breast cancer is the most frequently observed type of invasive cancer , affecting approximately 1 million women worldwide and causing bone metastases in 65% to 75% of patients .
bisphosphonates are some of the most effective treatments for preventing complications related to bone metastases . zoledronic acid ( za )
is the most effective molecule in reducing skeletal - related events ( sres ) in patients with breast cancer .
bisphosphonates inhibit bone resorption and protect bone structure by inhibiting the differentiation of osteoclastic precursors , promoting apoptosis of osteoclasts , and stimulating the secretion of osteoclast inhibitory factor from osteoblasts .
one of the most important adverse effects that limit its clinical use is osteonecrosis of the jaw ( onj ) .
according to the american oral and maxillofacial surgery association , current therapy or a history of therapy with bisphosphonates , no radiotherapy to the head and neck area , and the presence of exposed necrotic bone in the maxilla and/or mandible for at least 8 weeks support the diagnosis of onj .
following the first scientific report published by marx in 2003 that pointed to a link between bisphosphonates and onj , the number of studies focusing on this subject has rapidly increased . moreover , numerous risk factors for the development of onj have also been described ( cancer and anticancer therapy , dental risk factors , corticosteroids , alcohol and tobacco abuse , anemia , diabetes , obesity , and renal impairment ) .
trastuzumab is one of the most widely used agents for the management of all metastatic breast cancers with human epidermal growth factor receptor 2 ( her2 ) overexpression as indicated by 3 + her2 immunostaining or gene amplification on the fluorescence in situ hybridization test .
the development of onj has been reported to have occurred in 2 patients with concurrent use of trastuzumab and bisphosphonates . however , in both these reports , the authors did not correlate the occurrence of onj in their patients with the combined use of these 2 agents . in the present study
, we made an attempt to analyze the use of trastuzumab as an independent risk factor for the development of onj in metastatic breast cancer patients undergoing za treatment .
patient data were identified retrospectively from the archives of the florence nightingale breast study group , istanbul , between march 2006 and december 2013 . in this study
, we included 97 consecutive patients with metastatic breast cancer who had bone metastases and underwent treatment with za .
patients with < 12 months of follow - up and radiotherapy to the head and neck area were excluded from the study .
patients were analyzed according to their characteristics ( age , weight , number of za infusions , time of exposure to za [ months ] , smoking habits , dental procedures , receiving aromatase inhibitors [ ai ] , receiving chemotherapy [ ct ] , trastuzumab treatment , and renal dysfunction ) .
the diagnosis of bone metastasis was based on radiologic methods such as direct radiography , bone scintigraphy , and positron emission tomography - computed tomography .
the standard therapy involved intravenous infusion of 4  mg every 3 to 4 weeks ( in 150  cc of saline within 15 minutes ) .
patients were examined by a dentist every 6 to 12 months and all dental procedures performed before the initiation of therapy with za and during the therapy period were recorded .
the diagnosis of the onj was made through clinical and radiologic examinations , and biopsies were performed when necessary .
the study was approved by the bilim university ethics committee ( decision no : 27 - 200 ) .
statistical analysis was performed using the statistical package for social sciences social sciences ( spss inc . ,
chicago , il)for windows 17.0 software . during the evaluation of the study data , in addition to the descriptive statistical methods ( mean , median , number , and percentage ) ,
 was employed for the qualitative comparison of the development of onj along with the patient and disease - related characteristics , whereas quantitative comparisons were made through the independent samples t test .
evaluation of the independent parameters related to the development of onj was based on the multiple logistical regression ( forward stepwise ) model .
the results were assessed within a 95% confidence interval , and a value of p  <  0.05 was accepted as statistically significant .
statistical analysis was performed using the statistical package for social sciences social sciences ( spss inc . ,
chicago , il)for windows 17.0 software . during the evaluation of the study data , in addition to the descriptive statistical methods ( mean , median , number , and percentage ) ,
 was employed for the qualitative comparison of the development of onj along with the patient and disease - related characteristics , whereas quantitative comparisons were made through the independent samples t test .
evaluation of the independent parameters related to the development of onj was based on the multiple logistical regression ( forward stepwise ) model .
the results were assessed within a 95% confidence interval , and a value of p  <  0.05 was accepted as statistically significant .
the mean time of exposure to za was 37    18 months ( range : 1387 ) and the mean number of za infusions was 35    16 ( range : 1073 ) ( table 1 ) .
the median age of the patients who developed onj was 61 years ( range : 3973 ) .
the mean time of exposure to therapy with za was 47    22 months ( range : 1387 ) , and the mean number of intravenous za infusions was 41    15 ( range : 1566 ) . the 8 ( 62% ) of 13 patients developed onj had received transtuzumab , but 5 ( 38% ) of them had not received . among these patients , 1 patient ( 7.69% ) was asymptomatic , whereas 9 patients ( 69.24% ) were diagnosed through clinical and radiologic examinations . in 4 patients ( 30.76% ) , the probability of metastasis was ruled out by biopsy .
there were 15 lesions in total ; 11 patients had single lesions whereas 2 patients had double lesions .
six of the lesions were detected in the mandible and 5 in the maxilla , whereas 2 involved both the maxilla and the mandible ( table 2 ) .
when the diagnosis of onj was made , 9 patients ( 69.20% ) were under treatment with ais , 8 patients ( 62% ) were taking trastuzumab , and 3 patients ( 23% ) were receiving systemic ct .
the dental procedures included tooth extractions in all patients , root canal treatment in 8 patients , and dentures in 7 patients .
following conservative treatment , 4 patients ( 30.76% ) needed surgery ( table 2 ) .
there was no association of the development of onj with age ( p  =  0.241 ) , weight ( p  =  0.218 ) , number of za infusions ( p  =  0.111 ) , smoking habits ( p  =  0.989 ) , dental procedures ( tooth extraction [ p  =  0.349 ] , root canal treatment [ p  =  0.393 ] , dentures [ p  =  0.350 ] ) , diabetes mellitus ( p  =  0.752 ) , receiving ai ( p  =  0.510 ) , receiving ct ( p  =  0.357 ) , or renal dysfunction ( p  =  0.500 ) .
duration of exposure to za and the use of trastuzumab were associated with the development of onj ( p  =  0.049 and p  =  0.028 , respectively ) ( table 3 ) .
unless there is an interfering condition , bisphosphonates are currently regarded as the standard therapy for sres in the treatment of bone metastases .
onj is one of the most important complications associated with bisphosphonate therapy used in patients who have breast cancer with bone metastases .
this condition is due to accumulation of bisphosphonates in great amounts both in the alveolar bone and the surrounding soft tissue .
this increases the risk of avascular necrosis , which , in addition to disruption of the mucosal barrier mediated by stimulating the apoptosis of keratinocytes , delays wound healing and tissue repair by inhibiting the formation of blood vessels through antiangiogenic effects .
trastuzumab has been demonstrated to inhibit angiogenesis and this effect is believed to occur through the expression of antiangiogenic factors and inhibition of proangiogenic factors . combining bisphosphonates with antiangiogenic agents has been suggested to induce onj more frequently than using bisphosphonates alone . in this article , we focused on the impact of trastuzumab as well as the other factors in the development of onj in metastatic breast cancer patients receiving za .
although onj is mostly associated with dental procedures , other factors that play a role in its pathogenesis are listed in some studies : duration of exposure to za , number of infusions , type of bisphosphonate , route of administration ( oral , intravenous ) , concurrent ct , chronic use of corticosteroids , poor oral hygiene , smoking , and poorly fitting dentures .
although symptoms including orofacial pain , puffy face , and malodorous discharge during treatment with bisphosphonates support the diagnosis of onj , it may be necessary to rule out any metastases to the orofacial bones .
however , because of the risk of diagnostic biopsy of the bone that may lead to a compromise in wound healing , the diagnosis is usually based on clinical and radiologic examinations . in a retrospective study by bamias et al , the most important risk factors suggested to increase the risk of development of onj were found to be duration of exposure to treatment , the number of infusions , dental procedures , and the type of bisphosphonate used .
the duration of bisphosphonate treatment has also been marked as a risk factor for the development of onj in other clinical studies . in our study ,
duration of za treatment was detected as a significant risk factor in the development of onj , which strengthens the outcomes of the above studies .
although a relationship between dental procedures and onj was observed in certain studies , no statistically significant correlation was observed between dental procedures and onj in our study .
the fact that the majority of the patients in which no onj occurred had also undergone dental procedures may have led to this result .
antiangiogenic agents that are used with increasing frequency may enhance the risk of onj , especially when used concurrently with bisphosphonates .
for instance , there have been recent reports of patients with onj caused by antiangiogenic agents such as sunitinib ( multikinase inhibitors ) , bevacizumab ( a monoclonal antibody that targets vascular endothelial growth factor ) , and everolimus ( inhibitor of mammalian target of rapamycin ) , with or without bisphosphonates .
there have been no reports in the literature on development of onj solely due to trastuzumab treatment .
there have been a few cases of development of onj during concurrent treatment with bisphosphonates and trastuzumab ; however , an association of trastuzumab with the occurrence of onj has not been clearly stated in these reports . moreover , in a study by hoff et al , a large number of patients were evaluated for onj incidence and risk factors regarding the development of onj .
no relationship was observed between onj and treatment with trastuzumab , anthracycline , tamoxifen , taxane , or ais . in agreement with our findings
, the rate of treatment with trastuzumab in patients with onj was observed to be significantly higher than in those without onj ( p  =  0.028 ) .
the combination of za and other antiangiogenic agents ( sunitinib , everolimus , bevacizumab ) has recently been revealed to be associated with an onj rate of up to 16% .
in addition , treatment with bevacizumab alone has been correlated to onj in a few case presentations .
we suggest that our study brings up the matter of the effect of trastuzumab on onj when it is combined with za , as we observed a 13.6% occurrence rate of onj , which matches the previous reports .
the outcomes of our study may indicate that trastuzumab has antiangiogenic potency similar to that of other agents .
this study evaluated data obtained from patients with isolated metastatic breast cancer , whose files and treatments were regularly followed up . in this study ,
the development of onj was associated with longer treatment and higher cumulative doses of intravenous za therapy , and with concurrent treatment of za and trastuzumab in breast cancer patients .
the increased risk of onj should be kept in mind and all preemptive measures should be taken , especially when za is used with trastuzumab .
the retrospective nature of the study and the statistical analysis of a small number of cases of onj are limitations of our study .
we suggest that prospective studies should be performed to confirm these results , and more careful studies are also needed to define the minimum dose and duration of therapy with bisphosphonates necessary to prevent skeletal complications of malignancy .
 abstractone of the most important adverse effects of zoledronic acid ( za ) is osteonecrosis of the jaw ( onj ) . in previous literature , 
 several risk factors have been identified in the development of onj . in this study 
 , we aimed to determine the role of trastuzumab , an antiangiogenic agent , as an independent risk factor for the development of this serious side effect.our study included 97 patients ( mean age : 54    10 years ) with breast cancer , recorded in the archives of the istanbul florence nightingale breast study group , who received za therapy due to bone metastases between march 2006 and december 2013 . 
 we recorded the patients ages , weights , duration of treatment with za , number of za infusions , dental procedures , anticancer treatments ( chemotherapy , aromatase inhibitor , trastuzumab ) , the presence of diabetes mellitus or renal dysfunction , and smoking habits.thirteen patients ( 13.40% ) had developed onj . among the patients with onj , the mean time of exposure to za was 41 months ( range : 1382 ) and the mean number of za infusions was 38 ( range : 1556 ) . 
 the duration of treatment with za and the use of trastuzumab were observed to be 2 factors that influenced the development of onj ( p  =  0.049 and p  =  0.028 , respectively).the development of onj under za treatment may be associated solely with the duration of za treatment and the concurrent administration of trastuzumab . 
 these findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing za treatment are prone to developing onj . therefore , we recommend intense clinical observation to avoid this particular condition in patients receiving za and trastuzumab . 
INTRODUCTION
PATIENTS AND METHOD
Statistical Evaluation
RESULTS
DISCUSSION
CONCLUSION