Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01–04) for women with stage II/III breast cancer

Abstract

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

Osteonecrosis of the Jaw Developed in Mice

“…ONJ is most frequently reported in zoledronate (ZOL)-treated patients with a primary diagnosis of multiple myeloma or bone metastatic tumors such as breast cancer (8,9). These high risk patients are generally middle-aged to elderly, and they are often treated with immunosuppressive and chemotherapeutic agents, glucocorticoids, or both (10,11).…”

İlaçlara Bağli Çene Kemi̇ği̇ Osteonekrozu: Derleme

“…Antirezorptif veya antianjiojenik ilaç kullanma hikayesi olmayan kanser hastalarında İÇKON oluşma insidansı %0 ile %0,019 olarak bildirilmektedir ve bu oran zolendronat kullananlarda %0,7 ile %6,7 arasındadır [38][39][40] . Tümör tipine göre de insidans değişkenlik göstermektedir.…”

“…Diş çekim işlemi tek başına İÇKON oluşumunda %52 ile %61 arasında predispozan faktördür 40,57 . Oral BPs kullanan hastalarda diş çekimi sonrası osteonekroz gelişme insidansı %0,5 olarak rapor edilirken, IV yolla BPs kullananlarda ise %1,6 ile %14,8 arasında bildirilmektedir 58,59 .…”

“…Hareketli protez kullanım-ının bu insidansı artırtığı da bildirilmektedir 60 . Vahtsevanos ve ark'ları IV zolendronat, ibandronat veya pamidronat kullanan 1,621 kanser hastasında hareketli protez kullanımının bu riski 2 kat arrtırdığını bildirmektedir 40 . Periodontal veya periapikal patolojiler gibi varolan enflamatuar dental hastalıklar lokal risk faktör-leri olarak tanımlanmaktadır 58,61 .…”

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

“…While they have been tremendously successful in the treatment of osteoporosis and tumor-induced bone disease, they do not directly target the tumor cells, which are the root cause of the problem. Furthermore, some patients fail bisphosphonate treatment, and the recent discovery of clinical complications observed with long term bisphosphonate treatments, including osteonecrosis of the jaw and atypical subtrochanteric fractures, has made these drugs less ideal clinically [1,107,108]. The emerging drug for clinical use, Denosumab or XGEVA (Amgen), which targets RANKL, has been demonstrated to reduce bone turnover and increase bone density in clinical studies [109].…”