osteonecrosis of the jaw ( onj ) emerged as a well - known devastating side effect of parenteral bisphosphonate therapy since the widespread use of biphosphonates to reduce skeletal related events ( sre ) .
biphosphonates are commonly used every three to four weeks with around 1448% reduction of sre occurrence and onj occurrence in 1.23.8% despite preventive measures , , , .
although the positive results of 4 different trials , the use of biyearly biphosphonates regimens to reduce aibl is not approved , , , . this spaced interval of six months achieved an increase in median bone mineral density of 2.74.3% in the lumbar spine and 1.61.7% in the hip when used in post - menopausal women receiving adjuvant hormonal aromatase inhibitor , . however , the risk of developing onj with the bi - annually regimen of zoledronic acid is not well recognized .
a review of literature in women having breast cancer receiving zoledronate biannually to prevent aibl was conducted . reported cases of onj are collected from the selected studies and an estimation of the onj risk in this category of patients is reported .
electronic searches of the literature published until september 2014 were conducted using pubmed and the cochrane collaboration database to identify articles evaluating the onj as a side effect in women receiving zoledronic acid every six months for the prevention of aromatase inhibitor associated bone loss ( aibl ) in patients with early stage breast cancer . only randomized and non - randomized controlled clinical trials were included .
zoledronic acid ,  early breast cancer and  aromatase inhibitors. this search was augmented by a hand search of the reference lists of relevant articles included in the literature review .
two different investigators performed the search and the abstracts were independently reviewed for possible inclusion .
types of participants : included studies were limited to post - menopausal women receiving zoledronic acid every six months with aromatase inhibitors to prevent aibl .
selection of studies : the articles were first selected individually on the basis of their titles by two of the authors .
electronic searches of the literature published until september 2014 were conducted using pubmed and the cochrane collaboration database to identify articles evaluating the onj as a side effect in women receiving zoledronic acid every six months for the prevention of aromatase inhibitor associated bone loss ( aibl ) in patients with early stage breast cancer . only randomized and non - randomized controlled clinical trials were included .
zoledronic acid ,  early breast cancer and  aromatase inhibitors. this search was augmented by a hand search of the reference lists of relevant articles included in the literature review .
two different investigators performed the search and the abstracts were independently reviewed for possible inclusion .
types of participants : included studies were limited to post - menopausal women receiving zoledronic acid every six months with aromatase inhibitors to prevent aibl .
selection of studies : the articles were first selected individually on the basis of their titles by two of the authors .
the upfront biyearly regimen of zoledronic acid significantly increased bone mineral density ( bmd ) in postmenopausal women receiving aromatase inhibitors for early breast cancer , , , .
the z - fast trial enrolled 602 postmenopausal women with early hormone receptor - positive breast cancer receiving adjuvant letrozole .
patients were randomized equally to receive upfront or delayed zoledronic acid with a 4  mg intravenous regimen every 6 months for 5 years .
the investigators reported two cases of onj in the upfront group during the 60 months follow - up .
however , an onj adjudication committee deemed one of the cases inconsistent with onj and the other one indeterminate because of insufficient information .
the zo - fast trial recruited 1065 postmenopausal women receiving adjuvant letrozole that were randomly assigned to immediate zoledronic acid with a regimen of 4  mg every 6 months for 5 years , or delayed administration initiated at fracture occurrence or on - study bmd decrease .
a total of nine potential onj events from seven patients were reported in this study after 60 months follow up .
each event was independently adjudicated by an external panel that confirmed onj occurrence in three cases , deemed possible for insufficient data in two cases , and excluded the remaining cases .
therefore , in the zo - fast trial , onj occurred in 0.280.47% . in the e - zo - fast trial , 527 postmenopausal women receiving aromatase inhibitors were randomized to either immediate or delayed zoledronic acid treatment , at 4  mg every 6 months .
two reported cases of onj of the immediate zoledronic acid group were confirmed by the adjudication committee . at diagnosis
finally , the abcsg-12 trial is the largest study recruiting 1803 patients with early breast cancer receiving zoledronic acid 4  mg intravenously every 6 months .
all these studies are summarized in the table 1 . keeping in mind the limitation of these studies by the absence of long - term follow - up , the mean risk of developing onj varies between 0.230.41% in patients receiving immediate or late zoledronic acid .
zoledronic acid has been approved for prevention and treatment of osteoporosis and glucocorticoids - induced osteoporosis , treatment of paget 's disease , hypercalcemia , multiple myeloma and bone metastasis . in the particular case of breast cancer , it is recommended as a monthly administration in breast cancer patients with bone metastasis and as a biyearly administration in early breast cancer patients receiving adjuvant aromatase inhibitors for aibl prevention .
it is incorporated into the skeleton without being degraded and consequently decreases bone turnover and inhibits of the bone 's reparative ability , .
reports of the side effects of zoledronic acid most commonly describe bone pain , nausea , fever , fatigue and constipation .
onj is an uncommon , but severe , adverse event that has been reported with prolonged zoledronic acid therapy . in women with advanced breast cancer and bone metastases ,
the use of bisphosphonates in adjunction to hormone therapy or chemotherapy reduces the sre occurrence and the sre rate , as well as increases the time to skeletal event occurrence .
effectively , breast cancer patients receiving bisphophonates represent more than 20% of patients developing onj .
metastatic breast cancer patients treated by zoledronic acid monthly develop onj in 1.23.8% with the long - term treatment , . on the other hand ,
biyearly zoledronic acid for aibl prevention in early breast cancer is complicated with onj in less than 0.7% according to our literature review . unfortunately , these trials did not report the time of occurrence of the onj , , .
however , the azure trial used a regimen that consisted of monthly zoledronic acid for six doses then every three to six months to compete the 5 years treatment and reported a comparable prevalence of onj .
this comparison allows a safe administration of the  loading dose  of zoledronic acid .
effectively , the pharmacology of the zoledronic acid characterized by a long half - life correlates well with this finding . a recently published abstract , swog 0307 compared three different bisphosphonates clodronate , ibandronate and zoledronic acid administred in a specific schedules in the adjuvant setting of early breast cancer .
no evidence of differences in efficacy by type of bisphosphonate either in the intent to treat analysis or based on age and menopausal status was detected between the three arms . at 5 years
follow - up , the rate of onj was 1.2% in zoledronic acid arm administered monthly for six months then every 3 months for 2.5 years .
denosumab , a fully monoclonal antibody rankl inhibitor , was also evaluated at 60  mg every six months instead of zoledronic acid in patients presenting aromatase inhibitor associated bone loss in early breast cancer . in abcsg
18 trial comparing denosumab 60  mg every six months to placebo , 3425 patients were included ; overall lower number of fractures was demonstrated in the denosumab arm versus the placebo arm .
35 dental problems were identified by proactive monitoring of onj during the trial , 31 suspected cases of onj were detected but no case was eventually judged to meet the diagnosis criteria of onj .
denosumab seems to be safer concerning onj in the indication compared to zoledronic acid ; a randomized trial comparing these two agents can only confirm this hypothesis .
osteonecrosis of the jaw is a major complication of monthly biphosphonate regiments that seems to be encountered also in biyearly administration .
the literature review on zoledronic acid given every six months to prevent aibl , showed a relatively low risk for onj not exceeding 0.7% . despite this low prevalence , avoidance of dental manipulation and recommendations of oral hygiene
 osteonecrosis of the jaw ( onj ) is one of the most relevant and specific complication of biphosphonates . 
 onj in patients receiving zoledronic acid every 3 to 4 weeks is frequently described , but the onj biyearly regimen used to reduce aromatase inhibitor associated bone loss ( aibl ) , is rarely reported . a literature review , focusing on the important trials using zoledronic acid to reduce aibl , found that the mean risk of developing onj when zoledronic acid is used biyearly varies between 0.12% and 0.7% . 
Introduction
Material and methods
Search strategy for the identification of studies
Selection criteria
Results
Discussion
Conclusions