Bisphosphonates (BPs) are synthetic drugs used in the treatment of osteolytic bone disorders, including osteoporosis, Paget's disease, bone metastasis and multiple myeloma (MM) (1,2). BPs are pyrophosphate analogues with a high affinity for hydroxyapatite crystals (3,4). Once bound to hydroxyapatite crystals, BPs are slowly released during bone resorption and are subsequently internalised by osteoclasts. BPs inhibit osteoclastic bone resorption by interfering with osteoclast recruitment, differentiation and activity, and by promoting apoptosis (5–8). In addition, BPs are reported to exert direct antiproliferative and proapoptotic effects on cancer cells, thereby reducing bone metastases (9,10). Furthermore, BPs alter angiogenesis (11) and signal transduction between osteoclasts and osteoblasts (12). Depending on the presence or absence of a nitrogen atom, nitrogen-containing and non-nitrogen-containing BPs differ in the mechanism of action exerted on osteoclasts (13,14). Various BPs demonstrate different relative potencies and affinities for bone. The more recent nitrogen-containing BPs, such as zolendronic acid (ZA), are the most potent inhibitors of bone resorption (13,15). ZA is an agent that is administered intravenously, and patients receiving BPs intravenously are at a high risk of developing BP-related osteonecrosis of the jaws (BRONJ) (16).

Different definitions make it challenging to reach conclusions on the incidence of BRONJ, which has been reported to be <10% in various studies, and the associated risk factors (17–19). The present study reports a single-centre retrospective study that was performed to determine the frequency, risk factors and clinical presentation of BRONJ, and to also determine the progression of malignancy in patients with cancer treated by ZA once BRONJ develops.

BRONJ is a side-effect of BP therapy that is a relatively rare complication, but may have a notable impact on the quality of life of the affected patients. At present, the risk factors of BRONJ have been researched in numerous studies (15,21,22).

The present study determined that the frequency of BRONJ reached 3.6% in patients diagnosed with a malignancy that was treated using intravenous administration of ZA. In the literature, the rate of ONJ development in patients with malignancies treated using intravenous BP administration has been reported as 1.2, 3.1 and 5% in different studies (18,21–25). It was hypothesized that other factors such as the usage period of the medication, patient diagnoses, presence of chronic disease and presence of other medication usage may have had an effect on the difference in these rates (23). Also, the differences in ethnicity and particularly in dental hygiene habits affected the risk of BRONJ (15,21–24).

In the present study, 33% of the patients with ONJ were suffering from breast cancer (n=8), 33% (n=8) from MM, 25% (n=6) from prostate cancer and 8% (n=2) from other cancers, consisting of colon cancer and renal cell carcinoma. No significant association was detected between the diagnosed malignancy and the development of BRONJ (P=0.09). In certain previous studies, no association was found between the diagnosis and BRONJ, while in other studies it was identified that BRONJ was encountered at a higher rate in patients with MM in comparison to the patients with breast cancer (15,21–25).

While age was not assessed as a risk factor in the present study, the development of BRONJ occurred in patients with a mean age of 60.5 (range, 52.5–68.75), which was significantly different (P=0.04) from the age of the control individuals. This may be associated with the reduction in the metabolism of the medication and insufficient mouth care and hygiene in patients of advanced age.

The assessment of the association between the development of BRONJ in patients receiving ZA and the cumulative dose revealed that the cumulative dose of ZA was significantly higher in patients with BRONJ (P=0.03). The median cumulative dose was determined to be 88 mg (range, 36–120 mg) in the control group and 126 mg (range, 72–168 mg) in the BRONJ group. The time of exposure to ZA was determined to be 36 months in the BRONJ group and 27 months in the control group. In previous studies, the time of exposure to medication was identified as a risk factor in BRONJ development (15,21–23). However, an optimal treatment time or dose was not clearly suggested with regard to these patients. In another study, no association was determined between the cumulative BP dose and the risk of BRONJ (26).

In the present study, the risk of BRONJ development was found to be significantly higher in patients that underwent tooth extraction while using ZA (P=0.01). Surgical dental procedures have also been researched in previous studies, and the status of surgical dental procedures as an important risk factor for BRONJ development has been demonstrated (27).

The presence of DM and the incidence of smoking were researched in previous studies as risk factors for the development of BRONJ (23,28). In the present study, the association between DM and smoking and the risk of BRONJ was assessed in the BRONJ and control groups, and the results were not significantly different (P=0.09 and P=0.08, respectively). When the previous studies were considered, evaluating DM and smoking according to the time of exposure to smoking and the time since DM diagnosis and the state of DM regulation was considered to be an improved method for the evaluation of their effects in BRONJ development.

It is also critical to identify the involvement of steroid usage in this rare but important complication of ZA, since a notable number of patients using ZA have MM, and steroids constitute a component of the treatment for MM. Previous studies have identified steroid usage as a risk factor in BRONJ development (26,29). However, in the present study, steroid usage was not monitored as a risk factor (P=0.8).

The association between an increased risk of BRONJ and the administration of anti-angiogenic agents or other BPs has been investigated in a number of small scale studies (23,30–32). There is a previous study that specifies the use of sunitinib and ZA as a predisposing factor to the development of BRONJ (30), and there are studies that report bevacizumab to be a risk factor (31–33). However, there are also studies stating that bevacizumab is not a risk factor (23,34). No patients were co-administered with sunitinib and ZA in the present study, but there were patients that used bevacizumab and ZA together. The association of between bevacizumab and ZA and the development of BRONJ was not determined to be statistically significant (P=0.7).

In the present study, the course of disease was also investigated during the period of BRONJ development, as was the association between ONJ development and the state of malignancy. The state of disease in patients with ONJ was monitored, and was found to be improved during ZA usage, with a statistically significant association (P=0.031). The most likely cause of the situation may be associated with the long-term usage of ZA. The antitumour effect of the medication may have slowed or stopped the progress of malignancy, due to the long-term usage of ZA. However, BRONJ was encountered more frequently in these patients.

According to the results of the present study, advanced age, the application of dental treatment application and cumulative dose of ZA (median, 126 mg), were found to be risk factors for BRONJ development. Determination of ZA usage and net cumulative dosage in BRONJ development may be presented through a joint calculation to be carried out in the light of other studies that need to be performed. Also, the state of malign disease was determined to be improved during BRONJ development when compared with the patients that did not develop BRONJ. BRONJ development may therefore be a factor during ZA usage, particularly for patients with advanced age. In addition, more frequent and regular dental treatment should be administered to patients with ONJ development, and cooperation between patients, doctors and dentists is required for the treatment of these patients.