors of medication-related osteonecrosis of the jaw: a case- and literature-based review

Article

Full-text available

Aug 2019
CLIN ORAL INVEST

Objectives The purpose of this study was to investigate the treatment outcomes and prognostic factors of medication-related osteonecrosis of the jaw (MRONJ) in Japanese patients. Patients and methods Among 409 cases, treatment outcomes and prognostic factors were investigated in 275 patients. In statistical analyses, the 1-year cumulative curative rate was calculated with the Kaplan-Meier method, and significance was examined with the Wilcoxon test. Cox’s proportional hazards regression analysis was used for the multivariate analysis. Results Resolution of the disease was achieved in 137 out of 275 MRONJ patients (49.8%). One-year cumulative curative rates were 39.8% in stage 1 patients, 26.3% in stage 2, and 19.0% in stage 3. The 1-year cumulative curative rates of treatment interventions were 17.2% for conservative treatment, 34.5% for sequestrectomy, and 40.7% for extended surgery including bone resection and segmental resection. As the prognostic factors of treatment outcomes, the type of medication, stage of MRONJ, and type of surgical intervention were identified as independent factors in a multivariate analysis. Conclusion These results suggest that surgical interventions may lead to a good prognosis in MRONJ patients. Clinical relevance This study indicated that surgical intervention for MRONJ might lead to improvement of prognosis and quality of life in MRONJ patients.

Osteonecrosis of the Jaws

Chapter

Full-text available

Oct 2018

Bisphosphonate-related osteonecrosis of the jaw: A mechanobiology perspective

Article

Full-text available

Mar 2018

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a dramatic disintegration of the jaw that affects patients treated with bisphosphonates (BPs) for diseases characterized by bone loss. These diseases are often metastasizing cancers (like multiple myeloma, breast cancer and prostate cancer (Aragon-Ching et al., 2009)) as well as osteoporosis. BRONJ is incompletely understood, although it is believed to arise from a defect in bone remodeling—the intricate process by which sensory osteocytes signal to osteoclasts and osteoblasts to resorb and form bone in response to stimuli. Further, tooth extraction and infection have been overwhelmingly linked to BRONJ (Ikebe, 2013). Because bone cells are highly networked, the importance of multicellular interactions and mechanotransduction during the onset of these risk factors cannot be overstated. As such, this perspective addresses current research on the effects of BPs, mechanical load and inflammation on bone remodeling and on development of BRONJ. Our investigation has led us to conclude that improved in vitro systems capable of adequately recapitulating multicellular communication and incorporating effects of osteocyte mechanosensing on bone resorption and formation are needed to elucidate the mechanism(s) by which BRONJ ensues.

Acid-etching technique of non-decalcified bone samples for visualizing osteocyte-lacuno-canalicular network using scanning electron microscope

Article

Dec 2017

The aim of this study was to define the acid-etching technique for bone samples embedded in polymethyl metacrylate (PMMA) in order to visualize the osteocyte lacuno-canalicular network (LCN) for scanning electron microscopy (SEM). Human jaw bone tissue samples (N = 18) were collected from the study population consisting of patients having received dental implant surgery. After collection, the bone samples were fixed in 70% ethanol and non-decalcified samples embedded routinely into polymethyl metacrylate (PMMA). The PMMA embedded specimens were acid-etched in either 9 or 37% phosphoric acid (PA) and prepared for SEM for further analysis. PMMA embedded bone specimens acid-etched by 9% PA concentration accomplishes the most informative and favorable visualization of the LCN to be observed by SEM. Etching of PMMA embedded specimens is recommendable to start with 30 s or 40 s etching duration in order to find the proper etching duration for the samples examined. Visualizing osteocytes and LCN provides a tool to study bone structure that reflects changes in bone metabolism and diseases related to bone tissue. By proper etching protocol of non-decalcified and using scanning electron microscope it is possible to visualize the morphology of osteocytes and the network supporting vitality of bone tissue.

Further development of the MRONJ minipig large animal model

Article

Full-text available

Jul 2017
J CRANIO MAXILL SURG

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious and potentially severe side effect of antiresorptive therapy with bisphosphonates or denosumab. Recently, a large animal minipig MRONJ model was introduced which led to early necrotic lesions in the majority of extraction sites after bisphosphonate administration. The aim of this project was to modify the preoperative cumulative bisphosphonate dose (zoledronate) and hereby firstly to demonstrate the reliability and reproducibility of the established model. Secondly, the MRONJ lesions should be carefully investigated using clinical and μCT as well as detailed histological analyses. Twelve 1.5-year-old Göttingen minipigs were divided into three groups. In group 1 (n=3) minipigs received weekly doses of zoledronate intravenously (0.05 mg/kg body weight) for 20 weeks. No interventions were performed. In group 2 (n=6) animals received the identical zoledronate dosage as animals in group 1 and tooth extractions of two premolars (PM 2 and 4) in each jaw (maxilla and mandible) were performed after 12 weeks. Group 3 (n=3) served as tooth extraction only control (no zoledronate administrations). The jaw-bones were subjected to detailed macroscopic, radiological and histological investigations. All extraction sites (24/24) in animals of group 2 showed clinical, radiological and histological signs of MRONJ (mainly stage II), whereas no bone necrosis was found in group 3. Animals of group 1 and group 2 showed further MRONJ lesions in areas where infections (periodontitis) were present. This is the first large animal model to show a 100% incidence of MRONJ at all extraction sites in bisphosphonate pretreated animals (group 2). In addition, in this preclinical model for MRONJ it is shown that tooth extractions are not mandatory for a MRONJ manifestation. MRONJ also developed in areas of gingival or periodontal infections.

Maxillary osteonecrosis related to post-COVID-19: A report of case series and 6-month follow-up

Article

Jun 2024

Role of Actinomyces in the Progression of Medication-related Osteonecrosis of the Jaws in an Immunocompromised Mouse Model with Periapical Disease

Article

Feb 2024

Application of double-layer soft tissue suture closure technique in the surgical treatment of patients with mandible medication-related osteonecrosis of the jaw of early and medium stages

Article

Feb 2024

Are ministerial recommendations sufficient to avoid bisphosphonate related osteonecrosis of the jaw? A case report

Article

Full-text available

Jan 2023

A Massaria

Bisphosphonate related osteonecrosis of the jaw (BRONJ) can occur in patients affected by malignancy associated hypercalcemia, bone metastases of solid tumors or multiple myeloma intaking amino-bisphosphonates or other bone resorption inhibitors. BRONJ occurs initially with alveolar bone radiographic alterations, with peripheral facial neurological symptoms and thereafter with bone exposition and necrosis.Drug related ONJ were also reported in oncologic patients intaking angiogenesis inhibitors or monoclonal antibodies that inhibit bone resorption (e.g. Denosumab).In the present case report, Denosumab has been administered to treat bone lesions related to invasive ductal breast cancer.Before starting therapy with Denosumab, in order to restore oral and periodontal health, dental extractions were performed without any modifications to surgical protocols and waiting the complete healing of extraction sites (6 weeks).Even if ministerial recommendations were followed, even if we waited the biologic healing and even if denosumab therapy started without symptoms, BRONJ occurred in this patient.The mistake made in the management of the present case is that we did not carefully evaluated early radiological signs (alveolar crest thickening, bone sclerosis, persistent alveolar post-extraction socket, periodontal space widening, formation of bone sequestrum) that could bring the clinician to the diagnostic suspect of BRONJ before the onset of clinical signs (fistula, and bone exposure).Identifying early radiological signs could bring the clinician to an early diagnosis and consequently a better prognosis.

Komplikationen bei der Behandlung von medikamentenbedingter Osteonekrose des Kiefers (MRONJ)

Chapter

Sep 2023

Article

Sep 2022
GENESIS

Since the initial description of medication-related osteonecrosis of the jaw (MRONJ) almost two decades ago, the potential pathophysiology and risk factors have been elaborated on in many investigations and guidelines. However, the definitive pathophysiology based on scientific evidence remains lacking. Consequently, the optimal clinical treatment and prevention strategies for MRONJ have not been established. Despite their different mechanisms of action, many drugs, including bisphosphonates, denosumab, angiogenesis inhibitors, and other medications, have been reported to be associated with MRONJ lesions in cancer and osteoporosis patients. Importantly, MRONJ occurs predominantly in the jawbones and other craniofacial regions, but not in the appendicular skeleton. In this up-to-date review, the currently available information and theories regarding MRONJ are presented from both clinical and basic science perspectives. The definition and epidemiology of MRONJ, triggering medication, and histopathology are comprehensively summarized. The immunopathology and the potential pathophysiology based on immune cells such as neutrophils, T and B cells, macrophages, dendritic cells, and natural killer cells are also discussed. In addition, antiangiogenesis, soft tissue toxicity, necrotic bone, osteocyte death, and single-nucleotide polymorphisms are examined. Moreover, other possible mechanisms of MRONJ development are considered based on the unique embryological characteristics, different cell behaviors between jawbones and appendicular skeleton, unique anatomical structures, and sustained bacterial exposure in the oral cavity as a basis for MRONJ site specificity. Based on the literature review, it was concluded that multiple factors may contribute to the development of MRONJ, although which one is the key player triggering MRONJ in the craniofacial region remains unknown.

New and Innovative Treatment Strategies for Medication-Related Osteonecrosis of the Jaw

Book

Jan 2015

Prävalenz von medikamentenassoziierten Kiefernekrosen und deren Risikofaktoren bei Patienten mit Erkrankungen aus dem rheumatischen Formenkreis

Thesis

Jan 2022

Anne Streit

Einleitung: Das Ziel dieser Studie war die Einschätzung der Prävalenz der medikamentenassoziierten Kieferosteonekrose (MRONJ) in einem Kollektiv von Patienten mit Osteoporose und rheumatischer Grunderkrankung. Zudem wurden Risikofaktoren sowie präventive Maßnahmen betrachtet. Methoden: Insgesamt wurden 198 Patienten in der Rheumatologischen Ambulanz in Zusammenarbeit mit der Mund-Kiefer-Gesichtschirurgie (MKG) des Universitätsklinikums in Würzburg in einem Zeitraum von 14 Monaten rekrutiert. Es wurden Telefoninterviews mit allen Patienten geführt. Auffällige Patienten wurden in der MKG untersucht, zahnärztliche Unterlagen wurden angefordert und evaluiert. Zusätzlich erfolgte eine retrospektive Analyse der elektronischen Patientenakten. Ergebnisse: Die Prävalenz der MRONJ betrug in unserem Patientenkollektiv 1,5 % (n=3). Alle Patientinnen mit MRONJ bekamen das Bisphosponat (BP) oral, eine Patientin bekam es zusätzlich intravenös und eine weitere Patientin bekam zusätzlich Denosumab. Die Patientengruppe mit Kieferosteonekrose hatte im Vergleich zu den Patienten ohne Kieferosteonekrose innerhalb des Kollektivs eine statistisch signifikant höhere Gesamttherapiedauer der Osteoporose (p≤0,0001), einen niedrigeren durchschnittlichen FFbH (p=.031) und eine niedrigere Knochendichte (Femur) (p=.009). Nur 38,4 % der Patienten im Gesamtkollektiv fühlten sich über das Risiko einer MRONJ aufgeklärt. Nur 25,3 % der Patienten gaben an, zu Beginn der BP-Therapie bei einer zahnärztlichen Kontrolluntersuchung gewesen zu sein. Schlussfolgerung: Die Prävalenz von 1,5 % für diese dramatische unerwünschte Arztneimittelwirkung unterstreicht das hohe Risiko rheumatologisch erkrankter Patienten. Ein prospektives Register zur Erfassung von MRONJ bei diesem besonderen Risikokollektiv wäre empfehlenswert. Die Daten zur Prävention der MRONJ zeigen, dass die geforderten Maßnahmen zur Vermeidung einer MRONJ bisher nur unzureichend umgesetzt werden.

American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaw – 2022 Update

Article

Feb 2022
J ORAL MAXIL SURG

Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaws (MRONJ) – formerly referred to as bisphosphonate related osteonecrosis of the jaws (BRONJ) – were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007,¹ 2009² and 2014.³ The position papers were developed by a Committee appointed by the AAOMS Board of Trustees and comprised of clinicians with extensive experience in caring for these patients as well as clinical and basic science researchers. The knowledge base and experience in addressing MRONJ continues to evolve and expand, necessitating modifications and refinements to the previous position papers. Three members of the AAOMS Committee on Oral, Head and Neck Oncologic and Reconstructive Surgery (COHNORS) and three authors of the 2014 position paper were appointed to serve as a working group to analyze the current literature and revise the guidance as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis and management strategies and highlights current research status. AAOMS maintains that it is vitally important for this information be disseminated to other relevant healthcare professionals and organizations.

Embryologisch begründbares Expressionsverhalten von Connexin 43 im Rattenknochen unter Aminobisphosphonatexposition

Thesis

Jan 2022

Martin Schiller

Zusammenfassung Hintergrund und Ziele Die Bisphosphonat-assoziierte Kiefernekrose tritt mit steigender Prävalenz spontan oder als Nebenwirkung nach chirurgischen Eingriffen bei Patienten unter Bisphosphonattherapie auf. Klinisch imponiert sie als freiliegende, entzündlich veränderte, ossäre Läsion der Kieferknochen, welche keine Tendenz zur Selbstheilung zeigt. Paradoxerweise treten diese Läsionen ausschließlich in dem von der kranialen Neuralleiste abstammenden Kieferknochen auf, im extrakranialen Skelett zeigen sich keine derartigen Nekrosen. Das Gap Junction Protein Connexin 43 lässt sich in beiden Knochenarten nachweisen. Eine essentielle Notwendigkeit von Connexin 43 an dem durch Aminobisphosphonaten vermittelten anti-apoptotischen Effekt sowie zur Bildung interzellulärer Kommunikation wurde beschrieben. Daher soll ein möglicher Expressionsunterschied dieses Proteins zwischen Tibia- und Kieferknochen unter Aminobisphosphonateinfluss untersucht werden. Methoden Es wurden Gewebeproben von Wistar-Ratten zur Untersuchung des Expressionsverhaltens von Connexin 43 herangezogen. Neben einer unbehandelten Kontrollgruppe (Gruppe 1) wurden die Tiere mit einem Aminobisphosphonat behandelt (Gruppe 2). Um den Einfluss eines operativen Eingriffs zu simulieren, erfolgte bei Tieren in zwei weiteren Gruppen eine Zahnextraktion sowie die Erzeugung eines ossären Defekts am Tibiaknochen. Hierbei erfolgte der Eingriff einerseits ohne den Einfluss von Aminobisphosphonat (Gruppe 3), andererseits unter Aminobisphosphonat-Medikation (Gruppe 4). Die Entnahme der Proben erfolgte nach 12 und 16 Wochen zur jeweiligen Evaluierung des Expressionsverhaltens mittels immunhistochemischer Färbemethode und anschließender statistischer Auswertung anhand des Labeling Index. Ergebnisse Es zeigt sich eine Aminobisphosphonat-unabhängige, signifikant (p=0.01) höhere Expression von Connexin 43 innerhalb des Kiefers im Vergleich zur Tibia. Unter dem Einfluss von Aminobisphosphonat lässt sich in der 16. Woche eine signifikant (p<0.01) höhere Expression von Connexin 43 des Kiefers beobachten. Während der normalen Wundheilung, ohne Einfluss der Aminobisphosphonate, nach Defektsetzung bzw. Zahnextraktion lassen sich keine signifikanten Unterschiede zwischen Tibia und Kiefer beobachten. Unter zusätzlicher Gabe von Aminobisphosphonat zeigt sich innerhalb der 16. Woche eine signifikant (p<0.01) verminderte Expression von Connexin 43 im Kiefer, wohingegen es in der Tibia zu einer gesteigerten Expression kommt. Praktische Schlussfolgerung Die von Aminobisphosphonat unabhängig hohe Expression von Connexin 43 innerhalb des Kiefers im Vergleich zur Tibia lässt auf eine regionale, derivatspezifische Expressionsverteilung schließen. Die Tatsache, dass sich während der normalen Wundheilung bzw. Knochenregeneration keine Unterschiede im Expressionsverhalten von Connexin 43 innerhalb der Knochenstrukturen zeigen, sondern dass es erst unter zusätzlicher Medikation von Aminobisphosphonaten zu einem Abfall der Expression im Kiefer kommt, lässt lokal unterschiedliche Wirkmechanismen der Aminobisphosphonate vermuten.

Retrospective Evaluation of Pathologic Fractures in Medication Related Osteonecrosis of the Jaw

Article

Apr 2021
J CRANIO MAXILL SURG

Limited data are available concerning pathologic fractures related to medication-related osteonecrosis of the jaw (MRONJ), its incidence, and predisposing factors. The aim of this study was to focus on the MRONJ-related pathologic fractures, their incidence, and to analyze possible causative factors for their occurrence. A total of 116 MRONJ patients were included in this study, between 2012 and 2020. Pathologic fracture patients were identified, examined in detail, and the patient characteristics were evaluated. In 116 patients (73 female and 43 male; mean age 62.08 ± 13.6 years), pathologic fracture incidence was found to be 4.31%. Zoledronic acid was the most commonly used anti-resorptive drug (77.8%). Median antiresorptive usage was 24 months. Five patients had pathologic fractures in the mandible. Four fracture patients had metastatic prostate cancer, and one had metastatic renal cell cancer. This case series study can provide clinical insight into which factors are associated with pathologic fractures. Cancer type, medical comorbidities, additive toxicity of the combination of antiresorptive and antiangiogenic drugs, specific pathogens, and dento-alveolar surgical procedures may be some of the important factors that need to be considered. Since MRONJ-related pathologic fracture management can be complicated, it may be good to focus on the causative factors and prevent occurrence with regular follow-up as often as possible in line with these factors.

Complications Associated with Treatment of Medication-Related Osteonecrosis of the Jaws (MRONJ)

Chapter

Aug 2020

The aim of this chapter is to highlight the major complications associated with treatment of medication-related osteonecrosis of the jaw (MRONJ) and the reported measures that can minimize or control them based on the available literature. These complications include recurrence of MRONJ, pathological fractures, alteration of regional nerve function, and oroantral or oronasal communications that further affect quality of life in MRONJ patients. Identification of these potential treatment complications and utilizing the preventive recommendations are crucial to improve quality of life.

Analysis of the knowledge of the epidemiology and clinic of bisphosphonate-related osteonecrosis of the jaws

Article

Full-text available

Jan 2017

Bisphosphonate related osteonecrosis of the jaws (BRONJ) is a condition, first described in the 19th Century among workers in match factories as "Phossy Jaw", but officially reported in 2003. BRONJ is a side effect from the use of bisphosphonates (BP), a group of drugs that affect bone metabolism. The development of the condition is the cause of serious impairment and discomfort of part of the increasing number of patients treated with BР, especially by intravenous application. There are several dilemmas and controversies among different groups of experts on the definition, epidemiology and risk factors, mechanisms of development, classification, clinical manifestations and approaches to treatment and prevention. That’s why, in the literature,BRONJ is described as a complicated process requiring careful monitoring and individual approach to each patient. As the condition is considered to be irreversible, efforts should be directed primarily to its prevention, both before and after the onset of BP therapy. It is crucial to increase the awareness of dental practitioners, oncologists and patients and their willingness to work together as a team to minimize the risk of developing this complication.

Osteonecrose dos maxilares associada ao uso de bifosfonatos

Article

Full-text available

Apr 2020

Endogenous pyrophosphate is a substance responsible for inhibiting bone resorption in the body, but can not be used as a therapeutic agent in the treatment of diseases, as it rapidly undergoes enzymatic hydrolysis. Biphosphonates, the synthetic analogues of this substance, are potent inhibitors of osteoclastic activity and are chosen as the first treatment option for several diseases that relate to loss of bone mass such as osteoporosis, Paget's Disease, Skeletal Metastases and Multiple Myeloma. The first case of biphosphonate-related osteonecrosis of the jaw (BRONJ) was presented in 2003, and since then several studies have been carried out with the objective of understanding the mechanism that leads these compounds to induce a maxillary bone necrosis. Recently, new cases of BRONJ associated with another class of antiresorptive drugs, such as Desonumab, have been drawing attention. This paper aims to discuss, through a literature review, the knowledge about the action mechanism of these drugs and their relationship in the care of dental patients, seeking new updates that may help in the better understanding of their etiopathogeny. To do this study, a bibliographic survey was made regarding the occurrence of BRONJ, using Pubmed, Scielo, Google Scholar and Medline as search bases from 2001 to 2018. Through this study, it can be concluded that although several discoveries have been made since the appearance of the pathology until the present moment, a lot of research still has to be done to arrive at a adequate treatment protocol.

COMPARISION OF CLINICAL EFFICACY AND PATIENTS' ACCEPTANCE OF INTERDENTAL BRUSH AND SILICONE COATED INTERDENTAL PICK : A SPLIT MOUTH, PROSPECTIVE CLINICAL TRIAL

Conference Paper

Full-text available

Sep 2018

Purpose: The aim of this split-mouth, prospective controlled study is to compare the affects of two different interdental devices on clinical plaque elimination, gingival bleeding, and patient's acceptance and comfort. Materials and Methods: 30 participants who have been diagnosed as gingivitis,were included to study. After proffesional oral prophylaxis and 3 days wash out period, patients were advised to use two tested devices (TePe's interdental brushes Original and Tepe EasyPickTM ) according to instructions. Interdental brush (IDB) was recommended for first and forth quadrant of dentition, otherwise silicone coated interdental pick (SCIP) was recommended for the second and third quadrant. The plaque index (Turesky-Modified Quigley & Hein Index)and bleeding index (Papillary Bleeding Index) were recorded at baseline and after two weeks. Patients' satisfaction and comfortability were assesed by a questionnaire. Results:Both of the tested devices improved the plaque and bleeding index scores. There was no differences between two sides in terms of time dependent changes. The patients felt more satisfied with the cleansing capacity and more comfortable during usage of Silicone coated interdental pick than Interdental brush (p = 0.001). The feeling pain in the use of Silicone coated interdental pick was significantly lower than during usage of Interdental brush (p = 0.002). Conclusion: Clinical efficiency of the tested interdental devices were similar in terms of plaque removal and decreasing bleeding. Also silicon coated interdental pick found to be more comfortable and preferable than interdental brushes .

Bifosfonatlar ve çene kemiğinde görülen osteonekroz

Article

Full-text available

Aug 2015

The impact of surgical intervention and antibiotics on MRONJ stage II and III - Retrospective study

Article

Jun 2017
J CRANIO MAXILL SURG

Objectives: Metastatic bone disease and osteoporosis are the main indications for bisphosphonates and anti-resorptive agent therapy. Inhibition of bone turnover and angiogenesis are mainly responsible for the development of Medication Related Osteonecrosis of Jaws (MRONJ) as therapeutic side-effect. Yet, the role of infection for the development and recurrence of MRONJ is not fully elucidated. The aim of this retrospective study is to explore if a difference in antibiotic regimes has an impact on the surgical intervention needed to achieve a painless stable stage of the disease. Furthermore, we investigated concomitant submucosal infections in local relation to the MRONJ site. Methods: A retrospective study (2006-2015) of 143 patients treated with MRONJ stage II and stage III in a single institutional university hospital was performed. All patients experienced at least one surgical intervention and received antibiotics. Their medical records, pathological and microbial findings were reviewed. Data was controlled for the achievement of an event free time period of at least 12 months. Results: We investigated the number and kind of treatments that were performed on patients with MRONJ stage II and III to achieve a painless stable stage of the disease. The first and second healing approach differed significantly from each other (p < 0.05). In 7 (4.9%) cases up to four surgical interventions were needed to achieve oral rehabilitation. In 135 (95.1%) of all cases a segmental resection could be prevented, with extended decortication being the most applied method. Patients under perioperative ampicillin/sulbactam showed a significant reduction for a second or fourth intervention compared to the clindamycin group (p < 0.05). Results for a third intervention presented a similar difference between both groups, but were not significant (p = 0.06). Intraoperatively in 76 out of 241 (31.5%) cases presented putrid submucosal infections. The isolated bacteria were gram-negative facultative anaerobes (39.1%) and strictly anaerobic bacteria (gram-positive/38.2%, gram-negative/19.1%). Susceptibly of the cultured bacteria were significantly (p < 0.05) in favor to ampicillin/sulbactam (79.1%) compared to clindamycin (49.5%). Conclusion: The perioperative antibiotic regime for patients with MRONJ stage II and III undergoing surgically treatment does have an influence on the recurrence of the disease. Further investigation is needed to elucidate the role of infection in the treatment of MRONJ.

Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy

Article

Full-text available

Jun 2006

8528 There have been reports of osteonecrosis of the jaw (ONJ) in patients (pts) with metastatic bone disease (MBD) treated with IV bisphosphonates (IVBP). To estimate the frequency and identify risk factors for ONJ we performed a retrospective analysis of pts treated with IVBP. The cohort included 4019 patients identified through the MDACC pharmacy database (PD) treated with IVBP from 9/1996 to 2/2004, and 6 patients diagnosed with ONJ at the MDACC Dental Clinic. ONJ was defined as exposed non-healing bone of at least 3 months duration. Preliminary statistical analysis included 4000 patients. The most common diagnoses were breast cancer [BRCA] (1340), MM (550) and lung cancer (380).The indications for IVBP therapy included MBD (60%), hypercalcemia (25%), MM (14%) and osteoporosis (7%). We identified 34 patients with ONJ: 18 BRCA, 14 MM, 1 prostate cancer and 1 thyroid cancer. The frequency of ONJ was calculated by including patients from the PD only: 16/1338 (1.2 %) in BRCA and 14/448 (3.1%) in MM. Patients with ONJ received pamidronate [P] (6), zoledronate [Z] (10), combination of P and Z (15). The mean cumulative dose (MCD) of P was 2182 mg (720–4410) in MM and 2745mg (1980–3510) in BRCA. MCD of Z was 61 mg (24–152) in MM and 62 mg (28–110) in BRCA. The total doses of P and Z were significantly higher in the ONJ group VS NON-ONJ group (P<0.0001). Pts with ONJ had longer duration of disease and longer follow-up than NON-ONJ cases (P<0.0001). Univariate and multivariate logistic regression analyses (MLRA) revealed dental extractions (DE), ER positive tumors, and treatments with P and Z as significant factors associated with ONJ in BRCA pts. In MM, DE, periodontal disease and osteoporosis were significant factors. Further statistical analysis, including Cox regression analysis, is under way. ONJ pts were treated with aggressive oral hygiene, oral rinses, debridement of necrotic bone and antibiotics. 15 pts were followed at the dental clinic longer than 6 months. ONJ healed in 1, improved in 1, stable in 4 and progressed in 9 pts. In conclusion, ONJ is a significant but uncommon event. Higher doses of IVBP, longer treatment duration, DE, and periodontal disease are associated with a greater risk to develop ONJ. Good dental care and avoidance of dental interventions should be recommended to all patients treated with IVBP. [Table: see text]

Bisphosphonates and avascular necrosis of the jaw: A possible association

Article

Full-text available

May 2005

• Five patients presented to the Royal Adelaide Hospital, South Australia, in 2003 with painful exposed bone in the maxilla, or both the maxilla and mandible. • All had been receiving potent second- or third-generation bisphosphonate therapy - monthly intravenous pamidronate in four cases and daily oral alendronate in the other. • These cases are among the earliest reported occurrences of this condition in association with bisphosphonate therapy in Australia. • The condition presented after tooth extraction in four cases and denture pressure in the other. • Osteonecrosis continued for more than a year in three patients despite treatment.

Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats

Article

Full-text available

Dec 2002

Bisphosphonates (BPs) are used currently in the treatment of patients with bone metastases because these compounds inhibit bone resorption. We examined here the effects of BPs on inhibition of endothelial cell functions in vitro and in vivo. Treatment of endothelial cells with BPs (clodronate, risedronate, ibandronate, and zoledronic acid) reduced proliferation, induced apoptosis, and decreased capillary-like tube formation in vitro. Quantification of blood vessels in bone biopsy specimens from patients with Paget's disease before and after clodronate treatment showed a 40% reduction of the vascularization after BP treatment. However, such a decreased vascularity could be secondary to a reduction of bone resorption. Therefore, the tissue distribution of [14C]BPs in male rats was examined to develop an angiogenesis model in a noncalcified tissue where BPs could accumulate. [14C]BPs (zoledronic acid, ibandronate, and clodronate) not only accumulated in bone but also transiently accumulated in the prostate. The effects of BPs on testosterone-induced revascularization of the prostate gland in castrated rats were then studied. Testosterone in combination with ibandronate or zoledronic acid induced a 17-35% reduction of the prostate weight compared with castrated rats treated with testosterone alone. Blood vessel immunostaining on prostate tissue sections revealed that both ibandronate and zoledronic acid induced a 50% reduction of the revascularization of the prostate gland. Moreover, zoledronic acid did not alter testosterone-induced activity of a luciferase gene reporter construct transfected in androgen-dependent prostatic cells, indicating that this BP did not directly interfere with testosterone. In conclusion, BPs have in vivo antiangiogenic properties, which could be of relevance to improve therapy and prevention of bone metastasis. In addition, our results extend the potential clinical use of BPs to patients with early prostate cancer.

Osteonecrosis of the Jaw and Bisphosphonates

Article

Full-text available

Aug 2005
NEW ENGL J MED

Bisphosphonate Therapy Improves the Outcome of Conventional Periodontal Treatment: Results of a 12-Month, Randomized, Placebo-Controlled Study

Article

Full-text available

Aug 2005

Bone loss in periodontitis results from inflammatory reactions that stimulate osteoclastic bone resorption. Bisphosphonates inhibit bone resorption and increase bone mass. This study evaluated the effect of bisphosphonate therapy as an adjunct to non-surgical periodontal treatment in patients with moderate to severe chronic periodontitis. Patients were randomized (2:1) to one of two bisphosphonate therapies or placebo for 1 year. All patients received non-surgical periodontal treatment (scaling, root planing) and periodontal maintenance therapy every 3 months. Clinical assessments at baseline and 6 and 12 months included clinical attachment level (CAL), probing depth (PD), and bleeding on probing (BOP). Periodontal bone mass was assessed by dental radiographs at baseline and 12 months using fractal analysis and digital subtraction radiography (DSR). Seventy patients were randomized, 43 to the bisphosphonate group and 27 to the placebo group. Bisphosphonate therapy significantly improved CAL, PD, and BOP relative to the placebo group during the 6- to 12-month period (CAL, P = 0.0002; PD, P = 0.0156; BOP, P = 0.0079). There was no difference in the change in periodontal bone mass between the bisphosphonate and placebo groups as measured by fractal analysis and DSR. These data suggest that bisphosphonate treatment improves the clinical outcome of non-surgical periodontal therapy and may be an appropriate adjunctive treatment to preserve periodontal bone mass.

Oral Avascular bone necrosis associated with chemotherapy and bisphosphonate therapy

Article

Jan 2005
ORAL DIS

Osteonecrosis of the maxilla and mandible in patients treated with bisphosphonates: A retrospective study

Article

Jul 2004

8088 Background: Bisphosphonates (BP) inhibit osteoclast activity and decrease the risk of skeletal complications. Hence, intravenous BPs have been incorporated into the therapy of patients (pts) with osseous metastases of various tumor types. Anecdotal reports of osteonecrosis (ON) in the maxilla and mandible have raised concerns regarding BP toxicity. To further explore this potential drug complication, we preformed a retrospective chart review of pts with multiple myeloma and metastatic breast cancer who were receiving intravenous BP therapy. Methods: The medical and dental records of all pts with multiple myeloma or breast cancer who were treated in the Dental Service of Memorial Sloan-Kettering Cancer Center between 1/1/00 and 12/10/03 were reviewed. Pts who presented with exposed bone or ON of the maxilla or mandible and were previously treated with BP were further evaluated for various clinical and pathological characteristics. Results: 124 pts were identified within the time frame and disease type...

Osteonecrosis of the maxilla and mandible in patients treated with bisphosphonates: A retrospective study

Article

Jul 2004

Ten cases of osteonecrosis of the jaws following a treatment by diphosphonate within the framework of bone metastasis of breast cancer and multiple myeloma: Experience in summer 2004 of a single center

Article

Jun 2005

Mineralstoffpräparate und Osteoporosemittel

Chapter

Jan 2007

Hauptvertreter der Mineralstoffpräparate sind Calcium-, Kalium- und Magnesiumpräparate. Kaliumpräparate dienen der Korrektur eines höhergradigen Kaliummangels. Magnesiumpräparate sind bei Magnesiummangelzuständen indiziert, die aber bei der weiten Verbreitung von Magnesium in der Nahrung bei üblicher Kost selten sind.

Mineralstoffpräparate und Osteoporosemittel

Chapter

Jan 2003

The value of elementary phosphorus in rickets an experimental study

Article

Humble dignity: Tracing the lifeway of Kathryn Harrison

Article

Jan 2005

Kristine Olson

Case report. Bisphosphonate-associated osteonecrosis of the jaws - A review of current knowledge

Article

Dec 2005
J AM DENT ASSOC

Background: Increasing numbers of dental patients are taking bisphosphonate medications for a variety of indications. These drugs may be associated with poor healing, spontaneous intraoral ulceration and bone necrosis in the oral and maxillofacial region. Case description: The authors describe a case of osteonecroSis of the jaws in a patient receiving long-term bisphosphonate therapy for cancer. They offer recommendations for management and prevention of oral complications. Conclusion and clinical implications: It is important that clinicians are aware of the association between bisphosphonate treatment and delayed wound healing and osteonecrosis of the jaws. They should consider referring patients in this population to specialists for even the most routine oral surgery. Clinicians should perform a thorough oral examination in patients before they begin any chemotherapy regimen.

Placebo-controlled multicenter study of oral alendronate in postmenopausal osteoporotic women

Article

Nov 1998

Objectives: To evaluate effects on bone mineral density (BMD), safety, and tolerability of a single daily dose of alendronate (10 mg), administered for 1 year to postmenopausal women with osteoporosis. Methods: This interim analysis includes the first approximately 20% of patients to complete treatment in a large, placebo-controlled study (the Fosamax™1 International Trial (Fosit)), which enrolled 1908 patients from 34 countries. Patients≤85-years-old with osteoporosis (lumbar spinal BMD≥2 S.D. below mean for mature premenopausal Caucasian women) were randomly assigned to treatment with alendronate or placebo once daily in the morning; all patients received supplemental calcium (500 mg/day). Dual-Energy X-ray Absorptiometry (DXA) was used to measure BMD in spine and proximal femur. Results: A total of 297 patients had BMD data available for analysis. Patients treated with alendronate showed progressive increase of BMD during treatment. At 12 months, mean BMD had increased significantly (P<0.001) at the lumbar spine (5.6%), trochanter (3.6%), and femoral neck (2.6%) in the alendronate group. Increases in BMD were significantly (P<0.001) greater than in the placebo group at all sites. Among 442 patients assessed for safety, there were no statistically or clinically significant differences between treatment groups in the incidence of adverse events, including upper gastrointestinal adverse events, or laboratory abnormalities. Conclusions: Results of this multinational study show that oral alendronate, administered as 10 mg once daily for 1 year, is generally well tolerated and produces significant, progressive increases in BMD at the lumbar spine and proximal femur of postmenopausal women with osteoporosis.

Phosphorus Necrosis of the Jaw: A Present-day Study: With Clinical and Biochemical Studies

Article

Apr 1962

A historical note on the aetiology of phossy jaw shows that present-day knowledge is little greater than it was a century ago. The varied clinical course of the disease is described together with a report of 10 classical cases not previously reported. Six cases, not amounting to true necrosis but in which healing after dental extraction was delayed, and described, and mention is made of the noticeable differences in the oral state and appearances of tartar of healthy workmen exposed to phosphorus compared with healthy workmen not exposed. But no systematic differences of any kind were found in the incidence of general infections, fractures of bones, haematological findings, and biochemical studies of blood and urine in two groups of healthy men most exposed and least exposed to phosphorous in the same factory. An intensive study in hospital of a case of classical necrosis showed no departure from normal, except delayed healing following bone biopsy from the iliac crest, and a reversed polymorphonuclear/lymphocyte ratio. In the discussion the time of onset of necrosis after first exposure to phosphorus, clinical and radiological diagnosis, the organisms present, personal susceptibility, the appearance of the sequestra, and regeneration of bone are considered. An up-to-date note on prevention of the disease is given, although this has met with only partial success. Some persons are highly susceptible and, whilst complete protection is impossible in the light of our present knowledge, early diagnosis and modern treatment have robbed the disease of its terrible manifestations of Victorian times and turned it into a minor, although often uncomfortable complaint, with little or no resulting disability.

Der Einfluss des Phosphors auf den Organismus

Article

Georg Wegner

Kieferknochennekrosen als mögliche unerwünschte Wirkung von Bisphosphonaten

Article

Jul 2005

Background Bisphosphonates are widely used in the treatment of cancer patients with hypercalcemia and bone metastases or in osteoporosis therapy. Current reports have focused on therapy-resistant osteonecrosis of the jaws as a possible side effect of bisphosphonates. Official German drug committees have recently warned about the possibility of these side effects in the publication organs Deutsches Ärzteblatt and Deutsche Apotheker Zeitung. Case reports So far we have had experience with seven patients showing therapy-resistant osteonecrosis of the mandible under bisphosphonate medication. The presentation of these cases is intended to call attention to this clinically important side effect of bisphosphonate medication.

Bisphosphonate und Osteonekrosen im Kieferbereich

Article

Jul 2005

Background Since 2003, reports have been published on necrosis of the jaw bones possibly being associated with the administration of bisphosphonates. Bisphosphonates are highly active inhibitors of osteoclasts which have been used prophylactically or symptomatically in the treatment of plasmocytoma, bone metastasis of malignant disease, tumor-associated hypercalcaemia and in the treatment of osteoporosis. Due to the importance of this side effect of bisphosphonates, we report six cases. Case reports Six patients (two women and four men) with a median age of 69 years (range 55–37) were diagnosed with osteonecrosis of the maxilla and/or mandible. These osteonecroses did not react adequately to local treatment and systemic therapy with antibiotics. Four patients suffered from plasmocytoma and two patients had a history of metastasising breast cancer. Besides cytostatic chemotherapies, all patients received bisphosphonates over an extended period. Discussion Bisphosphonates are considered an important standard in the treatment of plasmocytoma and bone metastasis due to malignancies. Since 2003, several reports have been published describing patients in whom therapy resistant osteonecrosis of jaw bones occurred either after dental extractions or spontaneously. Until then, unknown side effects of bisphosphonate therapy had been suspected. Since patients with malignant diseases receive cytostatic therapy and a range of other drugs, including bisphosphonates, enhancement of the side effects may be presumed. Conclusions The probable association of the therapeutic use of bisphosphonates and the occurence of jaw bone necrosis has to be studied in further investigations. Patients receiving bisphosphonates should be followed-up regularly to avoid the occurrence of extended osteonecrotic lesions, which should be diagnosed early and treated adequately.

Guidelines for the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Article

Jan 2007

Salvatore L Ruggiero

Bisphosphonates are a class of agents used to treat osteoporosis and malignant bone metastases. Despite these benefits, osteonecrosis of the jaws has recently emerged as a significant complication in a subset of patients receiving these drugs. Based on a growing number of case reports and institutional reviews, bisphosphonate therapy may cause exposed and necrotic bone that is isolated to the jaw. This complication usually presents following simple dentoalveolar surgery and can cause a significant adverse effect on the quality of life for most patients. The pathogenesis for this complication appears to be related to the profound inhibition of osteoclast function and bone remodeling. This report will review the clinical signs and symptoms and risks associated with this new complication and provide a guideline for establishing a stage-specific diagnosis of BRONJ.

Oral complications in patients receiving treatment for malignancies other than the head and neck

Article

Oct 1978
J AM DENT ASSOC

Oral complications in patients being treated for malignancies that were not in the head and neck were studied. Age, type of therapy, and type of malignancy were factors related to the prevalence of oral complications. Mucosal ulcerations, xerostomia, and bacterial and fungal infections were the most frequently encountered oral problems. The frequency of oral complications in these patients indicates the need for an awareness and involvement of dental practitioners in their management.

Pathogenesis of abnormal remodeling of bones: Effects of yellow phosphorus in the growing rat

Article

Sep 1973

Histologic examination of metaphyseal bone of rats intoxicated with elemental phosphorus showed that inhibition of osteocytic osteolysis and chondrolysis account for widening of trabeculae and retention of the chondroid core. These changes are reflected in increased radiographic density and abnormal remodeling.

Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease

Article

May 1984

Transiliac bone biopsies carried out on 13 patients with Paget's disease to evaluate the effects of low-dose diphosphonate (disodium etidronate) therapy showed focal osteomalacia in the 9 patients in whom post-therapy specimens were taken through pagetic bone. Active bone resorption persisted in 5 of these. A mineralisation defect not amounting to osteomalacia--ie, osteoid of increased thickness but of normal extent--was present in the 4 specimens taken through non-pagetic bone. Although 9 patients experienced symptomatic improvement, 2 suffered fissure fractures in affected lower limbs. In Paget's disease, the combination of osteomalacia and continuing active resorption within a lytic lesion may increase the risk of fracture in a weight-bearing bone. It is suggested that although disodium etidronate often provides effective pain relief it should be administered with caution until the optimum dose and duration of therapy are further evaluated.

Osteonecrosis of the jaws: A complication of cancer chemotherapy

Article

Apr 1982

Harry C Schwartz

Two unusual cases of osteonecrosis of the jaws in edentulous patients are described. One case involved the maxilla and the other the mandible. Both patients were compromised hosts who were undergoing cancer chemotherapy. Both developed local mucosal infections beneath their dentures before the bone became involved. The role of dentures in producing local irritation and in masking the problem is discussed.

Lingual mandibular sequestration and ulceration

Article

Jul 1993
Oral Surg Oral Med Oral Pathol

This study analyzed 11 patients who had small sequestra associated with ulceration of the lingual mucosa in the posterior mandibular molar area at the level of the mylohyoid ridge. The patients were adults (mean age, 45.3 years) with complaints of sensitive, occasionally painful lesions that appeared for periods that ranged from 1 week to several months. No abnormalities were evident on periapical radiographs; however, in three cases in which occlusal radiographs were available, small irregular radiopacities contiguous with the cortex were noted. Spontaneous exfoliation or surgical removal of the sequestrum resulted in resolution of the lesion. The possible etiologic factors associated with this apparent clinical-pathologic entity are discussed.

Adverse Effects of Bisphosphonates: A Comparative Review

Article

Mar 1996

The bisphosphonates comprise a new class of drugs, and are increasingly being used to treat bone diseases characterised by increased osteoclastic bone resorption. These compounds are generally well tolerated, but toxicity may vary considerably from one compound to another. Dosages of etidronic acid above 800 mg/day impair the normal skeletal mineralisation and this may be associated with the appearance of fractures, but at the doses used for the treatment of osteoporosis, none of the bisphosphonates induce clinical or histological signs of impaired mineralisation. The skeletal half-life of bisphosphonates is of the order of several years, but this appears to be of little clinical consequence since the pharmacological effect is of relatively short duration. The mechanical properties of the skeleton of animals treated over long periods with high doses of various bisphosphonates have been shown to be perfectly preserved. However, in growing individuals, excess inhibition of bone remodelling might induce osteopetrotic-like alterations. When high doses of amino-bisphosphonates are given to patients who have never received bisphosphonate therapy, the patients may experience fevers up to 39°C for 1 to 3 days, associated with transient haematological changes resembling a typical acute-phase response. Rapid intravenous injection of bisphosphonates at doses greater than 200 to 300mg may cause severe renal failure; this can be prevented by slowing the rate of infusion ( The gastrointestinal absorption of bisphosphonates is low, and they must be taken without food. Oral amino derivatives may induce dose-related serious gastrointestinal lesions, with the sporadic appearance of erosive oesophagitis. Amino-bisphosphonate administration has been also associated with the sporadic occurrence of uveitis, scleritis and phlebitis and, in single cases, with irritative reactions at the skin, peritoneum and pericardium.

Placebo-controlled multicenter study of oral alendronate in postmenopausal osteoporotic women. FOSIT-Study-Group. Fosamax International Trial

Article

Dec 1998
MATURITAS

To evaluate effects on bone mineral density (BMD), safety, and tolerability of a single daily dose of alendronate (10 mg), administered for 1 year to postmenopausal women with osteoporosis. This interim analysis includes the first approximately 20% of patients to complete treatment in a large, placebo-controlled study (the Fosamax International Trial (Fosit)), which enrolled 1908 patients from 34 countries. Patients < or = 85-year-old with osteoporosis (lumbar spinal BMD > or = 2 S.D. below mean for mature premenopausal Caucasian women) were randomly assigned to treatment with alendronate or placebo once daily in the morning; all patients received supplemental calcium (500 mg/day). Dual-Energy X-ray Absorptiometry (DXA) was used to measure BMD in spine and proximal femur. A total of 297 patients had BMD data available for analysis. Patients treated with alendronate showed progressive increase of BMD during treatment. At 12 months, mean BMD had increased significantly (P < 0.001) at the lumbar spine (5.6%), trochanter (3.6%), and femoral neck (2.6%) in the alendronate group. Increases in BMD were significantly (P < 0.001) greater than in the placebo group at all sites. Among 442 patients assessed for safety, there were no statistically or clinically significant differences between treatment groups in the incidence of adverse events, including upper gastrointestinal adverse events, or laboratory abnormalities. Results of this multinational study show that oral alendronate, administered as 10 mg once daily for 1 year, is generally well tolerated and produces significant, progressive increases in BMD at the lumbar spine and proximal femur of postmenopausal women with osteoporosis.

Article

Dec 2000

Alendronate is widely used in the treatment of osteoporosis and other bone diseases. Although it is considered a well-tolerated drug, there are numerous reports of adverse effects on the mucosa in the upper aerodigestive tract, with oesophagitis as the most common complication. The strict regulations for the proper administration of the drug indicate that these side effects might well be the result of a direct, irritant mechanism on the upper aerodigestive tract. We present two clinical cases of patients who developed extensive palatal ulcers as a result of taking alendronate. We discuss possible mechanisms implicated in the production of the ulcers and some clinical factors of interest.

Bisphosphonate-Induced Osteopetrosis

Article

Aug 2003
NEW ENGL J MED

Bisphosphonates are increasingly used in conditions such as osteogenesis imperfecta and juvenile osteoporosis. Their potential adverse effects in growing children have been a concern, however, since bisphosphonates inhibit skeletal resorption by suppressing the activity and function of osteoclasts. The authors describe a case of drug-induced osteopetrosis in a 12-year-old boy who had received high doses of pamidronate for nearly three years.

Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic [1]

Article

Oct 2003
J ORAL MAXIL SURG

Robert E Marx

Osteonecrosis of the jaws associated with cancer therapy

Article

Oct 2003
J ORAL MAXIL SURG

Phosphorus Necrosis of the Jaw: A Present-day Study

Article

May 1962
Br J Ind Med

A historical note on the aetiology of phossy jaw shows that present-day knowledge is little greater than it was a century ago. The varied clinical course of the disease is described together with a report of 10 classical cases not previously reported. Six cases, not amounting to true necrosis but in which healing after dental extraction was delayed, and described, and mention is made of the noticeable differences in the oral state and appearances of tartar of healthy workmen exposed to phosphorus compared with healthy workmen not exposed. But no systematic differences of any kind were found in the incidence of general infections, fractures of bones, haematological findings, and biochemical studies of blood and urine in two groups of healthy men most exposed and least exposed to phosphorous in the same factory. An intensive study in hospital of a case of classical necrosis showed no departure from normal, except delayed healing following bone biopsy from the iliac crest, and a reversed polymorphonuclear/lymphocyte ratio.In the discussion the time of onset of necrosis after first exposure to phosphorus, clinical and radiological diagnosis, the organisms present, personal susceptibility, the appearance of the sequestra, and regeneration of bone are considered. An up-to-date note on prevention of the disease is given, although this has met with only partial success. Some persons are highly susceptible and, whilst complete protection is impossible in the light of our present knowledge, early diagnosis and modern treatment have robbed the disease of its terrible manifestations of Victorian times and turned it into a minor, although often uncomfortable complaint, with little or no resulting disability.

Avascular necrosis of the jaws: Risk factors in metastatic cancer patients [3]

Article

Nov 2003
J ORAL MAXIL SURG

Role of Apoptosis in Glucocorticoid-Induced Osteoporosis and Osteonecrosis

Article

Feb 2003
CRIT REV EUKAR GENE

Bone disease is a side effect of concern regarding chronic glucocorticoid (GC) administration. Most GC-treated patients exhibit a process of bone loss, frequently leading to osteoporosis, with increased fracture risk, especially in spinal vertebrae. Some GC-treated patients will develop osteonecrosis, a disease with distinct clinical and histopathological features, most often occurring underneath the articular surface of the femoral head. Remarkably, both of these GC-induced bone diseases are associated with osteoblast and osteocyte apoptosis, which is emerging as a potential primary pathogenic mechanism. Here, we review the evidence for osteoblast and osteocyte apoptosis in GC-induced bone disease and highlight current debates: (1) With recent reports describing the antiapoptotic effect of GCs in some in vitro osteoblast models, and with the known adverse effects of GCs on osteoblast cell cycle and differentiation, could the in vivo osteoblast apoptosis be an indirect rather than a direct effect of GCs? (2) What is the pathogenic relationship between GC-induced osteoporosis and osteonecrosis? Could the latter be a mere manifestation of the former? and (3) How does apoptosis fit into the traditional concept of ischemia as a key etiology in osteonecrosis? Regardless of the answers, recent studies with cells, animals, and humans point out bone cell apoptosis as a potential target in the design of treatment for GC-induced bone disease.

Osteonecrosis of the Jaws Associated with the Use of Bisphosphonates: A Review of 63 Cases

Article

Jun 2004
J ORAL MAXIL SURG

Bisphosphonates are widely used in the management of metastatic disease to the bone and in the treatment of osteoporosis. We were struck in the past 3 years with a cluster of patients with necrotic lesions in the jaw who shared 1 common clinical feature, that they had all received chronic bisphosphonate therapy. The necrosis that was detected was otherwise typical of osteoradionecrosis, an entity that we rarely encountered at our center, with less than 2 patients presenting with a similar manifestation per year. We performed a retrospective chart review of patients who presented to our Oral Surgery service between February 2001 and November 2003 with the diagnosis of refractory osteomyelitis and a history of chronic bisphosphonate therapy. Sixty-three patients have been identified with such a diagnosis. Fifty-six patients had received intravenous bisphosphonates for at least 1 year and 7 patients were on chronic oral bisphosphonate therapy. The typical presenting lesions were either a nonhealing extraction socket or an exposed jawbone; both were refractory to conservative debridement and antibiotic therapy. Biopsy of these lesions showed no evidence of metastatic disease. The majority of these patients required surgical procedures to remove the involved bone. In view of the current trend of increasing and widespread use of chronic bisphosphonate therapy, our observation of an associated risk of osteonecrosis of the jaw should alert practitioners to monitor for this previously unrecognized potential complication. An early diagnosis might prevent or reduce the morbidity resulting from advanced destructive lesions of the jaw bone.

Suppressed Bone Turnover by Long-Term Bisphosphonate Treatment Accumulates Microdamage but Maintains Intrinsic Material Properties in Cortical Bone of Dog Rib

Article

Jul 2004

Effects of long-term suppression of bone remodeling by bisphosphonate were investigated in cortical bone of dog rib. Although microdamage was accumulated, BMD was increased without increasing cortical bone area. Consequently, the intrinsic material properties were not reduced. Recently, we have reported that long-term suppression of bone remodeling increases microdamage accumulation but is not necessarily associated with vertebral fragility because of compensated increase of bone mass and improved microarchitecture. This study aimed to investigate the effect of long-term suppression of bone remodeling by bisphosphonate on the degree of mineralization, accumulation of microdamage, and mechanical properties of cortical bone in the same dogs. Twenty-nine 1-year-old beagles (15 males, 14 females) were divided into three groups and treated daily with vehicle (CNT) or with incadronate at a dose of 0.3 (LOW) or 0.6 mg/kg/day (HIGH) orally for 3 years. After death, pQCT, histomorphometry, microdamage measurements, and three-point bending mechanical test were performed using the ninth rib. Cortical BMD was increased in the incadronate-treated groups. Cortical activation frequency was suppressed by 82% and 70% in HIGH and LOW, respectively, compared with CNT, without impairment of mineralization. Microdamage accumulation was increased in both incadronate-treated groups. Although there were no significant differences in total and cortical area among the three groups, structural mechanical properties were significantly increased after incadronate treatment while intrinsic material properties were not changed in the incadronate-treated groups. This study suggests that long-term suppression of bone remodeling by bisphosphonate increases microdamage accumulation. However, this was not necessarily associated with a reduction of intrinsic material properties probably because of an increased degree of mineralization.

Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, Pawlicki M, De Souza P, Zheng M, Urbanowitz G, Reitsma D, Seaman JLong-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 100: 2613-2621

Article

Jun 2004

The authors previously reported the efficacy of a dose of 4 mg of zoledronic acid in reducing skeletal complications in patients with bone metastases secondary to lung carcinoma and other solid tumors (except carcinomas of the breast and prostate). In the current study, they update these results and report the long-term efficacy and safety of 21 months of treatment with zoledronic acid in a randomized, placebo-controlled trial. A total of 773 patients were randomized to receive zoledronic acid (4 mg or 8 mg) or placebo via a 15-minute infusion every 3 weeks for 21 months. The 8-mg dose later was reduced to 4 mg (8/4-mg group). The primary efficacy endpoint was the percentage of patients at 21 months with >/= 1 skeletal-related event (SRE) (pathologic fracture, spinal cord compression, radiation therapy to bone, or surgery to bone). Secondary analyses (time to first SRE, annual incidence of SREs, and multiple-event analysis) included hypercalcemia of malignancy. Fewer patients treated with zoledronic acid developed at least 1 SRE at 21 months compared with patients treated with placebo (39% of those treated at the 4-mg dose [P =0.127] and 36% of those treated at the 8/4-mg dose [P = 0.023], compared with 46% of those treated with placebo). Furthermore, 4 mg of zoledronic acid significantly delayed the median time to first SRE (236 days with 4 mg vs. 155 days with placebo; P = 0.009) and significantly reduced the annual incidence of SREs (1.74 per year with the 4-mg dose vs. 2.71 per year with placebo; P = 0.012). Moreover, the 4-mg dose of zoledronic acid was found to reduce the risk of developing a skeletal event by 31% (hazard ratio of 0.693; P = 0.003). Zoledronic acid was found to be well tolerated with long-term use; the most commonly reported adverse events in all treatment groups included bone pain and the transient, acute-phase reactions of nausea, anemia, and emesis. To the authors' knowledge, zoledronic acid is the first bisphosphonate to demonstrate long-term safety and efficacy in this patient population.

Severe osteomyelitis of the jaw in longterm survivors of multiple myeloma: A new clinical entity

Article

Oct 2004
AM J MED

Avascular jaw osteonecrosis in association with cancer chemotherapy: Series of 10 cases

Article

Mar 2005

We present a series of 10 patients with osteonecrosis of the jaws (ONJ) that appeared following cancer chemotherapy. Of the 10 cases with ONJ, six had bone metastases from breast cancers and the other four had multiple myeloma. We analysed the location of bone metastases, as well as the characteristics of the ONJ, and the drugs with which they had been treated for their bone metastases. Of the 10 patients, all had ONJ in the mandible; 50% also had maxillary involvement. The average number of areas of painful exposed was 2.1 per patient (range 1-5). In seven patients a tooth extraction preceded the onset of ONJ. Two patients developed oroantral communications and another a cutaneous fistula to the neck with suppuration. In all the 10 patients the histopatholological diagnosis was of chronic osteomyelitis without evidence of metastatic disease to the jaws. All the patients had received treatment for their malignant bone disease with bisphosphonates. These were the only drugs that all patients had received. ONJ appears to have a relationship with the use of bisphosphonates.

Osteonecrosis of the maxilla in a patient with a history of bisphosphonate therapy

Article

Mar 2005

Bisphosphonates, which inhibit osteoclasts, alleviate many of the devastating consequences of metastatic bone disease. However, bisphosphonates may play a role in the development of osteonecrosis of the jaws. We report our experience in the management of a patient with a history of bisphosphonate therapy who presented with osteonecrosis of the jaws following dental extraction to make others, particularly the broader dental community, aware of this potential complication. We also review the pharmacologic properties of bisphosphonates and their possible role in the pathophysiology of osteonecrosis. Until more is known about the role of bisphosphonates in the development of osteonecrosis of the jaws, we recommend that measures be taken to prevent osteonecrosis in those at risk, including, when feasible, a dental consultation before initiating bisphosphonate therapy.

Osteonecrosis of the jaw asociated with zoledronate therapy in a patient with multiple myeloma

Article

Apr 2005

Jaw avascular bone necrosis associated with long-term use of biphosphonates

Article

Aug 2005

Bisphosphonates and osteonecrosis of the jaw

Article

May 2005

• 13 cases of osteonecrosis of the jaw associated with bisphosphonate use have recently been reported to the Adverse Drug Reactions Advisory Committee. • Most cases were associated with intravenous bisphosphonate therapy (11 cases with zoledronic acid and one with pamidronate), but one was associated with oral alendronate used to treat osteoporosis. • The condition causes chronic pain, dysfunction and disfigurement; no treatment has proven consistently effective, and withdrawing the bisphosphonate does not seem to hasten recovery. • The focus should be on prevention through attending to any necessary dental treatment before bisphosphonate therapy begins.

Bisphosphonate Osteochemonecrosis (Bis-Phossy Jaw): Is This Phossy Jaw of the 21st Century?

Article

Jun 2005
J ORAL MAXIL SURG

Bisphosphonates are being implicated in a growing number of complications of the jaws. A number of terms are being applied to this phenomenon and perhaps the descriptive term bisphosphonate osteochemonecrosis has the most merit. But the eerie similarity of this 21st century disease process with the 19th century disease known as phossy jaw is striking. As the nomenclature continues to evolve, the term used in this article will be bis-phossy jaw. This article will explore historical and current aspects of these diseases. Although there may be other mitigating factors, such as oral health, chemotherapy history, immune status, Karnofsky performance status, or Kaplan-Feinstein index, bisphosphonates appear to be the necessary component in cases of bis-phossy jaw. This is primarily a review article on reported cases of bis-phossy jaw, with historical looks at phossy jaw and osteoradionecrosis. Our laboratory has reviewed 20 suspected cases of bis-phossy jaw and the typical histopathologic features of bis-phossy jaw are presented. Descriptions of phossy jaw and current bis-phossy jaw cases are remarkably similar. Histopathologic features of bis-phossy jaw showed intact vascular channels, even in areas with acute inflammatory infiltrates and bacterial overgrowth. Non-vital bone fragments with reduced evidence of osteoclastic action were also noted. Bis-phossy jaw may have more of a bacterial cofactor risk than osteoradionecrosis, and though altered angiogenesis may yet prove to be a factor, avascularity does not appear to be a major cofactor. The historical disease phossy jaw appears to serve as a possible analogous disease for current research and treatment of bis-phossy jaw. Prevention and early identification of patients at risk should be of prime concern.

[Bisphosphonates and osteonecrosis of the jaw].

Article

Aug 2005

Since 2003, reports have been published on necrosis of the jaw bones possibly being associated with the administration of bisphosphonates. Bisphosphonates are highly active inhibitors of osteoclasts which have been used prophylactically or symptomatically in the treatment of plasmocytoma, bone metastasis of malignant disease, tumor-associated hypercalcaemia and in the treatment of osteoporosis. Due to the importance of this side effect of bisphosphonates, we report six cases. Six patients (two women and four men) with a median age of 69 years (range 55-37) were diagnosed with osteonecrosis of the maxilla and/or mandible. These osteonecroses did not react adequately to local treatment and systemic therapy with antibiotics. Four patients suffered from plasmocytoma and two patients had a history of metastasising breast cancer. Besides cytostatic chemotherapies, all patients received bisphosphonates over an extended period. Bisphosphonates are considered an important standard in the treatment of plasmocytoma and bone metastasis due to malignancies. Since 2003, several reports have been published describing patients in whom therapy resistant osteonecrosis of jaw bones occurred either after dental extractions or spontaneously. Until then, unknown side effects of bisphosphonate therapy had been suspected. Since patients with malignant diseases receive cytostatic therapy and a range of other drugs, including bisphosphonates, enhancement of the side effects may be presumed. The probable association of the therapeutic use of bisphosphonates and the occurence of jaw bone necrosis has to be studied in further investigations. Patients receiving bisphosphonates should be followed-up regularly to avoid the occurrence of extended osteonecrotic lesions, which should be diagnosed early and treated adequately.

Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone - An emerging oral complication of supportive cancer therapy

Article

Aug 2005

The current report presented 17 patients with cancer with bone metastases and 1 patient with osteopenia who received treatment with bisphosphonates and who subsequently developed osteonecrosis of the mandible and/or maxilla. The authors reviewed information on 18 patients who were referred to oral medicine or oral surgery specialists for evaluation and treatment of mandibular and/or maxillary bone necrosis from June 2002 to September 2004. To be included in the current review, patients must have been treated with either pamidronate or zoledronic acid to control or prevent metastatic disease, or with alendronate for osteoporosis. All patients with cancer had received chemotherapy while receiving bisphosphonate management. The 17 patients with cancer were receiving active medical care for a malignancy. Cancer treatment included a variety of chemotherapeutic agents. They presented with metastatic disease to bone and were treated intravenously with the bisphosphonates pamidronate or zoledronic acid for a mean time of 25 months (range, 4-41 mos). There were 14 females and 4 males with a mean age of 62 years (range, 37-74 yrs). Malignancies included breast carcinoma (n = 10), multiple myeloma (n = 3), prostate carcinoma (n = 1), ovarian carcinoma (n = 1), prostate carcinoma/lymphoma (n = 1), and breast/ovarian carcinoma (n = 1). One female patient with osteopenia received alendronate. The most common clinical osteonecrosis presentations included infection and necrotic bone in the mandible. Associated events included dental extractions, infection, and trauma. Two patients appeared to develop disease spontaneously, without any clinical or radiographic evidence of local pathology. Despite surgical intervention, antibiotic therapy, hyperbaric oxygen therapy, and topical use of chemotherapeutic mouth rinses, most of the lesions did not respond well to therapy. Discontinuation of bisphosphonate therapy did not assure healing. However, 1 patient with cancer healed after discontinuation of bisphosphonate therapy for 4 months. The findings in the patient population combined with recent literature reports suggested that bisphosphonates may contribute to the pathogenesis of the oral lesions. The risk factors and precise mechanism involved in the formation of the osteonecrosis are not known. This condition represents a new oral complication in patients with cancer and can be termed bisphosphonate-associated osteonecrosis. Lesions in patients with osteoporosis are worrisome and need to be further evaluated.

Exposed Bone in Oral Cavities

Article

Jul 2005
Clin J Oncol Nurs

Osteonecrosis of jaw in patient with hormone-refractory prostate cancer treated with zoledronic acid

Article

Oct 2005

Intravenous bisphosphonates are widely used in the management of metastatic bone disease, as well as osteoporosis. Recent published reports have documented a possible link between treatment with intravenous bisphosphonates and osteonecrosis of the jaw. We report a case of osteonecrosis of the jaw in 1 patient with prostate cancer receiving both chemotherapy and intravenous zoledronic acid (Zometa). Bisphosphonates have been demonstrated to alter the normal bone microenvironment and appear to have direct effects on tumors as well. These changes may contribute to the development of osteonecrosis of the jaw, particularly after tooth extractions or other invasive dental procedures.

Avascular necrosis of the jaw bone after bisphosphonate therapy

Article

Sep 2005
Refuah

Bisphosphonates have an antiosteolytic effect by the inhibition of osteoclastic action. Although the exact mode of action is not completely understood, major progress on both the cellular and molecular levels has been made in recent years. Bisphosphonates alleviate pain and reduce complications, such as pathologic fractures, or hypercalcemia. Dental and periodontal research has shown great interest in clinical applications of bisphosphonates' antiosteolytic and antiosteoclastic traits, since they can be applied to counteract bone loss in chronic periodontitis. Investigations have associated avascular necrosis events in the jawbones with bisphosphonate therapy. Maxillary and mandibular osteonecrotic foci accompanied by pain, inconvenience and purulent exudates were incidentally found in patients who were taking pamidronate (Aredia), zolendronate (Zometa) and even alendronate (Fosalan). Our institutional database search over the past year yielded ten patients who were admitted to the Oral and Maxillofacial Surgery Unit at the Tel Aviv Sourasky Medical Center, due to an osteonecrotic bone lesion coupled with a prior history of bisphosphonate therapy. All these patients also had a recent dental extraction. They were all treated according to the osteomyelitis protocol, and their response to therapy varied from several weeks to many months, with some cases requiring repeat surgical intervention (curettage or sequestrectomy). This article strives to alert on the possible linkage between drug therapy using bisphosphonates and the serious event of avascular jawbone necrosis. The important role of the oral surgeon in following up on this group of patients should not be underestimated.

Bisphosphonate-Associated Osteonecrosis of the Jaws and Endodontic Treatment: Two Case Reports

Article

Nov 2005
J ENDODONT

Bisphosphonates are commonly used in the management of bone diseases, such as osteoporosis and Paget's disease, and to prevent bone complications and to treat malignant hypercalcemia in certain types of cancer. Although this class of drugs has clear evidence of medical efficacy, there are an increasing number of reports of bisphosphonate-associated osteonecrosis of the jaws that have substantial implications for the patient and for the treating dentist. This case report reviews proposed possible mechanisms of bisphosphonate-associated osteonecrosis of the jaws and describes two case reports where nonsurgical and surgical root canal treatments were precipitating factors. Recommendations for prevention and treatment of the disease follow. Thorough history taking and timely consultation with the patient's oral surgeon and oncologist are emphasized.

“Bis-phossy jaws”–High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw

Abstract

No full-text available

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