Knut A. Grötz

Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate.

BACKGROUND In addition to other treatments, patients with prostate cancer (pCA) and bone metastasis receive bisphosphonates. Since 2003, a previously unknown side-effect of bisphosphonates-bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ)-has been described, and frequency has since increased. An exact incidence is still unknown. OBJECTIVES The aim of this study was to assess the incidence and additional factors in the development of BP-ONJ. DESIGN, SETTING, AND PARTICIPANTS From July 2006 to October 2007, patients with advanced pCA and osseous metastasis receiving bisphosphonate therapy in the Department of Urology or Haematology and Oncology at the Johannes-Gutenberg-University Mainz, Germany, received a dental examination. In all, 43 patients were included. MEASUREMENTS Patients were checked for exposed bone, osteonecrosis, mucosal defects, inflammation, and oral hygiene. Further points were the applied bisphosphonate, co-medication, the duration of application, and possible trigger factors for BP-ONJ. RESULTS AND LIMITATIONS Eight of 43 patients developed BP-ONJ (18.6%). All patients had received zoledronate at least 14 times. Two patients had received bondronate, and one patient had received pamidronate before switching to zoledronate. All patients had had a previous tooth extraction or a denture pressure sore, and all patients had received additional chemotherapy and corticosteroids. CONCLUSIONS The reason for this relatively high incidence compared to other studies might be the prospective study design and thorough dental examination. In studies with such small numbers as have been published to date, nondetection or nonreported cases of BP-ONJ have an influence on the outcome. The incidence of BP-ONJ in patients with pCA might be an underestimated problem.

Incidence of Bisphosphonate-associated Osteonecrosis of the Jaws in Breast Cancer Patients

Bisphosphonate‐associated osteonecrosis of the jaws (BP‐ONJ) is a relatively new disease. The aim of this study was to evaluate the prevalence of BP‐ONJ in breast cancer patients with osseous metastasis and bisphosphonate therapy.

Prevalence of bisphosphonate associated osteonecrosis of the jaws in multiple myeloma patients

BackgroundBisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is an adverse effect of bisphosphonate treatment with varying reported incidence rates.MethodsIn two neighboring German cities, prevalence and additional factors of the development of BP-ONJ in multiple myeloma patients with bisphosphonates therapy were recorded using a retrospective (RS) and cross-sectional study (CSS) design. For the RS, all patients treated from Jan. 2000 - Feb. 2006 were contacted by letter. In the CSS, all patients treated from Oct. 2006 - Mar. 2008 had a physical and dental examination. Additionally, a literature review was conducted to evaluate all articles reporting on BP-ONJ prevalence. PubMed search terms were: bisphosphonat, diphosphonate, osteonecrosis, prevalence and incidence.ResultsIn the RS, data from 81 of 161 patients could be obtained; four patients (4.9%) developed BP-ONJ. In the CSS, 16 of 78 patients (20.5%) developed BP-ONJ. All patients with BP-ONJ had received zoledronate; 12 of these had had additional bisphosphonates. All except one had an additional trigger factor (tooth extraction [n = 14], dental surgical procedure [n = 2], sharp mylohyoid ridge [n = 3]).ConclusionThe prevalence of BP-ONJ may have been underestimated to date. The oral examination of all patients in this CSS might explain the higher prevalence, since even early asymptomatic stages of BP-ONJ and previously unnoticed symptomatic BP-ONJ were recorded. Since nearly all patients with BP-ONJ had an additional trigger factor, oral hygiene and dental care might help to reduce BP-ONJ incidence.

The Role of Inferior Alveolar Nerve Involvement in Bisphosphonate-Related Osteonecrosis of the Jaw

PURPOSE Hypesthesia or anesthesia of the lower lip (Vincents symptom) is a common sign in patients with osteomyelitis of the mandible, especially in severe cases. PATIENTS AND METHODS We observed an involvement of the inferior alveolar nerve in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ). Surprisingly, we found Vincents symptom also in patients with limited and early stages of BRONJ. RESULTS These patients were successfully treated by surgical removal of the necrotic bone combined with preoperative and postoperative administration of antibiotics. We report on the occurrence and management of an involvement of the inferior alveolar nerve in patients with BRONJ and discuss possible causes. CONCLUSION We conclude that impairment of inferior alveolar nerve function can be an important early symptom or even the presenting symptom of BRONJ that is also easily detectable by bisphosphonate-prescribing physicians. Concerning the management of BRONJ, we conclude that surgical removal of necrotic bone combined with antibiotics is an adequate treatment in patients with osteonecrosis of the jaw.

Protective effect of amifostine on dental health after radiotherapy of the head and neck

PURPOSE The cytoprotective agent amifostine has been shown to reduce the radiation-induced acute and chronic xerostomia in head and neck cancer patients. The purpose of this study was to evaluate whether or not amifostine also reduces the incidence of dental caries associated with the radiation-induced xerostomia. METHODS AND MATERIALS The dental status before and 1 year after radiotherapy was retrospectively compared in 35 unselected patients treated as part of the prospective randomized and multicenter open-label Phase III study (WR-38) at the University Hospitals of Heidelberg, Freiburg, and Erlangen. The WR-38 study compared radiotherapy in head and neck cancer with and without concomitant administration of amifostine. RESULTS Patient and treatment characteristics (particularly the radiation dose and percentage of parotids included in the treatment volume) were equally distributed between the patients who received (n = 17) or did not receive (n = 18) amifostine. Fifteen patients of the amifostine group showed no deterioration of the dental status 1 year after radiotherapy as compared to 7 patients who did not receive the cytoprotector (p = 0. 015, two-tailed Fisher exact test). CONCLUSION Our data suggest a protective effect of amifostine on the dental health after radiotherapy of the head and neck. The dental status should be used as a primary endpoint in future studies on amifostine.

The effect of amifostine or IMRT to preserve the parotid function after radiotherapy of the head and neck region measured by quantitative salivary gland scintigraphy

PURPOSE In this retrospective study, two approaches to preserve the parotid function after radiotherapy (RT) were compared: application of the radioprotective agent amifostine during RT and parotid-sparing intensity-modulated radiotherapy (IMRT). PATIENTS AND METHODS Patients were qualified for this analysis if (1) both parotid glands received a radiation dose of >or=50Gy using conventional radiotherapy techniques (cRT) or if they received a parotid-sparing IMRT as alternative, if (2) salivary gland scintigraphies before and after RT were performed, and if (3) a normal parotid function was present before RT. Quantitative salivary gland scintigraphy was used to assess the parotid gland function. RESULTS Altogether 275 salivary gland scintigraphies of 100 patients were analyzed. The mean relative tracer uptake (DeltaU) of patients treated with cRT, cRT with amifostine and IMRT 1-12 months after RT was 0.59 (95%CI 0.54-0.65), 0.67 (95%CI 0.59-0.76), and 0.93 (95%CI 0.78-1.07), respectively. The mean relative DeltaU 13-47 months after RT was 0.40 (95%CI 0.32-0.49), 0.60 (95%CI 0.48-0.71), and 0.92 (95%CI 0.56-1.28). At 1-12 months after RT, ANOVA testing with post-hoc comparison using the Bonferroni correction showed a significant difference between IMRT and cRT (p<0.001) or IMRT and amifostine (p<0.01). The difference between amifostine and cRT was not significant during the first year. At 13-47 months after RT, the difference between cRT and amifostine was significant (p=0.02). CONCLUSION Our data suggest that both amifostine and IMRT are able to partially preserve the parotid function after radiotherapy. The effect of IMRT appeared to be much greater.

Quantifying Radioxerostomia: Salivary Flow Rate, Examiner’s Score, and Quality of Life Questionnaire

Background and Purpose:Salivary flow rates alone are not sufficient to quantify all aspects of radioxerostomia. This is a problem in studies aiming to reduce radioxerostomia. The aim of this study was to evaluate the association between objectively measured salivary flow rate and subjective xerostomia ratings by the physician (RTOG scale) or the patients (quality of life [QoL] questionnaire).Patients and Methods:In a case-control study patients who underwent recall for oral cancer were screened. Inclusion criteria for this diagnostic, noninterventional study were: history of oral carcinoma, surgical and radiation therapy, time interval from start of radiation therapy > 90 days, salivary glands within the radiation field. The control group consisted of patients, who had not received radiotherapy. RTOG salivary gland score, quality of life (EORTC QLQ-C30 and H&N35), and sialometry were recorded.Results:Patients with RTOG score 0 had mean salivary flow rates of 0.3 ml/min, those with RTOG 1 0.12 ml/min, RTOG 2 0.02 ml/min, and RTOG 3 < 0.01 ml/min. RTOG score 4 (total fibrosis) did not occur. Based on salivary flow rates, all patients were grouped into xerostomia < 0.2 ml/min (30 patients) and nonxerostomia (twelve patients). QoL results revealed significant differences between patients with xerostomia and nonxerostomia for physical function, dyspnea, swallowing, social eating, dry mouth, nutritional support, and a tendency to higher values for appetite loss.Conclusion:The correlation between “subjective” QoL parameters and salivary flow was confirmed. The different subjective aspects of radioxerostomia seem to be better differentiated by the EORTC QoL questionnaire.Hintergrund und Ziel:Die Speichelfließrate allein reicht nicht aus, um alle Aspekte der Radioxerostomie zu erfassen. Dies stellt ein Problem für Studien dar, die auf die Reduktion der Radioxerostomie abzielen. Ziel dieser Studie war die Evaluation der Zusammenhänge zwischen objektiv gemessener Speichelfließrate und subjektiven Xerostomiebewertungen durch den Untersucher (RTOG-Score) oder den Patienten (Lebensqualitätsfragebogen).Patienten und Methodik:In einer Fall-Kontroll-Studie wurden Patienten im Rahmen des onkologischen Recalls untersucht. Einschlusskriterien für diese nichtinterventionelle, diagnostische Studie waren: chirurgische und Strahlentherapie nach Oropharynxkarzinom, Zeit nach Beginn der Strahlentherapie > 90 Tage, Speicheldrüsen im Strahlenfeld. Die Kontrollgruppe bestand aus Patienten ohne Strahlentherapie. Der RTOG-Speicheldrüsenscore, Lebensqualität (EORTC QLQ-C30 und H&N35) und Sialometrie wurden erfasst.Ergebnisse:Patienten mit RTOG 0 wiesen eine mediane Speichelfließrate von 0,3 ml/min auf, mit RTOG 1 0,12 ml/min, RTOG 2 0,02 ml/min und RTOG 3 < 0,01 ml/min. RTOG 4 (vollständige Fibrose) kam nicht vor. Basierend auf der Speichelfließrate wurden alle Patienten in die Gruppen „Xerostomie“ < 0,2 ml/min (30 Patienten) und „Nichtxerostomie“ (zwölf Patienten) eingeteilt. Die Ergebnisse der Lebensqualität erbrachten signifikante Unterschiede für diese beiden Gruppen für folgende Dimensionen: „physische Funktion“, Dyspnoe, Schlucken, Essen in Gesellschaft, trockener Mund, Zusatznahrung und eine Tendenz für höhere Werte bei Appetitverlust.Schlussfolgerung:Die Korrelation zwischen „subjektiven“ Lebensqualitätsparametern und der Speichelfließrate konnte bestätigt werden. Die verschiedenen subjektiven Aspekte der Xerostomie scheinen mit dem EORTC-Fragebogen deutlicher differenzier- und quantifizierbar.

Neue Erkenntnisse zur Ätiologie der sogenannten Strahlenkaries

ZusammenfassungFragestellungDie Ätiologie der Strahlenkaries wird trotz vieler Untersuchungen kontrovers diskutiert: Die These einer direkten radiogenen Läsion des Zahnhartgewebes steht der einer indirekten Pathogenese über die Radioxerostomie gegenüber.MethodeIn einer systematischen Studie wurden Zähne mit manifester Strahlenkaries (Gruppe 1, zirka 60 Gy, langes Intervall bis zur Extraktion) und klinisch kariesfreie Zähne (Gruppe 2, zirka 30 Gy, kurzes Intervall) Zahnproben nach experimenteller enoraler In-situ- (60 Gy; Gruppe 3) und In-vitro-Bestrahlung (500 bis 2500 Gy; Gruppe 4) gegenübergestellt (jeweils60Co-Bestrahlung). Diese Proben wurden mit gesunden Zähnen als Kontrollen (Gruppe 5) verglichen. Durch konfokale Laser-Scanning-Mikroskopie (CLSM) erfolgten zerstörungsfreie Histotomogramme an frischen Längsschliffen und an Technovit-eingebetteten Schliffen (Trenn-Dünnschliff-Methode) mit Darstellung der Schmelz-Dentin-Grenze.ErgebnisseDrei charakteristische Veränderungen traten nur an Zahnproben von Radiotherapiepatienten auf: 1. Die grenznahen Aufzweigungen (Ramifikationen) der Odontoblastenfortsätze waren rarefiziert, 2. die Dentinkanälchen erreichten die Hartgewebsgrenze nicht mehr und 3. zeigte sich grenznah eine zirka 10 μm breite Zone geringerer Intensität remittierten Lichtes im Dentin.SchlußfolgerungenDie Obliteration der Dentinkanälchen, der eine Degeneration der Odontoblastenfortsätze vorausgeht, ist offensichtlich das Ergebnis eines direkten radiogenen Zellschadens mit Vaskularisations- und Stoffwechseleinschränkung im Bereich der Endigungen der Odontoblasten („letzte Wiese”). Das Stoffwechseldefizit vermittelt mit einer Latenz einen Parenchymschaden (hyporemittierende Zone), der die funktionellen Symptome (unterminierende Karies) erklärt. Die mikromorphologische Manifestation dieses direkten Strahlenschadens setzt den vitalen Zahn voraus und kann deshalb in situ und in vitro nicht beobachtet werden.AbstractAimIn spite of a great number of relevant studies the etiology of radiation induced caries still is discussed in controversy: The assumption of direct radiation induced lesions in the hard tissue is in contrast to an indirect pathogenesis mediated via radio-xerostomia.MethodsA systematic study is presented, comparing teeth with a manifest radiation caries (group 1, about 60 Gy, long interval to the extraction) and clinically caries free teeth (group 2, about 30 Gy, short interval) with tooth specimens after an experimental enoral (in situ) irradiation (60 Gy, group 3) and after in vitro irradiation (500 to 2.500 Gy, group 4).60Co was the irradiation source. Sound teeth were used as a standard (group 5). For non destructive visualisation of subsurface histotomograms by confocal laser scanning microscopy (CLSM) teeth were either used as fresh sections or as Technovit embedded thin slices (sawing grinding technique).ResultsTooth samples from radiotherapy patients (cancer therapeutic doses, long interval before extraction; group 1) showed three characteristic changes: 1. rarefication of the branching (ramification) of odontoblast processes near the junction, 2. dentine tubules end infront of the interface to the hard tissue and 3. in dentine the interface is characterised by an zone (about 10 μm wide) of low intensity of the remitted light.ConclusionsThe obliteration of the dentine tubules, preceded by a degeneration of the odontoblast processes, is obviously the result of a direct radiogenic cell damage with hampered vascularisation and metabolism particularly in the area of the terminations of the odontoblast processes. The deficit in metabolism combined with a latent damage of the parenchyma (hypo-remitting zone) is evidence for the functional symptoms (subsurface caries). The prerequisite for the micromorphological manifestation of this direct irradiation damage is a vital tooth and in consequence cannot be simulated in situ or in vivo.AIM In spite of a great number of relevant studies the etiology of radiation induced caries still is discussed in controversy: The assumption of direct radiation induced lesions in the hard tissue is in contrast to an indirect pathogenesis mediated via radio-xerostomia. METHODS A systematic study is presented, comparing teeth with a manifest radiation caries (group 1, about 60 Gy, long interval to the extraction) and clinically caries free teeth (group 2, about 30 Gy, short interval) with tooth specimens after an experimental enoral (in situ) irradiation (60 Gy, group 3) and after in vitro irradiation (500 to 2,500 Gy, group 4). 60Co was the irradiation source. Sound teeth were used as a standard (group 5). For non destructive visualisation of subsurface histotomograms by confocal laser scanning microscopy (CLSM) teeth were either used as fresh sections or as Technovit embedded thin slices (sawing grinding technique). RESULTS Tooth samples from radiotherapy patients (cancer therapeutic doses, long interval before extraction; group 1) showed three characteristic changes: 1, rarefcation of the branching (ramification) of odontoblast processes near the junction, 2. dentine tubules end in front of the interface to the hard tissue and 3, in dentine the interface is characterised by an zone (about 10 microns wide) of low intensity of the remitted light. CONCLUSIONS The obliteration of the dentine tubules, preceded by a degeneration of the odontoblast processes, is obviously the result of a direct radiogenic cell damage with hampered vascularisation and metabolism particularly in the area of the terminations of the odontoblast processes. The deficit in metabolism combined with a latent damage of the parenchyma (hypo-remitting zone) is evidence for the functional symptoms (subsurface caries). The prerequisite for the micromorphological manifestation of this direct irradiation damage is a vital tooth and in consequence cannot be simulated in situ or in vivo.

[Relevance of bisphosphonate long-term therapy in radiation therapy of endosteal jaw metastases].

Hintergrund und Ziel:Bisphosphonate (BPs), die seit > 20 Jahren u.a. bei ossären Metastasen und malignem Myelom erfolgreich eingesetzt werden, stehen seit 2003 in Assoziation zu Osteonekrosen des Kiefers (ONJ [„osteonecrosis of the jaw“]). Ätiologie und Pathogenese sind nicht hinreichend geklärt, aber die zunehmende Manifestationshäufigkeit gibt Anlass zur Beunruhigung. Ausgehend von den Kollektiven zweier Kliniken für Mund-Kiefer-Gesichts-Chirurgie werden die Therapiefolgen unter der Koinzidenz systemischer BP-Therapie und lokaler Strahlentherapie (RT) untersucht.Patienten und Methodik:Im Verlauf von 33 Monaten (01/2003–09/2005) wurden in der Mund-Kiefer-Gesichts-Chirurgie der Universitätsklinik Mainz und der HSK Dr. Horst Schmidt Kliniken Wiesbaden 63 teils syn-, teils metachrone ONJ bei 42 Patienten als Neuerkrankung beobachtet. Bei drei der 42 Patienten erfolgte unter BP-Therapie die RT einer Kiefermetastase.Ergebnisse:Nur eine Patientin konnte im gesamten Therapieverlauf begleitet werden; diese zeigte trotz niedriger Strahlendosis (40 Gy) eine bereits unter der RT beginnende therapierefraktäre ONJ ähnlich einer Osteoradionekrose. Die Notwendigkeit einer langstreckigen Unterkieferkontinuitätsresektion ging mit völligem Kaufunktionsverlust einher. Bei den 39 Patienten bzw. den 60 ONJ-Ereignissen ohne RT ergab sich nicht ein Mal die Notwendigkeit einer Kieferkontinuitätsresektion.Schlussfolgerung:Die lokale RT unter BP-Langzeittherapie kann eine besondere Risikokonstellation darstellen. Solange die Pathogenese der BP-assoziierten ONJ nicht weiter geklärt ist, sollten alle Patienten mit BP-Therapie vor einer RT der Kiefer-Gesichts-Region enoral untersucht sowie Zahnstatus und Mundhöhlenbefunde saniert werden.Background and Purpose:Bisphosphonates are used in the treatment of bone metastasis and malignant myeloma. They have been associated with osteonecrosis of the jaw (ONJ) since the year 2003. Etiology and pathogenesis of this clinical problem are not clear. The high rate of newly diagnosed cases is alarming. Based on the collective of two departments of oral and maxillofacial surgery, the results of therapy in the coincidence of systemic bisphosphonate treatment and local radiotherapy (RT) are analyzed.Patients and Methods:In the course of 33 months (01/2003–09/2005), 63 synchronic or metachronic ONJs were seen in 42 patients as newly diagnosed episodes. Three of the 42 patients had an RT of jaw metastasis.Results:Only one patient was followed over the whole treatment period. Under RT she developed a therapy-refractory ONJ similar to osteoradionecrosis at a dose of 40 Gy. She required a wide segmental osteotomy of the mandible resulting in a total loss of masticatory function. In 39 patients with 60 ONJs without RT not a single segmental resection of the mandible was necessary.Conclusion:Local RT in bisphosphonate long-term therapy seems to be a high risk constellation. As long as the pathogenesis of bisphosphonate-associated ONJ is unclear, patients subjected to RT of the head-and-neck area should be examined and dental findings should be treated.

Chronische Strahlenfolgen an den Zahnhartgeweben (“Strahlenkaries”) Klassifikation und Behandlungsansätze

Fragestellung: Die rasche Zahnhartgewebszerstörung nach einer Kopf-Hals-Bestrahlung wurde bereits vor fast 80 Jahren als “Strahlenkaries” beschrieben und ist seither als klinischer Befund in der Routine etabliert. Dennoch findet sich in der international vereinheitlichten Befundaufnahme und Dokumentation von Strahlenfolgen nach RTOG/EORTC bislang keine Klassifizierung dieser radiogenen Organveränderung. Material und Methode: Daten- und Bildmaterial von Strahlenfolgen an Zähnen von über 1 500 Patienten, die sich in periradiotherapeutischer Betreuung befanden, liegen der repräsentativen Auswahl zugrunde. Makroskopisch erkennbare Veränderungen, insbesondere das Ausmaß später Läsionen an den Zahnkronen, waren Grundlage einer Einteilung in vier Schweregrade. Leitlinie dieser Einteilung war die Systematik der Klassifizierungen von Strahlenfolgen nach RTOG/EORTC für andere Organe. Ergebnisse: Am gesamten Patientengut fanden sich inspektorisch keine frühen Strahlenfolgen an den Zähnen. In den ersten 90 Tagen nach Bestrahlungsbeginn gibt ungefähr ein Drittel der Patienten spontan reversible Hypersensitivitäten an, wahrscheinlich als Ausdruck einer temporären Hyperämie der Pulpa. Dagegen gelang die rangskalierte Bewertung von Merkmalausprägungen der Strahlenkaries als später Strahlenfolge in einer vergleichbaren Systematik zu den bereits etablierten RTOG/EORTC-Scores anderer Organe. Es wurden damit die Voraussetzungen geschaffen, die Strahlenkaries in die international vereinheitlichte RTOG/EORTC-Klassifizierung zu integrieren. Schlussfolgerungen: Die Dokumentation früher Strahlenfolgen an den Zahnhartgeweben ist derzeit vernachlässigbar. Dagegen haben die Befunderhebung und Dokumentation später Strahlenfolgen eine hohe Bedeutung. Die Identifikation einer Initialläsion an den Prädilektionsstellen “Zahnhals” und “Inzisalkante” führt zur rechtzeitigen Therapieeinleitung. Individuell ist damit eine wesentliche Voraussetzung für den Erhalt der Kaufunktion gegeben. Eine vereinheitlichte Dokumentation ist die unabdingbare Basis für die Beurteilung von Nebenwirkungen der radioonkologischen Therapie sowie der Wirksamkeit protektiver und supportiver Maßnahmen.Objectives: Since the first description of rapid destruction of dental hard tissues following head and neck radiotherapy 80 years ago, “radiation caries” is an established clinical finding. The internationally accepted clinical evaluation score RTOG/EORTC however is lacking a classification of this frequent radiogenic alteration. Material and Methods: Medical recores, data and images of radiation effects on the teeth of more than 1,500 patients, who underwent periradiotherapeutic care, were analyzed. Macroscopic alterations regarding the grade of late lesions of tooth crowns were used for a classification into 4 grades according to the RTOG/EORTC guidelines. Results: No early radiation effects were found by macroscopic inspection. In the first 90 days following radiotherapy 1/3 of the patients complained of reversible hypersensitivity, which may be related to a temporary hyperemia of the pulp. It was possible to classify radiation caries as a late radiation effect on a graded scale as known from RTOG/EORTC for other organ systems. This is a prerequisite for the integration of radiation caries into the international nomenclature of the RTOG/EORTC classification. Conclusions: The documentation of early radiation effects on dental hard tissues seems to be neglectable. On the other hand the documentation of late radiation effects has a high clinical impact. The identification of an initial lesion at the high-risk areas of the neck and incisal part of the tooth can be lead to a successful therapy as a major prerequisite for orofacial rehabilitation. An internationally standardized documentation is a basis for the evaluation of the side effects of radiooncotic therapy as well as the effectiveness of protective and supportive procedures.