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UNIVERSITA’ DI PISA
FACOLTA’ DI MEDICINA E CHIRURGIA
CORSO DI LAUREA IN ODONTOIATRIA E PROTESI DENTARIA
PRESIDENTE: PROF. MARIO GABRIELE
L’osteonecrosi dei mascellari: fattori
di rischio
Fabio La Ferla, Mario Gabriele
Cattedra di Chirurgia Speciale
Odontostomatologica
Alessandria, 5 Giugno 2010
U.O. Odontostomatologia e Chirurgia Orale
Azienda Ospedaliero Universitaria
Pisana
Marx RE.
Ruggiero SL, Merotra B, Rosenberg TJ, Engroff SL.
Pamidronate (Aredia) and zoledronate (Zometa) induced avascolar necrosis of
the jaws: a growing epidemic.
Osteonecrosis of the jaws associated with the use of bisphosphonates: a review
of 63 cases.
Int J Oral Maxillofac Surg 2003;61:1115-1118.
Int J Oral Maxillofac Surg 2004;62:527-534.
Osteonecrosi (ONJ)
È una patologia necrotica sito specifica del
tessuto osseo dei mascellari caratterizzata da:
• una lenta progressione
• mancata tendenza alla guarigione spontanea
• persistenza lesione > 8 settimane
ONJ: Fattori di rischio
Fattori
Sistemici
Fattori
Locali
Durata del trattamento
Woo SB, Hellstein JW, Kalmar JR. Systematic Review: bisphosphonates
and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761
Amor vincit omnia Caravaggio (1602-1603)
Durata del trattamento con BPs
Oncologist. 2009 Nov;14(11):1154-66. Epub 2009 Nov 8.
Bisphosphonates and time to osteonecrosis development.
Palaska PK, Cartsos V, Zavras AI.
Harvard School of Dental Medicine, Department of Oral Health Policy & Epidemiology, Boston, Massachusetts, USA.
Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a complication of long-term bisphosphonate (BP) use.
Given the beneficial effects of BP on bone quality in patients with cancer or osteoporosis, it is of great importance to
understand the risk as it relates to time to event or cumulative dose until the onset of disease. Because there is no
information on the lowest toxic dose from clinical trials, here we report on a review of 71 case series published since 2003.
We calculated the weighted mean time to event, as well as the minimum reported time and dose for zoledronate,
pamidronate, and oral bisphosphonates. The mean time to BONJ after zoledronate treatment was calculated at 1.8 years
and the minimum was 10 months; after pamidronate, the mean time was 2.8 years and the minimum was 1.5 years; and
after oral BP therapy, the mean time was 4.6 years and the minimum was 3 years. Zoledronic acid seems to be the most
potent among the nitrogen-containing BPs. Factors that seem to affect BONJ and time to event were invasive dental
procedures and other comorbid factors such as advanced age, rheumatoid arthritis, diabetes, use of corticosteroids,
vitamin D deficiency, and more. Understanding the pathophysiology of the disease requires further research.
Durata del trattamento con BPs
Oncologist. 2009 Nov;14(11):1154-66. Epub 2009 Nov 8.
Bisphosphonates and time to osteonecrosis development.
Palaska PK, Cartsos V, Zavras AI.
Harvard School of Dental Medicine, Department of Oral Health Policy & Epidemiology, Boston, Massachusetts, USA.
Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a complication of long-term bisphosphonate (BP) use.
Given the beneficial effects of BP on bone quality in patients with cancer or osteoporosis, it is of great importance to
understand the risk as it relates to time to event or cumulative dose until the onset of disease. Because there is no
information on the lowest toxic dose from clinical trials, here we report on a review of 71 case series published since 2003.
We calculated the weighted mean time to event, as well as the minimum reported time and dose for zoledronate,
pamidronate, and oral bisphosphonates. The mean time to BONJ after zoledronate treatment was calculated at 1.8 years
and the minimum was 10 months; after pamidronate, the mean time was 2.8 years and the minimum was 1.5 years; and
after oral BP therapy, the mean time was 4.6 years and the minimum was 3 years. Zoledronic acid seems to be the most
potent among the nitrogen-containing BPs. Factors that seem to affect BONJ and time to event were invasive dental
procedures and other comorbid factors such as advanced age, rheumatoid arthritis, diabetes, use of corticosteroids,
vitamin D deficiency, and more. Understanding the pathophysiology of the disease requires further research.
Durata del trattamento con BPs
Oncologist. 2009 Nov;14(11):1154-66. Epub 2009 Nov 8.
Bisphosphonates and time to osteonecrosis development.
Palaska PK, Cartsos V, Zavras AI.
Harvard School of Dental Medicine, Department of Oral Health Policy & Epidemiology, Boston, Massachusetts, USA.
Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a complication of long-term bisphosphonate (BP) use.
Given the beneficial effects of BP on bone quality in patients with cancer or osteoporosis, it is of great importance to
understand the risk as it relates to time to event or cumulative dose until the onset of disease. Because there is no
information on the lowest toxic dose from clinical trials, here we report on a review of 71 case series published since 2003.
We calculated the weighted mean time to event, as well as the minimum reported time and dose for zoledronate,
pamidronate, and oral bisphosphonates. The mean time to BONJ after zoledronate treatment was calculated at 1.8 years
and the minimum was 10 months; after pamidronate, the mean time was 2.8 years and the minimum was 1.5 years; and
after oral BP therapy, the mean time was 4.6 years and the minimum was 3 years. Zoledronic acid seems to be the most
potent among the nitrogen-containing BPs. Factors that seem to affect BONJ and time to event were invasive dental
procedures and other comorbid factors such as advanced age, rheumatoid arthritis, diabetes, use of corticosteroids,
vitamin D deficiency, and more. Understanding the pathophysiology of the disease requires further research.
Durata del trattamento con BPs
Oncologist. 2009 Nov;14(11):1154-66. Epub 2009 Nov 8.
Bisphosphonates and time to osteonecrosis development.
Palaska PK, Cartsos V, Zavras AI.
Harvard School of Dental Medicine, Department of Oral Health Policy & Epidemiology, Boston, Massachusetts, USA.
Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a complication of long-term bisphosphonate (BP) use.
Given the beneficial effects of BP on bone quality in patients with cancer or osteoporosis, it is of great importance to
understand the risk as it relates to time to event or cumulative dose until the onset of disease. Because there is no
information on the lowest toxic dose from clinical trials, here we report on a review of 71 case series published since 2003.
We calculated the weighted mean time to event, as well as the minimum reported time and dose for zoledronate,
pamidronate, and oral bisphosphonates. The mean time to BONJ after zoledronate treatment was calculated at 1.8 years
and the minimum was 10 months; after pamidronate, the mean time was 2.8 years and the minimum was 1.5 years; and
after oral BP therapy, the mean time was 4.6 years and the minimum was 3 years. Zoledronic acid seems to be the most
potent among the nitrogen-containing BPs. Factors that seem to affect BONJ and time to event were invasive dental
procedures and other comorbid factors such as advanced age, rheumatoid arthritis, diabetes, use of corticosteroids,
vitamin D deficiency, and more. Understanding the pathophysiology of the disease requires further research.
Durata del trattamento con BPs
Mesi trattamento
50
40
Trattamento
medio
30
Minimo
20
10
0
Zoledronate
Pamidronate
Oral BPs
Principio attivo
Palaska PK, Cartsos V, Zavras AI. Epub 2009 Nov 8.
Bisphosphonates and time to osteonecrosis development.
Oncologist. 2009 Nov;14(11):1154-66.
Osteonecrosi
L’incidenza varia da 0.15%
in controlled clinical trials a
9.1% di alcuni studi
retrospettivi
Dose cumulativa:
62 mg di zoledronato
3.285 mg di pamidronato
9.060 mg di alendronato
15-16
somministrazioni
di zoledronato
130-135
somministrazioni
di alendronato
ONJ: Fattori di rischio
Fattori
Sistemici
Fattori
Locali
Woo SB, Hellstein JW, Kalmar JR. Systematic Review: bisphosphonates
and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761
Crocifissione di San Pietro Caravaggio (1600-1601)
Fattori di rischio sistemici
• Patologie sistemiche
• Terapie mediche
• Stile di vita
• Fattori genetici
Woo SB, Hellstein JW, Kalmar JR. Systematic Review: bisphosphonates and
osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Giuditta che taglia la testa ad Oloferne Caravaggio (1598-1599)
Fattori di rischio sistemici
• Patologie sistemiche
• Terapie mediche
• Stile di vita
• Fattori genetici
Diabete
Immunodepressione
Vasculopatie periferiche
Sindrome da iperviscosità
Anemia
Woo SB, Hellstein JW, Kalmar JR. Systematic Review: bisphosphonates and
osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Fattori di rischio sistemici: Diabete
Clin Calcium. 2009 Sep;19(9):1332-8.
Diabetes mellitus and bisphosphonate-related osteonecrosis of the jaws
Urade M.
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine.
Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a newly emerging condition in a long-term
administration of mainly intravenous bisphosphonates for the treatment of hypercalcemia associated with
malignancy, multiple myeloma, and metastatic breast and prostate cancers. The incidence of BRONJ is not so
high, but it is very refractory to ordinary dental treatments, and the bone exposure, a typical symptom, continues
for several months. Although many cases of BRONJ have been reported worldwide, the precise pathogenesis
remains obscure. Diabetes mellitus (DM) is one of the systemic risk factors contributing in the development of
BRONJ. DM is generally associated with microvascular ischemia of the bone, endothelial cell dysfunction,
decreased bone turnover and remodeling, resulting in a delayed wound healing and easy to infection. In this issue,
the relation of DM as a systemic risk factor with development of BRONJ as well as the incidence, clinical
manifestations and prevention and treatment of BRONJ are described.
Fattori di rischio sistemici: Diabete
Clin Calcium. 2009 Sep;19(9):1332-8.
Diabetes mellitus and bisphosphonate-related osteonecrosis of the jaws
Urade M.
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine.
Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a newly emerging condition in a long-term
administration of mainly intravenous bisphosphonates for the treatment of hypercalcemia associated with
malignancy, multiple myeloma, and metastatic breast and prostate cancers. The incidence of BRONJ is not so
high, but it is very refractory to ordinary dental treatments, and the bone exposure, a typical symptom, continues
for several months. Although many cases of BRONJ have been reported worldwide, the precise pathogenesis
remains obscure. Diabetes mellitus (DM) is one of the systemic risk factors contributing in the development of
BRONJ. DM is generally associated with microvascular ischemia of the bone, endothelial cell dysfunction,
decreased bone turnover and remodeling, resulting in a delayed wound healing and easy to infection. In this issue,
the relation of DM as a systemic risk factor with development of BRONJ as well as the incidence, clinical
manifestations and prevention and treatment of BRONJ are described.
Fattori di rischio sistemici
• Patologie sistemiche
• Terapie mediche
• Stile di vita
• Fattori genetici
Diabete
Immunodepressione
Vasculopatie periferiche
Sindrome da iperviscosità
Anemia
Woo SB, Hellstein JW, Kalmar JR. Systematic Review: bisphosphonates and
osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Malattia oncologica?
L’ONJ
colpisce
unicamente
i
L’incidenza dell’ONJ
pazienti oncologici?
46% Mieloma multiplo
No!
39% Carcinoma mammario
L’ONJ colpisce più
6%frequentemente
Carcinoma prostatico i pazienti
oncologici
poiché assumono
4.1%
Osteoporosi
una dose cumulativa di BPs
3.5% Altre neoplasie metastatiche
maggiore
1% Morbo di Paget
Woo SB, Hellstein JW, Kalmar JR. Systematic Review: bisphosphonates and
osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761
Deposizione nel sepolcro Caravaggio (1602-1603)
Fattori di rischio sistemici
Chemioterapia
• Patologie sistemiche
• Terapie mediche
• Stile di vita
• Fattori genetici
Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos, Bozas G,
Koutsoukon V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E,
Dimopoulos MA. Osteonecrosis of the jaw in cancer after treatment with
biphosphonates: incidence and risk factors. J Clin Oncol 2005;23:8580-87
Jadu F, Lee L, Pharoah M, Reece D, Wang L. A retrospective study
assessing the incidence, risk factor and comorbidities of pamidronaterelated necrosis of the jaws in multiple myeloma patients. Annals of
Oncology 2007;
Radioterapia
Terapia cortisonica
Ciclofosfamide
Eritropoietina
Metrotrexate
Talidomide
Dialisi
Fattori di rischio sistemici: Chemioterapia
Leuk Lymphoma. 2007 Jan;48(1):56-64.
Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases
and an evaluation of its frequency in multiple myeloma patients.
Pozzi S, Marcheselli R, Sacchi S, Baldini L, Angrilli F, Pennese E, Quarta G, Stelitano C, Caparotti G, Luminari S, Musto P, Natale D, Broglia C, Cuoghi A, Dini D, Di
Tonno P, Leonardi G, Pianezze G, Pitini V, Polimeno G, Ponchio L, Masini L, Musso M, Spriano M, Pollastri G; Gruppo Italiano Studio Linfomi.
Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy.
Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients
treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective,
multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of
ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the
period 2002 - 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In
these 35 cases of ONJ, 24 appeared 20 - 60 months after starting BP treatment. The time for the onset of
ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with
pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was
1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our
analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we
were unable to identify any definite risk factors with a retrospective study. The most frequently ONJassociated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female
sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).
Fattori di rischio sistemici: Chemioterapia
Leuk Lymphoma. 2007 Jan;48(1):56-64.
Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases
and an evaluation of its frequency in multiple myeloma patients.
Pozzi S, Marcheselli R, Sacchi S, Baldini L, Angrilli F, Pennese E, Quarta G, Stelitano C, Caparotti G, Luminari S, Musto P, Natale D, Broglia C, Cuoghi A, Dini D, Di
Tonno P, Leonardi G, Pianezze G, Pitini V, Polimeno G, Ponchio L, Masini L, Musso M, Spriano M, Pollastri G; Gruppo Italiano Studio Linfomi.
Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy.
Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients
treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective,
multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of
ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the
period 2002 - 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In
these 35 cases of ONJ, 24 appeared 20 - 60 months after starting BP treatment. The time for the onset of
ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with
pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was
1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our
analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we
were unable to identify any definite risk factors with a retrospective study. The most frequently ONJassociated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female
sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).
Fattori di rischio sistemici: Cortisonici
J Oral Maxillofac Surg. 2010 May;68(5):1055-63.
Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw--a serial
case analysis.
Chiu CT, Chiang WF, Chuang CY, Chang SW.
Department of Oral and Maxillofacial Surgery, Chang Gung Memorial Hospital, Kaohsiung Memorial Center, Kaohsiung City, and Chang Gung University, College of Medicine, Taiwan.
PURPOSE: To offer recommendations of risk factors, prevention, and treatment of oral bisphosphonate and steroid-related
osteonecrosis of the jaw (BSRONJ) in Taiwan. MATERIALS AND METHODS: Twelve patients were clinicopathologically proved
to have bisphosphonate-related osteonecrosis of the jaw (BRONJ). All of the patients were taking oral bisphosphonates and were
concurrently administered long-term steroids. Of the 12 patients, 3 patients were assigned to the first stage of BRONJ; 5 patients
were assigned to the second stage, and 4 patients were assigned to the third stage. The patients' symptoms, localization of
necrosis, presence of a fistula, and association with possible triggering factors for onset of the lesion were recorded. RESULTS:
The radiologic investigations revealed osteolytic areas and scintigraphy demonstrated increased bone metabolism. Microbiologic
analysis showed pathogenic actinomycosis organisms in a majority of patients (91.6%). Antibiotic therapy, minor debridement
surgery, and combined hyperbaric oxygen therapy were useful in obtaining short-term symptomatic relief. CONCLUSIONS:
Comorbidities of steroid use along with bisphosphonates may cause osteonecrosis of the jaw to occur sooner, be more severe,
and respond more slowly to a drug discontinuation. The clinical disease of BSRONJ is more severe and more unpredictable to
treat than BRONJ. From the data gained from other published studies of BRONJ and our clinical experience with the series of
cases of BSRONJ, we offer recommendations of risk factors, prevention, and treatment of BSRONJ in southern Taiwan.
Fattori di rischio sistemici: Cortisonici
J Oral Maxillofac Surg. 2010 May;68(5):1055-63.
Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw--a serial
case analysis.
Chiu CT, Chiang WF, Chuang CY, Chang SW.
Department of Oral and Maxillofacial Surgery, Chang Gung Memorial Hospital, Kaohsiung Memorial Center, Kaohsiung City, and Chang Gung University, College of Medicine, Taiwan.
PURPOSE: To offer recommendations of risk factors, prevention, and treatment of oral bisphosphonate and steroid-related
osteonecrosis of the jaw (BSRONJ) in Taiwan. MATERIALS AND METHODS: Twelve patients were clinicopathologically proved
to have bisphosphonate-related osteonecrosis of the jaw (BRONJ). All of the patients were taking oral bisphosphonates and were
concurrently administered long-term steroids. Of the 12 patients, 3 patients were assigned to the first stage of BRONJ; 5 patients
were assigned to the second stage, and 4 patients were assigned to the third stage. The patients' symptoms, localization of
necrosis, presence of a fistula, and association with possible triggering factors for onset of the lesion were recorded. RESULTS:
The radiologic investigations revealed osteolytic areas and scintigraphy demonstrated increased bone metabolism. Microbiologic
analysis showed pathogenic actinomycosis organisms in a majority of patients (91.6%). Antibiotic therapy, minor debridement
surgery, and combined hyperbaric oxygen therapy were useful in obtaining short-term symptomatic relief. CONCLUSIONS:
Comorbidities of steroid use along with bisphosphonates may cause osteonecrosis of the jaw to occur sooner, be more severe,
and respond more slowly to a drug discontinuation. The clinical disease of BSRONJ is more severe and more unpredictable to
treat than BRONJ. From the data gained from other published studies of BRONJ and our clinical experience with the series of
cases of BSRONJ, we offer recommendations of risk factors, prevention, and treatment of BSRONJ in southern Taiwan.
Fattori di rischio sistemici
• Patologie sistemiche
• Terapie mediche
Obesità
Malnutrizione
• Stile di vita
Alcool
• Fattori genetici
Fumo
Wessel JH, Dodson TB, Zarvas AI. Zoledronate and other risk factors
associated with osteonecrosis of the jaw in cancer patients: a case-control
study. J Oral Maxillofac Surg 2008;66(4):625-631.
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Fattori di rischio sistemico: stile di vita
Am J Health Syst Pharm. 2009 Sep 1;66(17):1541-7.
Risk of osteonecrosis of the jaw in cancer patients taking bisphosphonates.
Gebara SN, Moubayed H.
School of Pharmacy and Chemistry, Kingston University, Kingston KT1 2EE, United Kingdom.
PURPOSE: The risk of osteonecrosis of the jaw (ONJ) associated with bisphosphonate use in patients with cancer
is reviewed. SUMMARY: ONJ is a relatively new complication of supportive care in cancer. Bisphosphonateassociated ONJ can be generally defined as necrotic bone exposure to the oral cavity and inflammatory reactions
of the surrounding soft tissue in patients receiving bisphosphonates but not radiotherapy to the head and neck. The
risk of development of ONJ varies with the type of bisphosphonate used and the duration of exposure, with more
potent agents increasing the risk with shorter durations of exposure. From the current evidence, the incidence of
this disorder in cancer patients receiving bisphosphonates can be as high as 10% when patients have more than
one risk factor. Risk factors include type of bisphosphonate, duration of exposure, concomitant medications,
comorbidities (e.g., hypertension, dyslipidemia, diabetes, rheumatoid arthritis, lupus), and lifestyle behaviors (e.g.,
smoking, obesity). To minimize the risk of ONJ, patients initiated on bisphosphonates should optimize routine
dental care and have their baseline oral cavity status evaluated by both clinical and radiographic examinations
before initiation of bisphosphonate therapy. Current management of ONJ is difficult and empirical. At present, a
conservative approach is recommended, including systemic antibiotics, antiseptic oral rinses, pain control, and
limited debridement. CONCLUSION: Cancer patients receiving bisphosphonates are at risk for developing ONJ.
Clinicians should evaluate patients' oral integrity and existing risk factors before initiating bisphosphonate therapy.
Once treatment is started, patients should be closely monitored for signs and symptoms of ONJ.
Fattori di rischio sistemico: stile di vita
Am J Health Syst Pharm. 2009 Sep 1;66(17):1541-7.
Risk of osteonecrosis of the jaw in cancer patients taking bisphosphonates.
Gebara SN, Moubayed H.
School of Pharmacy and Chemistry, Kingston University, Kingston KT1 2EE, United Kingdom.
PURPOSE: The risk of osteonecrosis of the jaw (ONJ) associated with bisphosphonate use in patients with cancer
is reviewed. SUMMARY: ONJ is a relatively new complication of supportive care in cancer. Bisphosphonateassociated ONJ can be generally defined as necrotic bone exposure to the oral cavity and inflammatory reactions
of the surrounding soft tissue in patients receiving bisphosphonates but not radiotherapy to the head and neck. The
risk of development of ONJ varies with the type of bisphosphonate used and the duration of exposure, with more
potent agents increasing the risk with shorter durations of exposure. From the current evidence, the incidence of
this disorder in cancer patients receiving bisphosphonates can be as high as 10% when patients have more than
one risk factor. Risk factors include type of bisphosphonate, duration of exposure, concomitant medications,
comorbidities (e.g., hypertension, dyslipidemia, diabetes, rheumatoid arthritis, lupus), and lifestyle behaviors (e.g.,
smoking, obesity). To minimize the risk of ONJ, patients initiated on bisphosphonates should optimize routine
dental care and have their baseline oral cavity status evaluated by both clinical and radiographic examinations
before initiation of bisphosphonate therapy. Current management of ONJ is difficult and empirical. At present, a
conservative approach is recommended, including systemic antibiotics, antiseptic oral rinses, pain control, and
limited debridement. CONCLUSION: Cancer patients receiving bisphosphonates are at risk for developing ONJ.
Clinicians should evaluate patients' oral integrity and existing risk factors before initiating bisphosphonate therapy.
Once treatment is started, patients should be closely monitored for signs and symptoms of ONJ.
Fattori di rischio sistemico: stile di vita
J Oral Maxillofac Surg. 2008 Apr;66(4):625-31.
Zoledronate, smoking, and obesity are strong risk factors for
osteonecrosis of the jaw: a case-control study.
Wessel JH, Dodson TB, Zavras AI.
Harvard School of Dental Medicine, Boston, MA 02115, USA.
PURPOSE: Bisphosphonates (BPs) effectively treat metastatic bone disease, hypercalcemia, and osteoporosis.
BP exposure, however, may be associated with osteonecrosis of the jaw (ONJ). The aim of the present study
was to estimate the magnitude of the association between intravenous (IV) BP exposure and ONJ, and to
identify potential confounders. MATERIALS AND METHODS: Using a case-control study design, the
investigators identified and adjudicated a sample of cases with ONJ and matched them randomly with 5 controls
per case. The controls were matched to cases on age, gender, cancer type, and date of cancer diagnosis. The
medical records were abstracted and data on BP exposure, cancer therapy, and comorbidities were recorded.
Statistical analyses were carried out using conditional logistic regression in Stata 9.0 (Stata Corp, College
Station, TX). RESULTS: Thirty cases of ONJ were identified at Massachusetts General Hospital from February
2003 through February 2007. Zoledronate was found to confer significant risk toward development of ONJ
(adjusted odds ratio = 31.8, P < .05). Although a trend toward increased risk was noted for pamidronate, this
association was not significant after controlling for zoledronate. Obesity and smoking were associated
significantly with ONJ development, whereas oral BPs had no effect. CONCLUSION: In this study, cancer
patients who had received zoledronate exhibited a significant 30-fold increase in their risk to develop ONJ. More
studies are needed to elucidate the exact role of obesity and smoking in the development of ONJ, and the
complex interactions of IV BPs with other chemotherapies during cancer treatment.
Fattori di rischio sistemico: stile di vita
J Oral Maxillofac Surg. 2008 Apr;66(4):625-31.
Zoledronate, smoking, and obesity are strong risk factors for
osteonecrosis of the jaw: a case-control study.
Wessel JH, Dodson TB, Zavras AI.
Harvard School of Dental Medicine, Boston, MA 02115, USA.
PURPOSE: Bisphosphonates (BPs) effectively treat metastatic bone disease, hypercalcemia, and osteoporosis.
BP exposure, however, may be associated with osteonecrosis of the jaw (ONJ). The aim of the present study
was to estimate the magnitude of the association between intravenous (IV) BP exposure and ONJ, and to
identify potential confounders. MATERIALS AND METHODS: Using a case-control study design, the
investigators identified and adjudicated a sample of cases with ONJ and matched them randomly with 5 controls
per case. The controls were matched to cases on age, gender, cancer type, and date of cancer diagnosis. The
medical records were abstracted and data on BP exposure, cancer therapy, and comorbidities were recorded.
Statistical analyses were carried out using conditional logistic regression in Stata 9.0 (Stata Corp, College
Station, TX). RESULTS: Thirty cases of ONJ were identified at Massachusetts General Hospital from February
2003 through February 2007. Zoledronate was found to confer significant risk toward development of ONJ
(adjusted odds ratio = 31.8, P < .05). Although a trend toward increased risk was noted for pamidronate, this
association was not significant after controlling for zoledronate. Obesity and smoking were associated
significantly with ONJ development, whereas oral BPs had no effect. CONCLUSION: In this study, cancer
patients who had received zoledronate exhibited a significant 30-fold increase in their risk to develop ONJ. More
studies are needed to elucidate the exact role of obesity and smoking in the development of ONJ, and the
complex interactions of IV BPs with other chemotherapies during cancer treatment.
Fattori di rischio sistemici
• Patologie sistemiche
Farmacogenetica
• Terapie mediche
• Stile di vita
• Fattori genetici
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for jaw
surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, Balanzategui
A, Santamaria C, Rosiñol L, de la Rubia J, Hernandez MT, Garcia-Navarro I,
Lahuerta JJ, González M, San Miguel JF.
Bisphosphonate-related osteonecrosis of the jaw is associated with
polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genomewide single nucleotide polymorphism analysis. Blood. 2008 Oct 1;112(7):2709-12.
Cena di Emmaus Caravaggio (1602)
Fattori di rischio sistemici: farmacogenetica
Blood. 2008 Oct 1;112(7):2709-12. Epub 2008 Jul 1.
Bisphosphonate-related osteonecrosis of the jaw is associated with
polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a
genome-wide single nucleotide polymorphism analysis.
Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, Balanzategui A, Santamaria C, Rosiñol L, de la Rubia J,
Hernandez MT, Garcia-Navarro I, Lahuerta JJ, González M, San Miguel JF.
Department of Haematology, Molecular Biology, and Human Leukocyte Antigen (HLA) Unit, University Hospital of Salamanca, Spain.
We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in
multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was
performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated
MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four
SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene
(CYP2C8) showed a different distribution between cases and controls with statistically significant
differences (P = 1.07 x 10(-6), P = 4.231 x 10(-6), P = 6.22 x 10(-6), and P = 2.15 x 10(-6), respectively).
SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni
correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in
cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an
increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).
Fattori di rischio sistemici: farmacogenetica
Blood. 2008 Oct 1;112(7):2709-12. Epub 2008 Jul 1.
Bisphosphonate-related osteonecrosis of the jaw is associated with
polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a
genome-wide single nucleotide polymorphism analysis.
Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, Balanzategui A, Santamaria C, Rosiñol L, de la Rubia J,
Hernandez MT, Garcia-Navarro I, Lahuerta JJ, González M, San Miguel JF.
Department of Haematology, Molecular Biology, and Human Leukocyte Antigen (HLA) Unit, University Hospital of Salamanca, Spain.
We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in
multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was
performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated
MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four
SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene
(CYP2C8) showed a different distribution between cases and controls with statistically significant
differences (P = 1.07 x 10(-6), P = 4.231 x 10(-6), P = 6.22 x 10(-6), and P = 2.15 x 10(-6), respectively).
SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni
correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in
cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an
increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).
Fattori di rischio sistemici: farmacogenetica
The Pharmacogenomics Journal Submitted
An aromatese polymorphism predicts risk of Bisphosphonate-related osteonecrosis of
jaws in oncologic patients.
La Ferla F, Paolicchi E, Crea F, Cei S, Graziani F, Gabriele M, Danesi R.
University of Pisa, Italy.
Background: Osteonecrosis of jaws (ONJ) in subjects under intravenous bisphosphonates therapy is a very life spoiling
adverse effect. Several acquired factors have been recognized as predictors of ONJ in oncologic patients, especially dental
infection or trauma. Recently, genetic polymorphisms arose as promising tools to identify patients with higher risk of drugrelated adverse events.
Objective: Examine the correlation between aromatase, estrogen receptor polymorphisms, and the risk of BP-related ONJ.
Methods: A clinical and radiological examination has been conducted on a sample of 168 oncologic subjects treated with
zoledronate. Subjects with a good oral health and without any oral infections were included in control group. Subjects with
ONJ, confirmed by histological analysis, were included in test group. Estrogen receptor and aromatase polymorphisms have
been analyzed on blood cell DNA. χ2 test has been employed to compare genotype distribution.
Results: Only 83 subjects (30 in the test group and 53 in the control group) were included in the study. No significant
differences between groups has been found in age, zoledronate treatment period, cancer type and therapy. Aromatase
C132810T polymorphism displayed an overrepresentation of TT allele in the test group (36.67 vs 16.98%, p<0.05).
Conclusion: Our data suggested a possible role of aromatase C132810T polymorphism in predicting ONJ risk. These results
can pave the way to the personalization of BP therapy, based on individual genotype.
Fattori di rischio sistemici: farmacogenetica
The Pharmacogenomics Journal Submitted
An aromatese polymorphism predicts risk of Bisphosphonate-related osteonecrosis of
jaws in oncologic patients.
La Ferla F, Paolicchi E, Crea F, Cei S, Graziani F, Gabriele M, Danesi R.
University of Pisa, Italy.
Background: Osteonecrosis of jaws (ONJ) in subjects under intravenous bisphosphonates therapy is a very life spoiling
adverse effect. Several acquired factors have been recognized as predictors of ONJ in oncologic patients, especially dental
infection or trauma. Recently, genetic polymorphisms arose as promising tools to identify patients with higher risk of drugrelated adverse events.
Objective: Examine the correlation between aromatase, estrogen receptor polymorphisms, and the risk of BP-related ONJ.
Methods: A clinical and radiological examination has been conducted on a sample of 168 oncologic subjects treated with
zoledronate. Subjects with a good oral health and without any oral infections were included in control group. Subjects with
ONJ, confirmed by histological analysis, were included in test group. Estrogen receptor and aromatase polymorphisms have
been analyzed on blood cell DNA. χ2 test has been employed to compare genotype distribution.
Results: Only 83 subjects (30 in the test group and 53 in the control group) were included in the study. No significant
differences between groups has been found in age, zoledronate treatment period, cancer type and therapy. Aromatase
C132810T polymorphism displayed an overrepresentation of TT allele in the test group (36.67 vs 16.98%, p<0.05).
Conclusion: Our data suggested a possible role of aromatase C132810T polymorphism in predicting ONJ risk. These results
can pave the way to the personalization of BP therapy, based on individual genotype.
Risultati
Aromatasi C1531T
Aromatase
La frequenza dell’allele TT,
associato ad una maggiore attività
aromatasica, all’interno del gruppo
test (36,67%) è più che doppia
rispetto alla popolazione controllo
(16,98%) (p=0,0439)
100
90
Distribution %
80
70
Aromatase TT
60
50
Aromatase TC-CC
40
30
20
*
An
aromatese polymorphism predicts risk of Bisphosphonate-related
osteonecrosis of jaws in oncologic patients.
La Ferla F, Paolicchi E, Crea F, Cei S, Graziani F, Gabriele M, Danesi R.
10
0
Test
Control
Group
Molecular Diagnosis & Therapy Submitted
*p<0.05
ONJ: Fattori di rischio
Fattori
Sistemici
Fattori
Locali
Woo SB, Hellstein JW, Kalmar JR. Systematic Review: bisphosphonates
and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761
Bacco Caravaggio (1596-1597)
Fattori di rischio locali
• Avulsioni dentarie
• Processi infettivi oro-dento-parodontali
• Chirurgia implantare e/o rigenerativa
• Riabilitazioni protesiche incongrue
• Igiene orale non soddisfacente
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
David con la testa di Golia Caravaggio (1609-16010)
Fattori di rischio locali
La comparsa di lesioni osteonecrotiche è
secondaria ad estrazioni dentarie, interventi
iatrogeni ed a processi infettivi a carico delle
ossa mascellari nell’88,9% dei casi.
Le lesioni “Spontanee” sono rare!
Fattori di rischio locali: Avulsioni dentarie
La terapia con BPs
determina un ritardo nel
fisiologico processo di
guarigione dell’alveolo
post estrattivo con
conseguente aumento
della suscettibilità ad
infezioni batteriche
Prof. M. Gabriele
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Fattori di rischio locali: Processi infettivi
oro-dento-parodontali
La diffusione di processi
infettivi attraverso il
sistema endodontico e
parodontale determinano la
colonizzazione batterica del
tessuto osseo profondo
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Fattori di rischio locali:
Chirurgia implantare e/o rigenerativa
L’aumenta suscettibilità ai
processi infettivi ed il
ridotto rimodellamento
osseo riducono la
predicibilità di queste
tecniche
Goss A, Bartold M, Sambrook P, Hawker P. The nature and frequency of
bisphosphonate-associated osteonecrosis of the jaws in dental implant
patients: a South Australian case series. JOral Maxilofac Surg
2010;68(2):337-43.
Fattori di rischio locali:
Chirurgia implantare e/o rigenerativa
La terapia implantare nei
pazienti in trattamento con
BPs è controindicata
Ministero del Lavoro, della Salute e delle Politiche sociali
Raccomandazione per la prevenzione dell’osteonecrosi della
mascella/mandibola da bifosfonati n. 10, settembre 2009
Fattori di rischio locali: Protesi incongrue
La presenza di manufatti
protesici fissi e/o mobili
incongrui può determinare
lesioni ai tessuti molli dando
luogo alla formazione di ulcere
che potrebbero evolvere in
lesioni osteonecrotiche
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Prof. M. Gabriele
Prof. M. Gabriele
Fattori di rischio locali:
Igiene orale non soddisfacente
La riduzione dell’indice di
placca e di sanguinamento
è associato ad una
riduzione della comparsa
di processi infettivi acuti a
carico dei tessuti
oro-dento-parodontali
Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for
jaw surgery in medical claims data: is it osteonecrosis?
J Oral maxillofac Surg 2006;64:917-923.
Baseline
Follow-up 3 mesi
UNIVERSITA’ DI PISA
FACOLTA’ DI MEDICINA E CHIRURGIA
CORSO DI LAUREA IN ODONTOIATRIA E PROTESI DENTARIA
PRESIDENTE: PROF. MARIO GABRIELE
L’osteonecrosi dei mascellari: fattori
di rischio
Fabio La Ferla, Mario Gabriele
Cattedra di Chirurgia Speciale
Odontostomatologica
Alessandria, 5 Giugno 2010
U.O. Odontostomatologia e Chirurgia Orale
Azienda Ospedaliero Universitaria
Pisana