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Dentistry Journal
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New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws
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New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws

A special issue of Dentistry Journal (ISSN 2304-6767).

Deadline for manuscript submissions: closed (1 September 2016) | Viewed by 92905

Special Issue Editor

Prof. Dr. Christian Walter

E-Mail Website
Guest Editor
1. Oral and Maxillofacial Surgery of the Mediplus Clinic, Haifa-Allee 20, 55128 Mainz, Germany
2. Department of Oral and Maxillofacial Surgery, University Medical Centre, Johannes Gutenberg University Mainz, Augustusplatz 2, 55131 Mainz, Germany
Interests: dental implants; oral and maxillofacial surgery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

More than 10 years ago, bisphosphonate-associated osteonecrosis was described for the first time, opening a new research field describing epidemiologic and patho-etiologic data, as well as prevention, diagnostic, and therapy regimes for this new disease. In 2006, more than 150 articles on this topic were published, and since 2009 more than 200 new articles have been listed in PubMed each year, showing the progress of research in this area. In recent years, new active ingredients have been developed and implemented into anti-cancer and osteoporosis therapy, such as RankL inhibitors and tyrosine kinase inhibitors, which lead to osteonecrosis as well.

This Special Issue is interested in all aspects of all dental specialties dealing with this topic. In addition to basic research regarding pathology, prevention, and treatment, clinical topics are of interest. How is dental treatment affected by anti-resorptive therapies, e.g., surgical procedures (tooth extractions, implantology, etc.), periodontal, orthodontic, or endodontic treatment?

PD Dr. med. dent. Christian Walter
Guest Editor

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Keywords

  • Bisphosphonate associated/related/induced osteonecrosis of the jaws
  • Medication associated/related/induced osteonecrosis of the jaws
  • Bisphosphonate
  • RankL inhibitor
  • Tyrosine kinase inhibitors
  • VEGF inhibitors
  • Epidemiology
  • Prevalence and incidence
  • Etiology and pathology
  • Microbiological factors
  • Influence of bisphosphonates/medication on the bone
  • Influence of bisphosphonates/medication on the immune system
  • Influence of bisphosphonates/medication on soft tissues
  • Risk factors
  • Prevention
  • Diagnosis
  • Histology
  • Therapy
  • Periodontal treatment
  • Dental implants
  • Orthodontic treatment
  • Complications
  • Animal models

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Published Papers (12 papers)

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Research

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224 KiB  
Article
Osteonecrosis of the Jaws (ONJ) after Bisphosphonate Treatment in Patients with Multiple Myeloma: Decreasing ONJ Incidence after Adoption of Preventive Measures
by Gioacchino Catania, Federico Monaco, Giulia Limberti, Manuela Alessio, Iolanda De Martino, Cecilia Barile, Antonella Fasciolo, Anna Baraldi, Marco Ladetto and Vittorio Fusco
Dent. J. 2016, 4(4), 45; https://doi.org/10.3390/dj4040045 - 1 Dec 2016
Cited by 4 | Viewed by 4465
Abstract
Bisphosphonates (BPs) are administered to Multiple Myeloma (MM) patients with bone lytic lesion. Osteonecrosis of the Jaw (ONJ) is a complication reported since 2003 in patients treated with intravenous (IV) BPs such as zoledronic acid and pamidronate, with 6%–26.3% frequency in early literature [...] Read more.
Bisphosphonates (BPs) are administered to Multiple Myeloma (MM) patients with bone lytic lesion. Osteonecrosis of the Jaw (ONJ) is a complication reported since 2003 in patients treated with intravenous (IV) BPs such as zoledronic acid and pamidronate, with 6%–26.3% frequency in early literature series, before some preventive measures were recommended. We evaluated the occurrence of ONJ with and without dental preventive measures in MM patients treated with BPs in our centre between 1996 and 2015. Since 2005, MM patients (already under treatment or before treatment) underwent a baseline mouth assessment (dental visit, Rx orthopantomography, and eventual tooth avulsion or dental care if necessary) and were followed by a multidisciplinary team. We reviewed the charts of 119 MM patients receiving IV BPs, classified into 3 groups: (a) “historic group” (21 patients who had started BP treatment in years before the awareness of ONJ); (b) “screening group” (20 patients starting BPs without baseline evaluation); and (c) “prevention group” (78 patients starting therapy only after baseline preventive assessment and eventual dental care measures). ONJ was observed in 3/21 patients (14.2%) from group a, in 2/20 patients (10%) from group b, and in no patients from group c (0%). Notably, the median number of IV BP administrations decreased after 2005. Our data confirmed a meaningful reduction of ONJ risk in MM patients treated with BPs if preventive measures are applied. Both implementation of prevention measures and reduction of cumulative doses of IV BPs could have contributed to a decreased incidence of ONJ. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
177 KiB  
Article
Impact of Soft Tissue Pathophysiology in the Development and Maintenance of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)
by Thomas Ziebart, Frank Halling, Paul Heymann, Andreas Neff, Sebastian Blatt, Junho Jung, Andreas Pabst, Leonardo Righesso and Christian Walter
Dent. J. 2016, 4(4), 36; https://doi.org/10.3390/dj4040036 - 25 Oct 2016
Cited by 15 | Viewed by 5187
Abstract
Since the first description of bisphosphonate-related osteonecrosis of the jaw (BRONJ), numerous research groups have focused on possible pathological mechanisms including the suppression of the bone turnover of the jaw, antiangiogenic effects and soft tissue toxicity. In our review we focused on summarizing [...] Read more.
Since the first description of bisphosphonate-related osteonecrosis of the jaw (BRONJ), numerous research groups have focused on possible pathological mechanisms including the suppression of the bone turnover of the jaw, antiangiogenic effects and soft tissue toxicity. In our review we focused on summarizing the role of the soft tissues in the development and progression of BRONJ. The biological behavior of fibroblasts can be significantly influenced by bisphosphonates (BP) such as a concentration dependent reduction of cell viability. High concentrations of BP can induce apoptosis and necrosis of the cells. Comparable effects could be detected for keratinocytes. Compared to non-nitrogen containing bisphosphonates, nitrogen-containing BP have worse effects on cell biology by blocking the mevalonate pathway. Further, the cell architecture and expression levels of several genes and proteins are significantly disturbed by BP. These inhibitory effects of BP are in accordance with BP-related reduced angiogenesis and neovascularization and could underline the hypothesis that inhibition of fibroblasts and keratinocytes results in delayed wound healing and can induce and trigger BRONJ. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
192 KiB  
Article
Diabetes Mellitus and Its Association to the Occurrence of Medication-Related Osteonecrosis of the Jaw
by Roman K. Rahimi-Nedjat, Keyvan Sagheb, Andreas Pabst, Lukas Olk and Christian Walter
Dent. J. 2016, 4(2), 17; https://doi.org/10.3390/dj4020017 - 31 May 2016
Cited by 15 | Viewed by 4739
Abstract
To date there is no consensus on the role of diabetes in the development of medication-related osteonecrosis of the jaws (MR-ONJ). Therefore, this study aimed to investigate the prevalence of diabetes and pathological glucose metabolism in patients with MR-ONJ compared to the general [...] Read more.
To date there is no consensus on the role of diabetes in the development of medication-related osteonecrosis of the jaws (MR-ONJ). Therefore, this study aimed to investigate the prevalence of diabetes and pathological glucose metabolism in patients with MR-ONJ compared to the general population. All maxillofacial surgery inpatients in one year at our department were investigated regarding diagnosis, anamnesis, medication, and blood glucose readings. 1374 records were analyzed. 35 patients with MR-ONJ were identified. Diabetics accounted for 14.3%. No significant difference in the prevalence of known diabetes was found, except for pathological glucose metabolism in patients with MR-ONJ (p < 0.001). Diabetes does not necessarily promote the onset of MR-ONJ. Therefore, diabetes should not be considered as a standalone risk factor. On the contrary, hyperglycemia as a possible indicator for poorly managed or yet undetected diabetes is associated with MR-ONJ. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)

Review

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184 KiB  
Review
Angiogenesis in the Development of Medication-Related Osteonecrosis of the Jaws: An Overview
by Andreas Max Pabst, Maximilian Krüger, Sebastian Blatt, Thomas Ziebart, Roman Rahimi-Nedjat, Elisabeth Goetze and Christian Walter
Dent. J. 2017, 5(1), 2; https://doi.org/10.3390/dj5010002 - 26 Dec 2016
Cited by 15 | Viewed by 4510
Abstract
Medication-related osteonecrosis of the jaws (MR-ONJ) is one of the most relevant side effects of bisphosphonate therapy; it is clinically defined as a non-healing wound in combination with an avascular and necrotic jaw within ongoing bisphosphonate therapy or after completed bisphosphonate therapy. Different [...] Read more.
Medication-related osteonecrosis of the jaws (MR-ONJ) is one of the most relevant side effects of bisphosphonate therapy; it is clinically defined as a non-healing wound in combination with an avascular and necrotic jaw within ongoing bisphosphonate therapy or after completed bisphosphonate therapy. Different theories concerning the development of MR-ONJ have been reported, while the exact pathophysiology is still unknown. Recent studies have increasingly focused on angiogenesis and revascularization concerning MR-ONJ pathophysiology, which seems to be a relevant factor in the development of MR-ONJ and a possible and promising point of action for MR-ONJ prevention and therapy. Therefore, and with respect to the different aspects and specific forms of angiogenesis, the enclosed review summarizes the possible role of angiogenesis and revascularization in the pathophysiology of MR-ONJ. Special focus is given to the strong negative influence of bisphosphonates on progenitor and mature endothelial cells in vitro as well as on microvessel sprouting in vitro and in vivo, which might result in overall reduced wound healing of oral soft and hard tissues, and therefore in an exposed and avascular jaw from a clinical viewpoint. Further, it will be summarized whether and in what way the aspect of angiogenesis might be used for possible MR-ONJ prevention and therapy. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
186 KiB  
Review
Role of Teriparatide in Medication-Related Osteonecrosis of the Jaws (MRONJ)
by Yong-Dae Kwon and Deog-Yoon Kim
Dent. J. 2016, 4(4), 41; https://doi.org/10.3390/dj4040041 - 9 Nov 2016
Cited by 21 | Viewed by 9839
Abstract
While the optimal treatment concept of medication-related osteonecrosis of the jaws (MRONJ) is still in debate, several adjunct therapies have been introduced. Among these adjunctive measures, recombinant human parathyroid hormone (rhPTH, teriparatide) seems to be the most promising treatment modality. Several studies have [...] Read more.
While the optimal treatment concept of medication-related osteonecrosis of the jaws (MRONJ) is still in debate, several adjunct therapies have been introduced. Among these adjunctive measures, recombinant human parathyroid hormone (rhPTH, teriparatide) seems to be the most promising treatment modality. Several studies have presented the beneficial effect of short-term teriparatide; they have shown an improved level of bone markers and radiographic evidence of bone healing. Although clinical validation by a controlled trial with prospective design would be essential, short-term teripratide therapy would be a good treatment option for MRONJ patients with impaired bone remodeling. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
1187 KiB  
Review
Current Controversies on the Pathogenesis of Medication-Related Osteonecrosis of the Jaw
by Winnie Zee Man Wat
Dent. J. 2016, 4(4), 38; https://doi.org/10.3390/dj4040038 - 28 Oct 2016
Cited by 19 | Viewed by 6247
Abstract
Medication-related osteonecrosis of the jaw (MRONJ) was first reported more than a decade ago. Since then, numerous cases have been diagnosed. Currently, there are three groups of drugs related to MRONJ: bisphosphonates, denosumab and anti-angiogenic drugs. As MRONJ can lead to debilitating clinical [...] Read more.
Medication-related osteonecrosis of the jaw (MRONJ) was first reported more than a decade ago. Since then, numerous cases have been diagnosed. Currently, there are three groups of drugs related to MRONJ: bisphosphonates, denosumab and anti-angiogenic drugs. As MRONJ can lead to debilitating clinical sequels and limited effective treatment options are available, much research has been done in understanding its pathophysiology. Until now, the exact pathogenesis of MRONJ has not been fully elucidated. While history of invasive dental procedures or local trauma may be present, some cases occur spontaneously without any preceding factors. This review aims to examine and discuss the three main hypotheses for the pathogenesis of MRONJ, namely suppressed bone turnover, cellular toxicity and infection. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
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670 KiB  
Review
Prevalence of Medication-Related Osteonecrosis of the Jaw in Patients with Breast Cancer, Prostate Cancer, and Multiple Myeloma
by Petra Rugani, Christian Walter, Barbara Kirnbauer, Stephan Acham, Yvonne Begus-Nahrman and Norbert Jakse
Dent. J. 2016, 4(4), 32; https://doi.org/10.3390/dj4040032 - 27 Sep 2016
Cited by 27 | Viewed by 6853
Abstract
Medication-related osteonecrosis of the jaw is a known side-effect of antiresorptive therapy in patients with malignant diseases. Nevertheless, the exact pathogenesis is still unknown and published prevalences show a significant range. The aim of the presented paper was to assess the prevalence of [...] Read more.
Medication-related osteonecrosis of the jaw is a known side-effect of antiresorptive therapy in patients with malignant diseases. Nevertheless, the exact pathogenesis is still unknown and published prevalences show a significant range. The aim of the presented paper was to assess the prevalence of osteonecrosis (ONJ) in breast cancer, prostate cancer, and multiple myeloma patients receiving parenteral antiresorptive therapy. For this reason a PubMed search was performed and 69 matching articles comprising 29,437 patients were included in the analysis. Nine-hundred fifty-one cases of jaw necrosis were described. The overall ONJ-prevalence was 2.09% in the breast cancer group, 3.8% in the prostate cancer group, and 5.16% for multiple myeloma patients. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
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3825 KiB  
Review
Imaging in Patients with Bisphosphonate-Associated Osteonecrosis of the Jaws (MRONJ)
by Britt-Isabelle Berg, Andreas A. Mueller, Marcello Augello, Scott Berg and Claude Jaquiéry
Dent. J. 2016, 4(3), 29; https://doi.org/10.3390/dj4030029 - 2 Sep 2016
Cited by 19 | Viewed by 19271
Abstract
Background: Bisphosphonate-associated osteonecrosis of the jaws (MRONJ/BP-ONJ/BRONJ) is a commonly seen disease. During recent decades, major advances in diagnostics have occurred. Once the clinical picture shows typical MRONJ features, imaging is necessary to determine the size of the lesion. Exposed bone is not [...] Read more.
Background: Bisphosphonate-associated osteonecrosis of the jaws (MRONJ/BP-ONJ/BRONJ) is a commonly seen disease. During recent decades, major advances in diagnostics have occurred. Once the clinical picture shows typical MRONJ features, imaging is necessary to determine the size of the lesion. Exposed bone is not always painful, therefore a thorough clinical examination and radiological imaging are essential when MRONJ is suspected. Methods: In this paper we will present the latest clinical update on the imaging options in regard to MRONJ: X-ray/Panoramic Radiograph, Cone Beam Computed Tomography (CBCT) and Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Nuclear Imaging, Fluorescence-Guided Bone Resection. Conclusion: Which image modality is chosen depends not only on the surgeon’s/practitioner’s preference but also on the available imaging modalities. A three-dimensional imaging modality is desirable, and in severe cases necessary, for extended resections and planning of reconstruction. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
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195 KiB  
Review
Advantages and Disadvantages of Bone Protective Agents in Metastatic Prostate Cancer: Lessons Learned
by Christian Thomas, Georg Bartsch, Christian Walter, Hendrik Borgmann, Maximilian Peter Brandt, Thomas Höfner, Axel Haferkamp and Igor Tsaur
Dent. J. 2016, 4(3), 28; https://doi.org/10.3390/dj4030028 - 19 Aug 2016
Cited by 2 | Viewed by 4846
Abstract
Nine out of ten metastatic prostate cancer (PCa) patients will develop osseous metastases. Of these, every second will suffer from skeletal-related events (SRE). SRE are associated with an increased risk for death, which is markedly increased in the presence of pathological fracture. Moreover, [...] Read more.
Nine out of ten metastatic prostate cancer (PCa) patients will develop osseous metastases. Of these, every second will suffer from skeletal-related events (SRE). SRE are associated with an increased risk for death, which is markedly increased in the presence of pathological fracture. Moreover, health insurance costs nearly double in the presence of SRE. Zoledronic acid and denosumab are both approved drugs for the prevention or delay of SRE in castration-resistant prostate cancer (CRPC) patients with osseous metastases. However, long-term treatment with one of these two drugs is associated with the development of medication-related osteonecrosis of the jaw (MRONJ). Routine inspections of the oral cavity before and during treatment are mandatory in these patients. Regarding imaging techniques, bone scintigraphy seems to be a promising tool to detect early stage MRONJ. Zoledronic acid does not reduce the incidence of SRE in hormone-sensitive PCa. First data shows 3-monthly application of zoledronic acid to be equi-effective to monthly application. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)

Other

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4529 KiB  
Case Report
Osteonecrosis of the Jaw (ONJ) in Osteoporosis Patients: Report of Delayed Diagnosis of a Multisite Case and Commentary about Risks Coming from a Restricted ONJ Definition
by Mario Migliario, Giovanni Mergoni, Paolo Vescovi, Iolanda De Martino, Manuela Alessio, Luca Benzi, Filippo Renò and Vittorio Fusco
Dent. J. 2017, 5(1), 13; https://doi.org/10.3390/dj5010013 - 16 Mar 2017
Cited by 13 | Viewed by 11979
Abstract
Osteonecrosis of the jaws (ONJ) in osteoporosis patients has been defined as rare, but the number of reported cases is increasing. We report a case of delayed ONJ diagnosis in a patient, who was being treated with alendronate, developing bone alterations both in [...] Read more.
Osteonecrosis of the jaws (ONJ) in osteoporosis patients has been defined as rare, but the number of reported cases is increasing. We report a case of delayed ONJ diagnosis in a patient, who was being treated with alendronate, developing bone alterations both in maxilla and in mandible. Underestimation of ONJ incidence and missed or delayed ONJ diagnosis in osteoporosis patients might derive from lack of awareness of health providers as well as from an ONJ definition that is too restricted. The more recent definition of medication-related osteonecrosis of the jaws (MRONJ) released in 2014 by the American Association of Oral Maxillofacial Surgeons (AAOMS) accept fistula, besides bone exposure, as a major sign of disease, but it seems to be insufficient since it excludes all cases of ONJ disease without bone exposure. A new MRONJ definition is needed to avoid missing or delayed diagnosis. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
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5151 KiB  
Case Report
Delayed Diagnosis of Osteonecrosis of the Jaw (ONJ) Associated with Bevacizumab Therapy in Colorectal Cancer Patients: Report of Two Cases
by Francesco Erovigni, Alessio Gambino, Marco Cabras, Antonella Fasciolo, Silvio Diego Bianchi, Elisa Bellini and Vittorio Fusco
Dent. J. 2016, 4(4), 39; https://doi.org/10.3390/dj4040039 - 29 Oct 2016
Cited by 15 | Viewed by 8222
Abstract
Medication-induced Osteonecrosis of the Jaw (MRONJ) has been reported not only after use of antiresorptive agents (bisphosphonates and denosumab), but also in cancer patients receiving antiangiogenic agents, alone or combined with antiresorptive drugs. We report two cases of MRONJ observed in colorectal cancer [...] Read more.
Medication-induced Osteonecrosis of the Jaw (MRONJ) has been reported not only after use of antiresorptive agents (bisphosphonates and denosumab), but also in cancer patients receiving antiangiogenic agents, alone or combined with antiresorptive drugs. We report two cases of MRONJ observed in colorectal cancer patients after bevacizumab therapy only. MRONJ was diagnosed, respectively, two and seven months after a tooth extraction; both the patients had received two courses of bevacizumab infusions (for a total of 29 and 10 administrations, respectively). We discuss if tooth extraction during or after antiangiogenic therapy could be a potential trigger of MRONJ, but also if an underlying bone disease not evident before oral surgery might be a possible cause. A careful drug history has to be registered by dental specialists in cancer patients before oral surgery and adequate imaging might be obtained to avoid a delayed diagnosis. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
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3994 KiB  
Case Report
‘Autoreconstruction’ of the Mandible—Report of a Case
by Sarina E.C. Pichardo, Pieter De Roos and J.P. Richard Van Merkesteyn
Dent. J. 2016, 4(2), 9; https://doi.org/10.3390/dj4020009 - 13 Apr 2016
Viewed by 5346
Abstract
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) was first mentioned in the literature in 2003. Since then, several reports have been published referring to this disease. The etiology of BRONJ still remains unclear. The treatment of BRONJ also remains a topic of discussion between [...] Read more.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) was first mentioned in the literature in 2003. Since then, several reports have been published referring to this disease. The etiology of BRONJ still remains unclear. The treatment of BRONJ also remains a topic of discussion between those who are in favor of a conservative treatment and those who are convinced that surgical treatment gives the best results. In this case report, a patient is presented with BRONJ in the mandible which has been treated surgically in combination with antibiotic treatment. During surgery it appeared that a large part of the jaw was sequestrated full-thickness with, at the same time, formation of a substantial amount of subperiosteal bone that was formed around the BRONJ, supporting the sequestrated part of the mandible and, after sequestrectomy, serving as a neo-mandible. This case shows the capacity of the jawbone despite bisphosphonate use to regenerate itself. Full article
(This article belongs to the Special Issue New Cancer and Osteoporosis Therapies and Osteocrosis of the Jaws)
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