REVIEW Ramírez ARTICLE et al
New Non-Bisphosphonate Drugs That Produce Osteonecrosis of the Jaws Lucía Ramíreza/Rosa María López-Pintorb/Elisabeth Casañasc/Lorenzo de Arribad/ Gonzalo Hernándeze Purpose: The aim of this paper was to review the current literature associating the non-bisphosphonate cancer-treatment drugs Denosumab, Bevacizumab and Sunitinib (used with or without bisphosphonate [BP]) with the presence of osteonecrosis of the jaws (ONJ) in patients. Materials and Methods: A literature review was conducted using the keywords osteonecrosis of the jaws, oral biphosphosnates, Denosumab, Bevacizumab and Sunitinib. Articles were obtained that reported cases of ONJ associated with the use of Denosumab, Bevacizumab and Sunitinib. Results: The literature shows that Denosumab can cause ONJ associated with triggers such as microtraumas or dental extractions. The combination of the drug along with zoledronic acid may have a synergistic effect. Bevacizumab may cause ONJ; however, there is much controversy regarding its synergistic action when used with BP. Sunitinib causes ONJ, and together with BP could increase the risk of developing lesions. Conclusion: Denosumab, Sunitinib or Bevacizumab are causal agents in the development of ONJ. The combination of any of these along with BPs could increase the risk of developing ONJ over that posed by BP treatment alone. Key words: Bevacizumab, Denosumab, osteonecrosis, Sunitinib Oral Health Prev Dent 2015;13:385-393 doi: 10.3290/j.ohpd.a34055
O
steonecrosis of the jaw (ONJ) is a bone disorder in which bone devitalisation takes place along with hypovascularity, hypocellularity and local tissue hypoxia. These changes lead to the death of osseous jaw tissues. ONJ is described as a condition very often associated with patients who have had cancer and have been treated with certain medicaa
Dentist, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Wrote manuscript.
b
Assistant Professor, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Idea, revised manuscript.
c
Assistant Professor, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Wrote manuscript.
d
Associate Professor, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Idea, revised manuscript.
e
Professor, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Revised manuscript.
Correspondence: Lucía Ramírez Martínez Acitores. C/ Joaquín Costa, 51 28002 Madrid, Spain. Tel: +34-66-930-5353. Email: [email protected]
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Submitted for publication: 16.12.13; accepted for publication: 23.04.14
tions and/or radiotherapy. Currently, ONJ is classified into two types based on aetiology: osteoradionecrosis (ORN), a condition in which irradiated bone fails to heal within three months in the absence of a local tumour;29 and bisphosphonate (BP)-induced ONJ lesions developing over 6 to 8 weeks in patients that have not undergone prior irradiation. In addition, performing invasive dental procedures can be considered a predisposing factor in terms of ONJ.3,18,31 Currently, three new drugs have become commercially available – Denosumab, Bevacizumab and Sunitinib – whose use separately or together with a BP may be associated with the onset of ONJ. Therefore, the aim of this paper was to review the literature available on ONJ produced by these three new drugs and to examine any possible relationship of these drugs with the occurrence of ONJ.
MATERIALS AND METHODS A literature review was conducted using the following key words: non-oral bisphosphonate osteone-
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crosis AND oral osteonecrosis, oral osteonecrosis AND Sunitinib, oral osteonecrosis AND Denosumab, oral osteonecrosis AND Bevacizumab. Articles published between the years 2007 and 2012 were included, and articles were excluded that were not published in journals or indexed in MEDLINE.
RESULTS Thirty-five articles published in English between 2007 and 2012 were obtained. Nine articles were found on the relationship of Denosumab with the development of ONJ: 5 clinical trials, 3 literature reviews and one case report. Fifteen articles on the emergence of treatment-related ONJ with Bevacizumab were found: 4 clinical trials, 3 literature reviews and 8 case reports. Nine articles (3 literature reviews and 6 case reports) on the relationship of Sunitinib to the development of ONJ were found.
DISCUSSION ONJ associated with Denosumab Denosumab (Prolia 60 mg and Xgeva 120 mg) is a human monoclonal antibody (IgG2) produced by a hybrid cell fusion product of a B-cell clone descendant of one mother cell and a tumour plasma cell.6 In June 2010, the US Federal Drug Administration (FDA) approved its use in the treatment of osteoporosis in postmenopausal women with a high risk of fractures. In July 2011, the European Commission approved its use for the prevention of fractures, spinal cord compression and severe bone pain in patients with malignancies who had bone metastases. Currently, its use is being studied for treating lung cancer or multiple myeloma with better results than the BPs.10,11,17,23,24,30 Denosumab is able to bind with high affinity and specificity to the receptor activator of nuclear factor-kB ligand (RANKL), preventing activation of its receptor RANK on surfaces of osteoclast precursors into osteoclasts. To prevent the interaction of RANKL/RANK, it inhibits the formation, function and survival of osteoclasts, which in turn causes a decrease in bone resorption.1,10,11,23,24,30 Denosumab has a mechanism of action similar to the BPs. It causes an alteration of the formation, function and survival of osteoclasts. Impaired healing takes place after microtraumas or invasive dental treatment in these patients, thus triggering the
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appearance of ONJ in some cases (Table 1a).1,6 However, the risk of ONJ in these patients is similar to that of patients being treated with oral BP, a relatively low 0.09% to 0.34% of cases.6 Due to its mechanism of action this drug can be considered a cause of ONJ. However, in cancer patients, polypharmacy exists with chemotherapy and/or non-specified antiangiogenic drugs that may be associated with emergence of ONJ (Table 1). Therefore, even though the literature shows a direct relationship between Denosumab and ONJ, further clinical trials are necessary in this regard to confirm this relationship.1 In their three articles, Lipton et al11,23,24 could not find an association of ONJ with the use of Denosumab and/or intravenous BPs. In the first two articles, 255 patients were evaluated, 43 treated with intravenous BPs and 212 with Denosumab in different concentrations for a period of 4 or 12 weeks. In the third study conducted in 2009, they evaluated 111 patients, 37 treated with intravenous BPs and 17 with Denosumab for 25 weeks. It is important to note that the treatment time in all the studies is very short, perhaps explaining the lack of ONJ cases in patients treated with Denosumab or BP. However, Stopeck et al30 conducted a study in which 1026 patients were treated with Denosumab and 1020 with zoledronic acid. After three years, 2% of the patients treated with Denosumab suffered ONJ vs 1.4% of those treated with intravenous BPs. In most cases, the aetiological cause associated with the onset was a poorly fitting prosthesis (90% in the Denosumab group, and 75% in the BP group). In 50% of patients treated with Denosumab, the ONJ was cured after removal of the drug compared to 43% of the patients treated with BPs. In the study by Henry et al,17 886 patients treated with Denosumab and 890 with zoledronic acid were observed. 1.3% of the patients treated with Denosumab experienced ONJ after three years, as did 1.1% of the patients treated with zoledronic acid. Most of the cases were caused by microtraumas from poorly fitting dentures (91% in patients treated with Denosumab and 70% of those treated with BPs). 40% of the patients treated with Denosumab and experiencing ONJ improved with drug withdrawal compared to 27% of those patients treated with zoledronic acid. Denosumab is a circulating protein that is not deposited in the bone and after discontinuation does not persist in the bloodstream as long as do BPs. Thus, the withdrawal of this drug in cases of ONJ onset appears to be more effective in terms of
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Table 1a ONJ in patients treated with denosumab
Authors
Year
Patients
Stopeck et al30
2010
20
Henry et al17
Fizazi et al10
2011
2011
10
17
Location and cause of osteonecrosis (ON)
Progression
Not described
Not described
Denosumab 180 mg every 4 weeks for 3 years
Not described
4 patients cured with antibiotic treatment. The authors did not report if denosumab was withdrawn in these patients. 4 patients needed surgical treatment. The authors did not report if denosumab was withdrawn in these patients. 2 patients with no described progression. The authors did not report if denosumab was withdrawn in these patients.
Denosumab 120 mg every 4 weeks for 11.9 months
ONJ (no precise localization described), history of prosthesis use, poor hygiene or dental extraction
5 patients cured with antibiotic treatment. The authors did not report if denosumab was withdrawn in these patients. 10 patients needed surgical treatment (desbridement, osseous curettage). The authors did not report if denosumab was withdrawn in these patients. 2 patients needed osseous resection. The authors did not report if denosumab was withdrawn in these patients.
Scheduled medication Denosumab 120 mg every 4 weeks for 3 years
Table 1b ONJ in patients treated with denosumab + BP Authors
Aghaloo et al1
Year
2011
Patients
Scheduled medication
Location and cause of ON
Progression
Denosumab 120 mg intramuscular (IM)/ week for 3 weeks, and 120 mg/month until improvement for up to 2 years. Alendronate 70 mg/weeks for 4 weeks, 4 years prior.
ONJ of right side of mandible (no cause described)
No elimination of medication, no healing of lesion
healing than does the withdrawal of BPs in cases of ONJ due to BPs, although the healing rates reviewed in articles vary as noted earlier.6 In short, Denosumab is a drug that has an action mechanism similar to that of BPs, and it may have a direct relationship with the development of ONJ, with an incidence similar to that produced by oral BPs in cases of ONJ onset.
ONJ associated with Denosumab and BP There is only one case report of combined BP-Denosumab therapy and the onset of ONJ (Table 1b), and those authors1 indicate that BPs may have a synergistic action with Denosumab. In the single case report, the patient was medicated with Denosumab 120 mg/week for 3 weeks and 120 mg/ month until there were signs of improvement. It is necessary to conduct further work to properly assess the possible relationship, as there are no dependable scientific studies that demonstrate the synergy of the two treatments.
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ONJ associated with Bevacizumab Bevacizumab (Avastin) is a G1-humanised monoclonal antibody. The drug binds to endothelial growth factor (VEGF), thus inhibiting the attachment of cells to its receptors Flt-1 (VEGFR-1) and the kinase insert domain receptor (KDR) (VEGFR-2) located on the surface of endothelial cells. By neutralising the biological activity of VEGF, tumour vascularisation is reduced, thus inhibiting its growth.19 Bevacizumab is indicated in patients with metastatic carcinoma of the colon or rectum, glioblastoma, lung cancer and neoplasic neurovascular diseases. It has other nonneoplasic uses, in ophthalmology, for example.19 ONJ caused by Bevacizumab may be due to reduced VEGF action and the consequent decrease of angiogenesis. VEGF factor is essential for the formation, self-regulation and survival of osteoclasts. Thus, any alteration of this factor results in a decrease in bone repair ability. This, together with microtraumas (brushing and chewing) or invasive dental treatments may cause a mandibular lesion and development of ONJ.16,28
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The first case of ONJ caused by Bevacizumab was described in 2008 (Tables 2a and 2b).9 Since then, new clinical cases of ONJ have been described15,19,28 in which there is no clear risk factor except the use of Bevacizumab (Table 2a). Other authors25,32 mention that there is no relationship between the use of Bevacizumab without added BPs and the increased risk of ONJ. In a retrospective study with 1076 patients treated with Bevacizumab, only two cases of ONJ were reported.16 Those authors16 therefore stated that the ONJ described in Bevacizumab-treated patients may be due to other aetiologies present in the development of this pathology. In short, the involvement of Bevacizumab in the onset of ONJ is controversial, since in most cases (see below), it has been linked to the association of the use of this drug with BP treatment (Table 2c).
ONJ associated with Bevacizumab and BP Several authors5,8,27 have published 7 isolated cases of ONJ with or without an added risk factor (extractions, poorly fitting dentures, etc) in patients with a combined therapy of BPs and Bevacizumab. Katsenos et al20 published the only case that exists in the literature of development of ONJ in a patient
undergoing radiotherapy along with a combined treatment of BPs and Bevacizumab (Tables 2c and 2d). In the study by Guarneri et al,16 two cases of ONJ were described among 233 patients treated with BPs and Bevacizumab at the same time. There is some controversy about the increased risk of ONJ in patients given this combined therapy. Some authors claim that the risk of ONJ increases around 1.1% to 1.4% vs 2% increased risk with BPs plus Bevacizumab.5,8,14,25 In fact, in the combined therapy with intravenous BPs and Bevacizumab, the BPs can increase the avascularization caused by Bevacizumab.16 However, if a patient has ONJ due to the use of BPs, he/she does not have an increased risk of developing another form of ONJ if Bevacizumab is added to their treatment.13,16,32 There are only four trials that directly evaluate ONJ in patients treated with bevazucimab with or without BPs.4,13,16,25 McArthur et al25 conducted a study in which 1711 patients were treated with Bevacizumab and 409 with Bevacizumab and pamidronate and/or zoledronic acid. Only 8 patients developed ONJ, and all received a combined treatment of Bevacizumab and BPs (2%). In another study4 with a sample size of 60 patients, 55 were treated with BPs and Bevacizumab, and 5 with Bevacizumab alone. Eleven patients (18.3%) receiving a combination therapy developed ONJ, while those
Table 2a ONJ in patients treated with Bevacizumab alone Authors
Year
Scheduled medication
Location and cause of ON
Evolution
Estilo et al9
2008
Bevacizumab 15 mg/kg every 3 weeks for 24 weeks
Spontaneous ON of mandible weeks after finishing treatment
Improvement after eliminating drug; it reappeared spontaneously.
Greuter et al15
2008
Bevacizumab (dosage not specified) for 1 month
ON of right side of maxilla after extracting teeth 25 and 26
Improvement after eliminating drug.
Serra et al28
2009
Bevacizumab 7.5 mg/kg every 3 weeks for 1 week (one dose)
ON of right side of mandible post-extraction of tooth 37
Improvement after eliminating drug.
Bevacizumab 7.5 mg/kg every 3 weeks for 7 months
ON of mandible post-extraction
Bevacizumab 7.5 mg/kg every 3 weeks for 2 months
ONJ (location and cause not described)
Improvement after eliminating drug; treatment with antibiotic.
Bevacizumab 2.5 mg intravitreal administration (duration of treatment not specified)
ON of right side of mandible post-extraction 2 years after treatment
16
Guarneri et al
Hopp et al19
2010
2012
Improvement with antibiotic treatment
Table 2b ONJ in patients treated with Bevacizumab + radiotherapy Authors
Estilo et al
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9
Year
Scheduled medication
Location and cause of ON
Progression
2008
Bevacizumab 10 mg/kg every 2 weeks for 13 weeks, radiotherapy for 1 year, radiation total of 5940 Gy/33 fractions
Spontaneous ONJ of the right side of the mandible
Bevacizumab was not suspended and the lesion did not improve.
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Table 2c ONJ in patients treated with Bevacizumab + BP Authors
Year
McArthur et al25
2008
Aragon-Ching 2009 et al4
Scheduled medication 4 case reports: Bevacizumab + intravenous BP (pamidronate or zoledronic acid) Bevacizumab 15 mg/kg/21 days + zoledronic acid for 5 weeks, prior medication oral alendronate for 3 years
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 12 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 36 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 30 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 24 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 3 months
Aragon-Ching 2009 et al4
2 case reports: Bevacizumab 15 mg/kg/21 days + zoledronic acid for 6 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 19 months
Ayllon et al5
2009
Christodoulou 2009 et al8
Guarneri et al16
2010
Salort-Llorca 2011 et al27
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Zoledronic acid 4 mg IV every 3 weeks for 4 months, clodronic acid (dosage not specified) after zoledronic acid for 15 months, Bevacizumab 2–3 months. Ibandronic acid 6 mg for 7 years, Bevacizumab and chemotherapy (not specified) Zoledronic acid 4 mg every 3 weeks for 20 months, Bevacizumab 20 months, chemotherapy (8 cycles of 3 weeks) Zoledronic acid 4 mg every 3 weeks for 38 months, Bevacizumab 8 months, chemotherapy 8 months. Bevacizumab 7.5 mg/kg every 3 weeks, zoledronic acid (dose not speficied) for 3 weeks Bevacizumab 7.5 mg/kg every 3 weeks, zoledronic acid (time not specified) Bevacizumab 15 mg/kg/21 days for 30 weeks + IV BP (not specified) Bevacizumab (dose not specified + IV BP (not specified) Bevacizumab 10 mg/day/14 days for 13 weeks + IV BP (not specified)
Location and cause of ON
Progression
Not described
Not described
ONJ (mandible), no cause described
ONJ ulcer healed and was asymptomatic, along with good oral hygiene (OH). Zoledronic acid was withdrawn, and treatment with Bevacizumab continued.
ONJ of maxilla and mandible; no cause described ONJ of mandible; no cause described ONJ of mandible; no cause described ONJ of maxilla no cause described ONJ mandibular caused by tooth extraction ONJ of mandible; no cause described ONJ of mandible caused by tooth extraction ONJ (mandible) postextraction
Improvement along with maintaining good OH. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. Complete healing after cleaning with Peridex (CHX 0.12%); sequestrectomy, surgery performed and antibiotics given. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. ONJ remained stable with Peridex (CHX 0.12%) cleaning, sequestrectomy performed and antibiotics administered. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. Healing with Peridex (CHX 0.12%). Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. No improvement after Peridex (CHX 0.12%) and sequestrectomy. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. Complete healing after Peridex (CHX 0.12%) and sequestrectomy. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. No healing present after Peridex (CHX 0.12%). Zoledronic acid was withdrawn, and treatment with Bevacizumab continued.
None described.
Temporary improvement after eliminating the BP.
ONJ (location not described) post-extraction
No improvement after eliminating medication + antibiotic treatment.
Temporary improvement after eliminating all medication + antibiotic therapy.
Spontaneous ONJ
ONJ (pertinent information not described)
No improvement after eliminating the treatment.
Improvement after dental, antibiotic and surgical treatment.
Spontaneous improvement.
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Table 2d ONJ in patients treated with Bevacizumab + BP+ Radiotherapy Scheduled medication
Location and cause of ON
Aragon-Ching 2009 et al4
Bevacizumab 15mg/kg/21 days + RT+ zoledronic acid 7 months
ONJ (mandible); no cause described
Improvement but no healing after Peridex (CHX 0.12%), and sequestrectomy. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued.
Aragon-Ching 2009 et al4
Bevacizumab 15mg/kg/21 days + RT+ zoledronic acid 36 months
ONJ (mandible); no cause described
Improvement but no healing after Peridex (CHX 0.12%). Zoledronic acid was withdrawn, and treatment with Bevacizumab continued.
Katsenos et al20
Zoledronic acid 4 mg IV monthly for 3 months, Bevacizumab 15 mg/kg every 3 weeks for 3 months, radiotherapy (dosage not described)
ONJ (right side of mandible) in patients with dental prosthesis
None described
Authors
Year
2012
treated with Bevacizumab alone did not. Two of them had also received radiotherapy. In a study with 1309 patients treated with Bevacizumab (1076 treated with BPs and Bevacizumab, and 233 with Bevacizumab only), Guarneri et al16 found that 4 patients developed ONJ: 2 with combined therapy and 2 with monotherapy. In contrast, Francini et al13 found no cases of ONJ after 19.7 months of follow-up in 59 patients treated with Bevacizumab and BPs. Notably, none of these patients underwent invasive dental procedures during treatment, even if they had other risk factors such as poorly fitting dentures, periodontal disease or tooth extractions performed six weeks before treatment. Therefore, there appears to be an increased risk of ONJ in patients receiving combination therapy of Bevacizumab and BPs, although it might be necessary to do well-designed clinical studies.
ONJ associated with Sunitinib (Tables 3a and 3b) Sunitinib (Sustent) is an oral drug that reduces angiogenesis. It is highly potent in the treatment of tumours, including gastrointestinal, lung, thyroid and hematologic ones. In 2006, it was introduced in the US by the pharmaceutical company Pfizer. This drug inhibits cell signaling by binding to multiple receptor tyrosine kinases (RTKs). These include all platelet-derived growth receptor factors (PDGFRs) and vascular endothelial growth factors (VEGFRs). The inhibition of these receptors impair proliferation, migration, differentiation, neoangiogenesis and invasion of cancer cells, thereby providing an attractive target for anticancer therapy.7,12,18,21 Unlike conventional chemotherapy administered dur-
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Progression
ing defined periods, Sunitinib can be used as a maintenance drug for a longer period of time, even years.12,18 A publication from 201121 describes a case of ONJ in a patient treated with Sunitinib without BPs. After tooth extraction, this patient consequently suffered the emergence of a bone injury with swelling and purulent exudate. As there was no scarring present, a CT scan was performed which confirmed the development of ONJ. A histology sample of the lesion reflected the existence of a small necrotic bone invasion of polymorphonuclear cells and actinomyces. The patient underwent surgery once the subnitinib treatment was finished. In 2012, Fleissing et al12 published another case of ONJ after the extraction of mandibular third molars in a patient treated with Sunitinib. The patient’s condition improved after surgical removal of those teeth along with the help of antibiotics. Although there are few cases of ONJ in patients treated with Sunitinib, the use of this medication must be taken into consideration when performing invasive dental treatments for the hypothetical risk of developing ONJ.
ONJ associated with Sunitinib and BP (Tables 3b and 3c) The combination of Sunitinib with intravenous BPs causes an increased risk of developing ONJ compared to using either drug separately; an incidence of 0.9% to 2.4% has been reported.8,12 There are two possible reasons to explain the synergy of the two drugs:5,12,22,26 • Sunitinib causes oral mucositis in 10%–30% of the patients,22,26,31 which increases the suscep-
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Table 3a ONJ in patients treated with Sunitinib Location and cause of ON
Authors
Year
Scheduled medication
Progression
Koch et al21
2011
Sunitinib 50 mg day, 4 weeks and 2 weeks of drug holiday for 5 months
ON of left side of mandible post-extraction of tooth 36
Improvement after eliminating drug.
Fleissing et al12
2012
Sunitinib 50 mg day for 4 weeks, 2 weeks of drug suspension, for 1 year
ON of right side of mandible post-extraction of tooth 48
Improvement after eliminating drug; antibiotic and surgical treatment.
Location and cause of ON
Progression
Table 3b ONJ in patients treated with BP + Sunitinib Authors
Year
Scheduled medication
Brunello et al7
2009
Zoledronic acid 4 mg iv monthly/11 months, Sunitinib 50 mg day 4 weeks, 2 weeks of drug suspension, for 5 months
Spontaneous ON of left side of mandible
Improvement after eliminating the drug.
Ayllon et al5
2009
Zoledronic acid 4 mg iv every 3 weeks for 19 months, Sunitinib (dosage not described) 14 months
ON of mandible postextraction
None described.
Christodoulou 2009 et al8
Zoledronic acid 4 mg iv every 4 weeks + Sunitinib (dosage not described), for 15 months
ON (location and cause not described)
Improvement after eliminating BP + antibiotic therapy.
Mignogna et al26
2009
Subnitinib 3 cycles of 25 mg orally 3x/day (every cycle 14 days + 7 days drug suspension) for 42 days, zoledronic acid 4 mg iv monthly, for 42 days.
ON on the palate
None described.
Hoerfert and Eutinger18
2010
Zoledronic acid 4 mg iv/month for 13 months, Sunitinib 50 mg day for 4 weeks, 2 weeks drug suspension + zoledronic acid 4 mg iv/month for 13 months for 4 days.
ON of the mandible after extraction of teeth 36 and 48
Improvement after eliminating drug therapy and relapse occurs once Sunitinib is reinstated.
Hoerfert and Eutinger18
2010
Zoledronic acid 4 mg iv/ months1 month after extraction for 6 months. Sunitinib 50 mg day 4 weeks and 2 weeks of drug holiday for 1 year.
ON of the mandible post-extraction of teeth 36 and 48.
Treatment is not discontinued for oncologic reasons.
Salort-Llorca et al27
2011
Zoledronic acid 4 mg iv/ month for 6 months Sunitinib 50 mg day4 weeks and 2 weeks of drug holiday. For 3 months.
ON of the mandible
Improvement after eliminating drug therapy and relapse occurs when treatment is reinstated.
Agrillo et al2
2012
Zoledronic acid 4 mg iv/ months + Sunitinib 50 mg day 4 weeks and 2 weeks of drug holiday for 1 year
Spontaneous ON of the maxilla
Treatment is not discontinued for oncologic reasons.
2012
Zoledronic acid 4 mg iv/month 1 year. Sunitinib 50 mg day 4 weeks and 2 weeks of drug holiday for 3 months
Spontaneous ON after 1 year of treatment with zoledronic acid which worsens with Sunitinib
Treatment is not discontinued for oncologic reasons.
Agrillo et al2
Table 3c ONJ in patients treated with Sunitinib + BP+ radiotherapy Authors Hoefert and Eutinger18
Year
Scheduled medication
2010
Radiotherapy 30 gy, Ibandronate iv 6 mg/ month for 10 months, Sunitinib 50 mg/day 4 weeks, 2 weeks of drug suspension, for 10 months
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Location and cause of ON ONJ of right side of mandible post-extraction
Progression No improvement after eliminating drug and surgical treatment.
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tibility of the mucosa or gingiva to the action of the BPs. Mucositis usually occurs when starting the drug, and during rest periods, the pathology lessens. Therefore, it is necessary to prevent mucositis in these patients. For this, we recommend the use of non-alcoholic mouthwashes, toothpastes without peroxide, viscous lidocaine and changing dietary habits to avoid spicy, acidic and very cold or hot foods.18,21,22,26 In patients with mucositis who commence treatment with BPs, it is recommended to discontinue Sunitinib for 4 weeks if possible, until the level of toxicity caused by the drug has fallen.18 • The combination of these two drugs causes an alteration in the healing of oral lesions together with inactivation of VEGFR in areas of major vascular injury and causes the greatest risk of ONJ lesions.18 Since 2009, multiple articles2,5,7,8,12,18,26,27 have described the occurrence of ONJ during combined treatment with Sunitinib and BPs. Brunello et al7 described a patient with renal cell carcinoma treated with zoledronic acid. BP treatment was replaced by Sunitinib to prevent the occurrence of ONJ after a dental abscess, but the patient developed spontaneous ONJ from the second cycle of Sunitinib. After three cycles of the drug, the ONJ worsened, so a cause-effect relationship was suspected with Sunitinib, and consequently the drug was withdrawn. Ayllon et al5 described a case of ONJ in a patient treated with zoledronic acid for 19 months and Sunitinib for 14 months. An ONJ lesion was developed which was then attributed to treatment with BPs. Christodoulou et al8 reported a case of ONJ in a patient after two years of treatment with Sunitinib and zoledronic acid. The patient improved when BP treatment was discontinued and Sunitinib was maintained. Mignogna et al26 reported a case of spontaneous ONJ in the palate during combination therapy with Sunitinib and BPs, without specifying whether there was improvement after Sunitinib was discontinued. Hoefert and Eufinger18 presented the case of a patient with renal cell carcinoma who developed ONJ after extraction of a mandibular right first molar. The patient had 5 months of treatment with Sunitinib, and began treatment with zoledronic acid one month after the extraction. It was decided to treat the ONJ with surgery, antibiotic therapy and suspension of both treatments. A month later, when the bone lesion had healed, both treatments
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(Sunitinib and zoledronic acid) were resumed for oncological reasons. The patient developed ONJ in the mandibular left alveolar ridge with worsening periods that coincided with the cycles of Sunitinib. The lesion continued to progress up to about 10 mm, but the treatment was not discontinued for oncological reasons. The same study included a patient treated with zoledronic acid for a year; this was subsequently replaced with a combination of zoledronic acid and Sunitinib. A year after starting with the combination therapy, the patient developed ONJ. The lesion was treated three times with surgery and antibiotic therapy, during which the cancer treatment was interrupted for a month, but resumed shortly after surgery for oncological reasons. This process recurred up to four times and a similar treatment regimen of surgery and antibiotic therapy was performed; however, the fourth time, only zoledronic acid was administered, without any signs of a new relapse. Salort-Llorca et al27 describe a case of a patient receiving Sunitinib combined with BPs who developed ONJ. The lesion improved after suspension of treatment, but worsened when treatment was restored for oncologic reasons. Two patients exhibiting ONJ who were treated with zoledronic acid and Sunitinib are described by Agrillo et al.2 One of these patients had a lesion in the maxilla and the other patient in the mandible; both lesions appeared spontaneously and did not improve with antibiotics and surgery. Therefore, as published in the literature and according to the mechanism of action of bisphosphonates and Sunitinib, there might be a synergistic action between the two drugs when developing ONJ. Thus, this risk must be taken into account before performing any invasive dental treatment.
CONCLUSION Documented cases of the development of ONJ exist in which the main causal agent is treatment with the following drugs: Denosumab, Sunitinib or Bevacizumab. The combination of any of these along with BPs could increase the existing BP-related risk of developing ONJ. Nonetheless, the incidence rates of ONJ at this stage is uncertain, necessitating prospective controlled studies.
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REFERENCES 1. Aghaloo TA, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in a patient on Denosumab. J Oral Maxillofac Surg 2010;68:959–963. 2. Agrillo A, Nastro Siniscalchi E, Filiaci F, Ungari C. Osteonecrosis of the jaws in patients assuming bisphosphonates and Sunitinib: two case reports. Eur Rev Med Pharm Sci 2012;16:952–957. 3. American Association of Oral and Maxillofacial Surgeons, Advisory Task Force on bisphosphonate-related osteonecrosis of the jaws. Position paper on bisphosphonate related to osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65:369–376. 4. Aragon-Ching JB, Ning YM, Chen CC, Latham L, Guadagninin JP, Gulley JL. Higher incidence of Osteonecrosis of the Jaw (ONJ) in patients with metastatic castration resistant prostate cancer treated with anti-angiogenic agents. Cancer Invest 2009;27:221–226. 5. Ayllon J, Launay-Vacher V, Medioni J, Cros C, Spano JP, Oudard S. Osteonecrosis of the jaw under bisphosphonate and antiangiogenic therapies: cumulative toxicity profile? Ann Oncol 2009;20:600–601. 6. Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 2011;48:677–692. 7. Brunello A, Saia G, Bedogni A, Scaglione D, Basso U. Worsening of osteonecrosis of the jaw during treatment with Sunitinib in a patient with metastatic renal cell carcinoma. Bone 2009;44:173–175. 8. Christodoulou C, Pervena A, Klouvas G et al. Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology 2009;76:209–211. 9. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G, Huryn JM. Osteonecrosis of the jaw related to Bevacizumab. J Clin Oncol 2008;26:4037–4078. 10. Fizazi K, Carducci M, Smith M, Damiäo R, Brown J, Karsh L et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813–822. 11. Fizazi K, Lipton A, Mariette X. Randomized phase II trial of Denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009;27:1564–1571. 12. Fleissig Y, Regev E, Lehman H. Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2012;13:1–3. 13. Francini F, Pascucci A, Francini E, TindaraMiano S, Bargagil G, Ruggiero G, Petrioli R et al. Osteonecrosis mandibular en pacientes oncológicos tratados con ácido zoledrónico y Bevacizumab. J Am Dent Assoc 2011;6:176–183. 14. Fusco V, Galassi C, Berruti A, Ciuffreda L, Orgeta C, Ciccone G. Osteonecrosis of the jaw after zoledronic acid and Denosumab treatment. J Clin Oncol 2011;29:e521–522. 15. Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab-associated ONM of the jaw. Ann Oncol 2008;19:2091–2092. 16. Guarneri V, Miles D, Robert N, Dieras V, Glaspy J, Smith I et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat. 2010;122:181–188.
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17. Henry DH, Costa L, Goldwasser F, Hirsh V, Prausova J, Scagliotti GV et al. Randomized, double-blind study of Denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:1125–1132. 18. Hoefert S, Eufinger H. Sunitinib may raise the risk of bisphosphonate- related osteonecrosis of the jaw: presentation of three cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;110:463–469. 19. Hopp RN, Pucci J, Santos-Silva AR, Jorge J. ONM after administration of intravitreous Bevacizumab. J Oral Maxillofac Surg 2012;70:632–635. 20. Katsenos S, Christophylakis C, Psathakis K. Osteonecrosis of the jaw in a patient with advanced non-small-cell lung cancer receiving Bevacizumab. Arch Bronconeumol 2012;48:218–219. 21. Koch FP, Walter C, Hansen T, Jager E, Wagner W. Osteonecrosis of the jaw related to Sunitinib. Oral Maxillofac Surg 2011;15:63–66. 22. Kollmannsberger C, Soulieres D, Wong R, Scalera A, Gaspo R, Bjarnason G. Sunitinib therapy for metastatic renal cell carcinoma recommendations for management of side effects. Can Urol Assoc J 2007;1:41–54. 23. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ et al. Extended efficacy and safety of Denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 2008;14:6690–6696. 24. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, et al.Randomized-controlled phase II study of Denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 2007;25:4431–4437. 25. McArthur HL, Estilo C, Huryn J, Williams T, Fornier M, Traina TA, et al. Osteonecrosis of the jaw (ONJ) among intravenous (IV) bisphosphonate- and/or Bevacizumab-treated patients (pts) at Memorial Sloan-Kettering Cancer Center (MSKCC). J Clin Oncol 2008;26:9588. 26. Mignogna MD, Fortuna G, Leuci S, Pollio A, Ruoppo E. Sunitinib adverse event: oral bullous and lichenoid mucositis. Ann Pharmacother 2009;43:546–547. 27. Salort-Llorca C, Mínguez-Serra MP, Silvestre-Donat FJ. Maxillary ONJ associated to antiangiogenic drugs. Med Oral Patol Oral Cir Bucal 2011;16:e137–138. 28. Serra E, Paolantonio M, Spoto G, Mastrangelo F, Tete S, Dolci M. Bevacizumab-related osteneocrosis of the jaw. Int J Immunopathol Pharmacol 2009;22:1121–1123. 29. Silvestre Ragil J, Silvestre FJ. Manejo clínico terapéutico de la osteorradionecrosis: Revisión de la literatura y puesta al día. Medicina Oral Patología Oral y cirugía bucal. 2012;17:33–38. 30. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronicacidfor the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study. J Clin Oncol 2010;28:5132–5139. 31. Troeltzsch M, Woodlock T, Kriegelstein S, Steiner T, Messlinger K, Troeltzsch M. Physiology and pharmacology of non-bisphosphonate drugs implicated in osteonecrosis of the jaw. J Can Dent Assoc 2012;78:c85. 32. Van Poznak C. Osteonecrosis of the jaw and Bevacizumab therapy. Breast Cancer Res Treat 2010;122:189–191.
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New Non-Bisphosphonate Drugs That Produce Osteonecrosis of the Jaws Lucía Ramíreza/Rosa María López-Pintorb/Elisabeth Casañasc/Lorenzo de Arribad/ Gonzalo Hernándeze Purpose: The aim of this paper was to review the current literature associating the non-bisphosphonate cancer-treatment drugs Denosumab, Bevacizumab and Sunitinib (used with or without bisphosphonate [BP]) with the presence of osteonecrosis of the jaws (ONJ) in patients. Materials and Methods: A literature review was conducted using the keywords osteonecrosis of the jaws, oral biphosphosnates, Denosumab, Bevacizumab and Sunitinib. Articles were obtained that reported cases of ONJ associated with the use of Denosumab, Bevacizumab and Sunitinib. Results: The literature shows that Denosumab can cause ONJ associated with triggers such as microtraumas or dental extractions. The combination of the drug along with zoledronic acid may have a synergistic effect. Bevacizumab may cause ONJ; however, there is much controversy regarding its synergistic action when used with BP. Sunitinib causes ONJ, and together with BP could increase the risk of developing lesions. Conclusion: Denosumab, Sunitinib or Bevacizumab are causal agents in the development of ONJ. The combination of any of these along with BPs could increase the risk of developing ONJ over that posed by BP treatment alone. Key words: Bevacizumab, Denosumab, osteonecrosis, Sunitinib Oral Health Prev Dent 2015;13:385-393 doi: 10.3290/j.ohpd.a34055
O
steonecrosis of the jaw (ONJ) is a bone disorder in which bone devitalisation takes place along with hypovascularity, hypocellularity and local tissue hypoxia. These changes lead to the death of osseous jaw tissues. ONJ is described as a condition very often associated with patients who have had cancer and have been treated with certain medicaa
Dentist, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Wrote manuscript.
b
Assistant Professor, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Idea, revised manuscript.
c
Assistant Professor, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Wrote manuscript.
d
Associate Professor, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Idea, revised manuscript.
e
Professor, Department of Oral Medicine and Orofacial Surgery, Faculty of Odontology, Complutense University, Madrid, Spain. Revised manuscript.
Correspondence: Lucía Ramírez Martínez Acitores. C/ Joaquín Costa, 51 28002 Madrid, Spain. Tel: +34-66-930-5353. Email: [email protected]
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Submitted for publication: 16.12.13; accepted for publication: 23.04.14
tions and/or radiotherapy. Currently, ONJ is classified into two types based on aetiology: osteoradionecrosis (ORN), a condition in which irradiated bone fails to heal within three months in the absence of a local tumour;29 and bisphosphonate (BP)-induced ONJ lesions developing over 6 to 8 weeks in patients that have not undergone prior irradiation. In addition, performing invasive dental procedures can be considered a predisposing factor in terms of ONJ.3,18,31 Currently, three new drugs have become commercially available – Denosumab, Bevacizumab and Sunitinib – whose use separately or together with a BP may be associated with the onset of ONJ. Therefore, the aim of this paper was to review the literature available on ONJ produced by these three new drugs and to examine any possible relationship of these drugs with the occurrence of ONJ.
MATERIALS AND METHODS A literature review was conducted using the following key words: non-oral bisphosphonate osteone-
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crosis AND oral osteonecrosis, oral osteonecrosis AND Sunitinib, oral osteonecrosis AND Denosumab, oral osteonecrosis AND Bevacizumab. Articles published between the years 2007 and 2012 were included, and articles were excluded that were not published in journals or indexed in MEDLINE.
RESULTS Thirty-five articles published in English between 2007 and 2012 were obtained. Nine articles were found on the relationship of Denosumab with the development of ONJ: 5 clinical trials, 3 literature reviews and one case report. Fifteen articles on the emergence of treatment-related ONJ with Bevacizumab were found: 4 clinical trials, 3 literature reviews and 8 case reports. Nine articles (3 literature reviews and 6 case reports) on the relationship of Sunitinib to the development of ONJ were found.
DISCUSSION ONJ associated with Denosumab Denosumab (Prolia 60 mg and Xgeva 120 mg) is a human monoclonal antibody (IgG2) produced by a hybrid cell fusion product of a B-cell clone descendant of one mother cell and a tumour plasma cell.6 In June 2010, the US Federal Drug Administration (FDA) approved its use in the treatment of osteoporosis in postmenopausal women with a high risk of fractures. In July 2011, the European Commission approved its use for the prevention of fractures, spinal cord compression and severe bone pain in patients with malignancies who had bone metastases. Currently, its use is being studied for treating lung cancer or multiple myeloma with better results than the BPs.10,11,17,23,24,30 Denosumab is able to bind with high affinity and specificity to the receptor activator of nuclear factor-kB ligand (RANKL), preventing activation of its receptor RANK on surfaces of osteoclast precursors into osteoclasts. To prevent the interaction of RANKL/RANK, it inhibits the formation, function and survival of osteoclasts, which in turn causes a decrease in bone resorption.1,10,11,23,24,30 Denosumab has a mechanism of action similar to the BPs. It causes an alteration of the formation, function and survival of osteoclasts. Impaired healing takes place after microtraumas or invasive dental treatment in these patients, thus triggering the
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appearance of ONJ in some cases (Table 1a).1,6 However, the risk of ONJ in these patients is similar to that of patients being treated with oral BP, a relatively low 0.09% to 0.34% of cases.6 Due to its mechanism of action this drug can be considered a cause of ONJ. However, in cancer patients, polypharmacy exists with chemotherapy and/or non-specified antiangiogenic drugs that may be associated with emergence of ONJ (Table 1). Therefore, even though the literature shows a direct relationship between Denosumab and ONJ, further clinical trials are necessary in this regard to confirm this relationship.1 In their three articles, Lipton et al11,23,24 could not find an association of ONJ with the use of Denosumab and/or intravenous BPs. In the first two articles, 255 patients were evaluated, 43 treated with intravenous BPs and 212 with Denosumab in different concentrations for a period of 4 or 12 weeks. In the third study conducted in 2009, they evaluated 111 patients, 37 treated with intravenous BPs and 17 with Denosumab for 25 weeks. It is important to note that the treatment time in all the studies is very short, perhaps explaining the lack of ONJ cases in patients treated with Denosumab or BP. However, Stopeck et al30 conducted a study in which 1026 patients were treated with Denosumab and 1020 with zoledronic acid. After three years, 2% of the patients treated with Denosumab suffered ONJ vs 1.4% of those treated with intravenous BPs. In most cases, the aetiological cause associated with the onset was a poorly fitting prosthesis (90% in the Denosumab group, and 75% in the BP group). In 50% of patients treated with Denosumab, the ONJ was cured after removal of the drug compared to 43% of the patients treated with BPs. In the study by Henry et al,17 886 patients treated with Denosumab and 890 with zoledronic acid were observed. 1.3% of the patients treated with Denosumab experienced ONJ after three years, as did 1.1% of the patients treated with zoledronic acid. Most of the cases were caused by microtraumas from poorly fitting dentures (91% in patients treated with Denosumab and 70% of those treated with BPs). 40% of the patients treated with Denosumab and experiencing ONJ improved with drug withdrawal compared to 27% of those patients treated with zoledronic acid. Denosumab is a circulating protein that is not deposited in the bone and after discontinuation does not persist in the bloodstream as long as do BPs. Thus, the withdrawal of this drug in cases of ONJ onset appears to be more effective in terms of
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Table 1a ONJ in patients treated with denosumab
Authors
Year
Patients
Stopeck et al30
2010
20
Henry et al17
Fizazi et al10
2011
2011
10
17
Location and cause of osteonecrosis (ON)
Progression
Not described
Not described
Denosumab 180 mg every 4 weeks for 3 years
Not described
4 patients cured with antibiotic treatment. The authors did not report if denosumab was withdrawn in these patients. 4 patients needed surgical treatment. The authors did not report if denosumab was withdrawn in these patients. 2 patients with no described progression. The authors did not report if denosumab was withdrawn in these patients.
Denosumab 120 mg every 4 weeks for 11.9 months
ONJ (no precise localization described), history of prosthesis use, poor hygiene or dental extraction
5 patients cured with antibiotic treatment. The authors did not report if denosumab was withdrawn in these patients. 10 patients needed surgical treatment (desbridement, osseous curettage). The authors did not report if denosumab was withdrawn in these patients. 2 patients needed osseous resection. The authors did not report if denosumab was withdrawn in these patients.
Scheduled medication Denosumab 120 mg every 4 weeks for 3 years
Table 1b ONJ in patients treated with denosumab + BP Authors
Aghaloo et al1
Year
2011
Patients
Scheduled medication
Location and cause of ON
Progression
Denosumab 120 mg intramuscular (IM)/ week for 3 weeks, and 120 mg/month until improvement for up to 2 years. Alendronate 70 mg/weeks for 4 weeks, 4 years prior.
ONJ of right side of mandible (no cause described)
No elimination of medication, no healing of lesion
healing than does the withdrawal of BPs in cases of ONJ due to BPs, although the healing rates reviewed in articles vary as noted earlier.6 In short, Denosumab is a drug that has an action mechanism similar to that of BPs, and it may have a direct relationship with the development of ONJ, with an incidence similar to that produced by oral BPs in cases of ONJ onset.
ONJ associated with Denosumab and BP There is only one case report of combined BP-Denosumab therapy and the onset of ONJ (Table 1b), and those authors1 indicate that BPs may have a synergistic action with Denosumab. In the single case report, the patient was medicated with Denosumab 120 mg/week for 3 weeks and 120 mg/ month until there were signs of improvement. It is necessary to conduct further work to properly assess the possible relationship, as there are no dependable scientific studies that demonstrate the synergy of the two treatments.
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ONJ associated with Bevacizumab Bevacizumab (Avastin) is a G1-humanised monoclonal antibody. The drug binds to endothelial growth factor (VEGF), thus inhibiting the attachment of cells to its receptors Flt-1 (VEGFR-1) and the kinase insert domain receptor (KDR) (VEGFR-2) located on the surface of endothelial cells. By neutralising the biological activity of VEGF, tumour vascularisation is reduced, thus inhibiting its growth.19 Bevacizumab is indicated in patients with metastatic carcinoma of the colon or rectum, glioblastoma, lung cancer and neoplasic neurovascular diseases. It has other nonneoplasic uses, in ophthalmology, for example.19 ONJ caused by Bevacizumab may be due to reduced VEGF action and the consequent decrease of angiogenesis. VEGF factor is essential for the formation, self-regulation and survival of osteoclasts. Thus, any alteration of this factor results in a decrease in bone repair ability. This, together with microtraumas (brushing and chewing) or invasive dental treatments may cause a mandibular lesion and development of ONJ.16,28
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The first case of ONJ caused by Bevacizumab was described in 2008 (Tables 2a and 2b).9 Since then, new clinical cases of ONJ have been described15,19,28 in which there is no clear risk factor except the use of Bevacizumab (Table 2a). Other authors25,32 mention that there is no relationship between the use of Bevacizumab without added BPs and the increased risk of ONJ. In a retrospective study with 1076 patients treated with Bevacizumab, only two cases of ONJ were reported.16 Those authors16 therefore stated that the ONJ described in Bevacizumab-treated patients may be due to other aetiologies present in the development of this pathology. In short, the involvement of Bevacizumab in the onset of ONJ is controversial, since in most cases (see below), it has been linked to the association of the use of this drug with BP treatment (Table 2c).
ONJ associated with Bevacizumab and BP Several authors5,8,27 have published 7 isolated cases of ONJ with or without an added risk factor (extractions, poorly fitting dentures, etc) in patients with a combined therapy of BPs and Bevacizumab. Katsenos et al20 published the only case that exists in the literature of development of ONJ in a patient
undergoing radiotherapy along with a combined treatment of BPs and Bevacizumab (Tables 2c and 2d). In the study by Guarneri et al,16 two cases of ONJ were described among 233 patients treated with BPs and Bevacizumab at the same time. There is some controversy about the increased risk of ONJ in patients given this combined therapy. Some authors claim that the risk of ONJ increases around 1.1% to 1.4% vs 2% increased risk with BPs plus Bevacizumab.5,8,14,25 In fact, in the combined therapy with intravenous BPs and Bevacizumab, the BPs can increase the avascularization caused by Bevacizumab.16 However, if a patient has ONJ due to the use of BPs, he/she does not have an increased risk of developing another form of ONJ if Bevacizumab is added to their treatment.13,16,32 There are only four trials that directly evaluate ONJ in patients treated with bevazucimab with or without BPs.4,13,16,25 McArthur et al25 conducted a study in which 1711 patients were treated with Bevacizumab and 409 with Bevacizumab and pamidronate and/or zoledronic acid. Only 8 patients developed ONJ, and all received a combined treatment of Bevacizumab and BPs (2%). In another study4 with a sample size of 60 patients, 55 were treated with BPs and Bevacizumab, and 5 with Bevacizumab alone. Eleven patients (18.3%) receiving a combination therapy developed ONJ, while those
Table 2a ONJ in patients treated with Bevacizumab alone Authors
Year
Scheduled medication
Location and cause of ON
Evolution
Estilo et al9
2008
Bevacizumab 15 mg/kg every 3 weeks for 24 weeks
Spontaneous ON of mandible weeks after finishing treatment
Improvement after eliminating drug; it reappeared spontaneously.
Greuter et al15
2008
Bevacizumab (dosage not specified) for 1 month
ON of right side of maxilla after extracting teeth 25 and 26
Improvement after eliminating drug.
Serra et al28
2009
Bevacizumab 7.5 mg/kg every 3 weeks for 1 week (one dose)
ON of right side of mandible post-extraction of tooth 37
Improvement after eliminating drug.
Bevacizumab 7.5 mg/kg every 3 weeks for 7 months
ON of mandible post-extraction
Bevacizumab 7.5 mg/kg every 3 weeks for 2 months
ONJ (location and cause not described)
Improvement after eliminating drug; treatment with antibiotic.
Bevacizumab 2.5 mg intravitreal administration (duration of treatment not specified)
ON of right side of mandible post-extraction 2 years after treatment
16
Guarneri et al
Hopp et al19
2010
2012
Improvement with antibiotic treatment
Table 2b ONJ in patients treated with Bevacizumab + radiotherapy Authors
Estilo et al
388
9
Year
Scheduled medication
Location and cause of ON
Progression
2008
Bevacizumab 10 mg/kg every 2 weeks for 13 weeks, radiotherapy for 1 year, radiation total of 5940 Gy/33 fractions
Spontaneous ONJ of the right side of the mandible
Bevacizumab was not suspended and the lesion did not improve.
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Table 2c ONJ in patients treated with Bevacizumab + BP Authors
Year
McArthur et al25
2008
Aragon-Ching 2009 et al4
Scheduled medication 4 case reports: Bevacizumab + intravenous BP (pamidronate or zoledronic acid) Bevacizumab 15 mg/kg/21 days + zoledronic acid for 5 weeks, prior medication oral alendronate for 3 years
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 12 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 36 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 30 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 24 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 3 months
Aragon-Ching 2009 et al4
2 case reports: Bevacizumab 15 mg/kg/21 days + zoledronic acid for 6 months
Aragon-Ching 2009 et al4
Bevacizumab 15 mg/kg/21 days + zoledronic acid for 19 months
Ayllon et al5
2009
Christodoulou 2009 et al8
Guarneri et al16
2010
Salort-Llorca 2011 et al27
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Zoledronic acid 4 mg IV every 3 weeks for 4 months, clodronic acid (dosage not specified) after zoledronic acid for 15 months, Bevacizumab 2–3 months. Ibandronic acid 6 mg for 7 years, Bevacizumab and chemotherapy (not specified) Zoledronic acid 4 mg every 3 weeks for 20 months, Bevacizumab 20 months, chemotherapy (8 cycles of 3 weeks) Zoledronic acid 4 mg every 3 weeks for 38 months, Bevacizumab 8 months, chemotherapy 8 months. Bevacizumab 7.5 mg/kg every 3 weeks, zoledronic acid (dose not speficied) for 3 weeks Bevacizumab 7.5 mg/kg every 3 weeks, zoledronic acid (time not specified) Bevacizumab 15 mg/kg/21 days for 30 weeks + IV BP (not specified) Bevacizumab (dose not specified + IV BP (not specified) Bevacizumab 10 mg/day/14 days for 13 weeks + IV BP (not specified)
Location and cause of ON
Progression
Not described
Not described
ONJ (mandible), no cause described
ONJ ulcer healed and was asymptomatic, along with good oral hygiene (OH). Zoledronic acid was withdrawn, and treatment with Bevacizumab continued.
ONJ of maxilla and mandible; no cause described ONJ of mandible; no cause described ONJ of mandible; no cause described ONJ of maxilla no cause described ONJ mandibular caused by tooth extraction ONJ of mandible; no cause described ONJ of mandible caused by tooth extraction ONJ (mandible) postextraction
Improvement along with maintaining good OH. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. Complete healing after cleaning with Peridex (CHX 0.12%); sequestrectomy, surgery performed and antibiotics given. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. ONJ remained stable with Peridex (CHX 0.12%) cleaning, sequestrectomy performed and antibiotics administered. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. Healing with Peridex (CHX 0.12%). Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. No improvement after Peridex (CHX 0.12%) and sequestrectomy. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. Complete healing after Peridex (CHX 0.12%) and sequestrectomy. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued. No healing present after Peridex (CHX 0.12%). Zoledronic acid was withdrawn, and treatment with Bevacizumab continued.
None described.
Temporary improvement after eliminating the BP.
ONJ (location not described) post-extraction
No improvement after eliminating medication + antibiotic treatment.
Temporary improvement after eliminating all medication + antibiotic therapy.
Spontaneous ONJ
ONJ (pertinent information not described)
No improvement after eliminating the treatment.
Improvement after dental, antibiotic and surgical treatment.
Spontaneous improvement.
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Table 2d ONJ in patients treated with Bevacizumab + BP+ Radiotherapy Scheduled medication
Location and cause of ON
Aragon-Ching 2009 et al4
Bevacizumab 15mg/kg/21 days + RT+ zoledronic acid 7 months
ONJ (mandible); no cause described
Improvement but no healing after Peridex (CHX 0.12%), and sequestrectomy. Zoledronic acid was withdrawn, and treatment with Bevacizumab continued.
Aragon-Ching 2009 et al4
Bevacizumab 15mg/kg/21 days + RT+ zoledronic acid 36 months
ONJ (mandible); no cause described
Improvement but no healing after Peridex (CHX 0.12%). Zoledronic acid was withdrawn, and treatment with Bevacizumab continued.
Katsenos et al20
Zoledronic acid 4 mg IV monthly for 3 months, Bevacizumab 15 mg/kg every 3 weeks for 3 months, radiotherapy (dosage not described)
ONJ (right side of mandible) in patients with dental prosthesis
None described
Authors
Year
2012
treated with Bevacizumab alone did not. Two of them had also received radiotherapy. In a study with 1309 patients treated with Bevacizumab (1076 treated with BPs and Bevacizumab, and 233 with Bevacizumab only), Guarneri et al16 found that 4 patients developed ONJ: 2 with combined therapy and 2 with monotherapy. In contrast, Francini et al13 found no cases of ONJ after 19.7 months of follow-up in 59 patients treated with Bevacizumab and BPs. Notably, none of these patients underwent invasive dental procedures during treatment, even if they had other risk factors such as poorly fitting dentures, periodontal disease or tooth extractions performed six weeks before treatment. Therefore, there appears to be an increased risk of ONJ in patients receiving combination therapy of Bevacizumab and BPs, although it might be necessary to do well-designed clinical studies.
ONJ associated with Sunitinib (Tables 3a and 3b) Sunitinib (Sustent) is an oral drug that reduces angiogenesis. It is highly potent in the treatment of tumours, including gastrointestinal, lung, thyroid and hematologic ones. In 2006, it was introduced in the US by the pharmaceutical company Pfizer. This drug inhibits cell signaling by binding to multiple receptor tyrosine kinases (RTKs). These include all platelet-derived growth receptor factors (PDGFRs) and vascular endothelial growth factors (VEGFRs). The inhibition of these receptors impair proliferation, migration, differentiation, neoangiogenesis and invasion of cancer cells, thereby providing an attractive target for anticancer therapy.7,12,18,21 Unlike conventional chemotherapy administered dur-
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Progression
ing defined periods, Sunitinib can be used as a maintenance drug for a longer period of time, even years.12,18 A publication from 201121 describes a case of ONJ in a patient treated with Sunitinib without BPs. After tooth extraction, this patient consequently suffered the emergence of a bone injury with swelling and purulent exudate. As there was no scarring present, a CT scan was performed which confirmed the development of ONJ. A histology sample of the lesion reflected the existence of a small necrotic bone invasion of polymorphonuclear cells and actinomyces. The patient underwent surgery once the subnitinib treatment was finished. In 2012, Fleissing et al12 published another case of ONJ after the extraction of mandibular third molars in a patient treated with Sunitinib. The patient’s condition improved after surgical removal of those teeth along with the help of antibiotics. Although there are few cases of ONJ in patients treated with Sunitinib, the use of this medication must be taken into consideration when performing invasive dental treatments for the hypothetical risk of developing ONJ.
ONJ associated with Sunitinib and BP (Tables 3b and 3c) The combination of Sunitinib with intravenous BPs causes an increased risk of developing ONJ compared to using either drug separately; an incidence of 0.9% to 2.4% has been reported.8,12 There are two possible reasons to explain the synergy of the two drugs:5,12,22,26 • Sunitinib causes oral mucositis in 10%–30% of the patients,22,26,31 which increases the suscep-
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Table 3a ONJ in patients treated with Sunitinib Location and cause of ON
Authors
Year
Scheduled medication
Progression
Koch et al21
2011
Sunitinib 50 mg day, 4 weeks and 2 weeks of drug holiday for 5 months
ON of left side of mandible post-extraction of tooth 36
Improvement after eliminating drug.
Fleissing et al12
2012
Sunitinib 50 mg day for 4 weeks, 2 weeks of drug suspension, for 1 year
ON of right side of mandible post-extraction of tooth 48
Improvement after eliminating drug; antibiotic and surgical treatment.
Location and cause of ON
Progression
Table 3b ONJ in patients treated with BP + Sunitinib Authors
Year
Scheduled medication
Brunello et al7
2009
Zoledronic acid 4 mg iv monthly/11 months, Sunitinib 50 mg day 4 weeks, 2 weeks of drug suspension, for 5 months
Spontaneous ON of left side of mandible
Improvement after eliminating the drug.
Ayllon et al5
2009
Zoledronic acid 4 mg iv every 3 weeks for 19 months, Sunitinib (dosage not described) 14 months
ON of mandible postextraction
None described.
Christodoulou 2009 et al8
Zoledronic acid 4 mg iv every 4 weeks + Sunitinib (dosage not described), for 15 months
ON (location and cause not described)
Improvement after eliminating BP + antibiotic therapy.
Mignogna et al26
2009
Subnitinib 3 cycles of 25 mg orally 3x/day (every cycle 14 days + 7 days drug suspension) for 42 days, zoledronic acid 4 mg iv monthly, for 42 days.
ON on the palate
None described.
Hoerfert and Eutinger18
2010
Zoledronic acid 4 mg iv/month for 13 months, Sunitinib 50 mg day for 4 weeks, 2 weeks drug suspension + zoledronic acid 4 mg iv/month for 13 months for 4 days.
ON of the mandible after extraction of teeth 36 and 48
Improvement after eliminating drug therapy and relapse occurs once Sunitinib is reinstated.
Hoerfert and Eutinger18
2010
Zoledronic acid 4 mg iv/ months1 month after extraction for 6 months. Sunitinib 50 mg day 4 weeks and 2 weeks of drug holiday for 1 year.
ON of the mandible post-extraction of teeth 36 and 48.
Treatment is not discontinued for oncologic reasons.
Salort-Llorca et al27
2011
Zoledronic acid 4 mg iv/ month for 6 months Sunitinib 50 mg day4 weeks and 2 weeks of drug holiday. For 3 months.
ON of the mandible
Improvement after eliminating drug therapy and relapse occurs when treatment is reinstated.
Agrillo et al2
2012
Zoledronic acid 4 mg iv/ months + Sunitinib 50 mg day 4 weeks and 2 weeks of drug holiday for 1 year
Spontaneous ON of the maxilla
Treatment is not discontinued for oncologic reasons.
2012
Zoledronic acid 4 mg iv/month 1 year. Sunitinib 50 mg day 4 weeks and 2 weeks of drug holiday for 3 months
Spontaneous ON after 1 year of treatment with zoledronic acid which worsens with Sunitinib
Treatment is not discontinued for oncologic reasons.
Agrillo et al2
Table 3c ONJ in patients treated with Sunitinib + BP+ radiotherapy Authors Hoefert and Eutinger18
Year
Scheduled medication
2010
Radiotherapy 30 gy, Ibandronate iv 6 mg/ month for 10 months, Sunitinib 50 mg/day 4 weeks, 2 weeks of drug suspension, for 10 months
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Location and cause of ON ONJ of right side of mandible post-extraction
Progression No improvement after eliminating drug and surgical treatment.
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tibility of the mucosa or gingiva to the action of the BPs. Mucositis usually occurs when starting the drug, and during rest periods, the pathology lessens. Therefore, it is necessary to prevent mucositis in these patients. For this, we recommend the use of non-alcoholic mouthwashes, toothpastes without peroxide, viscous lidocaine and changing dietary habits to avoid spicy, acidic and very cold or hot foods.18,21,22,26 In patients with mucositis who commence treatment with BPs, it is recommended to discontinue Sunitinib for 4 weeks if possible, until the level of toxicity caused by the drug has fallen.18 • The combination of these two drugs causes an alteration in the healing of oral lesions together with inactivation of VEGFR in areas of major vascular injury and causes the greatest risk of ONJ lesions.18 Since 2009, multiple articles2,5,7,8,12,18,26,27 have described the occurrence of ONJ during combined treatment with Sunitinib and BPs. Brunello et al7 described a patient with renal cell carcinoma treated with zoledronic acid. BP treatment was replaced by Sunitinib to prevent the occurrence of ONJ after a dental abscess, but the patient developed spontaneous ONJ from the second cycle of Sunitinib. After three cycles of the drug, the ONJ worsened, so a cause-effect relationship was suspected with Sunitinib, and consequently the drug was withdrawn. Ayllon et al5 described a case of ONJ in a patient treated with zoledronic acid for 19 months and Sunitinib for 14 months. An ONJ lesion was developed which was then attributed to treatment with BPs. Christodoulou et al8 reported a case of ONJ in a patient after two years of treatment with Sunitinib and zoledronic acid. The patient improved when BP treatment was discontinued and Sunitinib was maintained. Mignogna et al26 reported a case of spontaneous ONJ in the palate during combination therapy with Sunitinib and BPs, without specifying whether there was improvement after Sunitinib was discontinued. Hoefert and Eufinger18 presented the case of a patient with renal cell carcinoma who developed ONJ after extraction of a mandibular right first molar. The patient had 5 months of treatment with Sunitinib, and began treatment with zoledronic acid one month after the extraction. It was decided to treat the ONJ with surgery, antibiotic therapy and suspension of both treatments. A month later, when the bone lesion had healed, both treatments
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(Sunitinib and zoledronic acid) were resumed for oncological reasons. The patient developed ONJ in the mandibular left alveolar ridge with worsening periods that coincided with the cycles of Sunitinib. The lesion continued to progress up to about 10 mm, but the treatment was not discontinued for oncological reasons. The same study included a patient treated with zoledronic acid for a year; this was subsequently replaced with a combination of zoledronic acid and Sunitinib. A year after starting with the combination therapy, the patient developed ONJ. The lesion was treated three times with surgery and antibiotic therapy, during which the cancer treatment was interrupted for a month, but resumed shortly after surgery for oncological reasons. This process recurred up to four times and a similar treatment regimen of surgery and antibiotic therapy was performed; however, the fourth time, only zoledronic acid was administered, without any signs of a new relapse. Salort-Llorca et al27 describe a case of a patient receiving Sunitinib combined with BPs who developed ONJ. The lesion improved after suspension of treatment, but worsened when treatment was restored for oncologic reasons. Two patients exhibiting ONJ who were treated with zoledronic acid and Sunitinib are described by Agrillo et al.2 One of these patients had a lesion in the maxilla and the other patient in the mandible; both lesions appeared spontaneously and did not improve with antibiotics and surgery. Therefore, as published in the literature and according to the mechanism of action of bisphosphonates and Sunitinib, there might be a synergistic action between the two drugs when developing ONJ. Thus, this risk must be taken into account before performing any invasive dental treatment.
CONCLUSION Documented cases of the development of ONJ exist in which the main causal agent is treatment with the following drugs: Denosumab, Sunitinib or Bevacizumab. The combination of any of these along with BPs could increase the existing BP-related risk of developing ONJ. Nonetheless, the incidence rates of ONJ at this stage is uncertain, necessitating prospective controlled studies.
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