The ZO FAST trial recruited postmenopausal women receiving

The ZO-FAST trial recruited 1065 postmenopausal women receiving adjuvant letrozole that were randomly assigned to immediate zoledronic order ll-37 with a regimen of 4mg 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 [7]. Therefore, in the ZO-FAST trial, ONJ occurred in 0.28–0.47%. In the E-ZO-FAST trial, 527 postmenopausal women receiving aromatase inhibitors were randomized to either immediate or delayed zoledronic acid treatment, at 4mg every 6 months. Two reported cases of ONJ of the immediate zoledronic acid group were confirmed by the adjudication committee. At diagnosis, patients had received 3 and 6 doses of zoledronic acid. Treatment was discontinued in both patients but ONJ only resolved in one patient [8]. Accordingly, the E-ZO-FAST trial report ONJ in 0.38%. Finally, the ABCSG-12 trial is the largest study recruiting 1803 patients with early breast cancer receiving zoledronic acid 4mg intravenously every 6 months. There were no confirmed cases of ONJ during a follow up of 84 months [9]. All these studies are summarized in the Table 1.
Discussion 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 [10]. Zoledronic acid is a high potency aminobiphosphonate with an osteoclastic inhibiting activity. It is incorporated into the skeleton without being degraded and consequently decreases bone turnover and inhibits of the bone\'s reparative ability [11,12]. Prolonged use of zoledronic acid suppresses bone turnover disabling repair of microdamage [13]. 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 [2]. Their major adverse event remains the ONJ. Effectively, breast cancer patients receiving bisphophonates represent more than 20% of patients developing ONJ [14]. Metastatic breast cancer patients treated by zoledronic acid monthly develop ONJ in 1.2–3.8% with the long-term treatment [3,4]. 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 [6–8]. 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 [15]. 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 [16]. Denosumab, a fully monoclonal antibody RANKL inhibitor, was also evaluated at 60mg 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 60mg 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 [17]. 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.
Conclusions
Introduction Osteosarcoma is the most common primary bone cancer in children and adolescents [1]. Surveillance, Epidemiology and End Results (SEER) programme data indicates an annual incidence of 4.4 per million population in patients younger than 25 years of age [2]. The presence of metastases, at time of presentation, has been shown to be an independently significant risk factor in the prognosis of a patient with osteosarcoma [3]. Pakos et al. analysed the prognostic factors in 2 680 osteosarcoma cases in an international multicentre study and found that metastases at diagnosis increased the risk of mortality by a factor of 2.89 [4]. In developed regions approximately 15% of patients with osteosarcoma present with metastatic disease [5]. In under-developed regions higher rates of metastases have been found at time of diagnosis. This is illustrated in previous studies from South Africa, where evidence of systemic spread was found in 47–66% of patients at time of presentation [6,7].