One of the biggest news stories from SABCS in 2010 was the AZURE trial. The results of the trial showed no effect of zoledronic acid on breast cancer recurrence or overall survival. However, subgroup analysis showed a significant effect on recurrence and survival in postmenopausal women (more than 5 years after menopause) but no effect in premenopausal women (1). The latest follow-up results from four other clinical trials of bisphosphonates were announced by SABCS on December 7 of this year and were also a hot topic at this year’s conference. A press conference was held later that day to summarize the use of bisphosphonates in the treatment of breast cancer. The Austrian Breast Colorectal Cancer Study Group reported the latest long-term follow-up data from the ABCSG-12 study. A total of 1,800 patients, all with premenopausal estrogen receptor-positive early-stage breast cancer, were enrolled in the study between 1996 and 2003 and received goserelin plus tamoxifen or anastrozole along with adjuvant zoledronic acid. The latest 84-month follow-up showed a significant disease-free survival (28%) and overall survival (37%) advantage in the zoledronic acid group, reducing local recurrence, distant metastases, and contralateral breast cancer occurrence, again demonstrating that bisphosphonates for osteoporosis and bone metastases may have concurrent antitumor effects. Stratified studies have shown that the primary population of benefit is those with low estrogen levels, including those using ovarian suppression or aged 40 years or older. With regard to safety, the zoledronic acid group showed more problems with bone and joint pain and fever, but no reports of osteonecrosis of the jaw or renal failure. The lead investigator, Prof. Gnant from the Medical University of Vienna, concluded that the results of the ABCSG-12 study were consistent with the results of the ZO-FAST study, as well as with the results of the AZURE study in the subgroup that had been menopausal for more than 5 years, and that zoledronic acid had a sustained and long-term effect. However, in a retrospective subgroup analysis of 185 patients who developed disease recurrence, the risk of death was significantly higher in the anastrozole group (including anastrozole alone or anastrozole plus zoledronic acid) than in the tamoxifen group (including TAM alone or TAM plus zoledronic acid) in the 62-month follow-up results of the ABCSG published in The Lancet Oncology in July 2011. plus zoledronic acid) (2). Another bisphosphonate trial, ZO-FAST, was reported by Professor Boer from Australia on behalf of the study group.The ZO-FAST trial is a global Z/ZO/E-ZO-FAST open randomized multicenter adjuvant treatment program with enrollment criteria of ER+/PgR+, postmenopausal, and breast cancer patients with amenorrhea due to ovariectomy, chemotherapy, or LHRH treatment, and a T score ≥C2. Of these, Z-FAST was conducted in North America; E-ZO-FAST was conducted in Europe, Argentina, South Africa, South Korea, Lebanon, and the United Arab Emirates; and ZO-FAST was conducted in 30 countries other than the United States and Canada, with enrollment beginning in May 2003 and a total of 1066 patients enrolled at 150 centers (3). The final 5-year follow-up results showed that the study also met the primary study endpoint. Concomitant adjuvant zoledronic acid treatment with letrozole in postmenopausal hormone receptor-positive breast cancer patients protected bone mineral density. The initial treatment group achieved a 34% improvement in disease-free survival and a 3.6% absolute benefit compared to the delayed treatment group (91.9% vs 88.3%), with a reduction in both local and distant recurrence and contralateral breast events. In the ABCSG-12 study, although the effects of age, degree of estrogen suppression, and chemotherapy remain unclear, it can be used as Class I evidence for the safety and efficacy of adjuvant zoledronic acid in hormone-receptor-positive premenopausal patients receiving ovarian suppression and endocrine therapy in conjunction with ovarian suppression. Evidence of safety and efficacy is warranted. The ZO-FAST results achieved a significant disease-free survival benefit, but this unscheduled analysis does not yet support the use of zoledronic acid as standard adjuvant therapy in postmenopausal patients. Other issues with the study include the type of bisphosphonate, frequency and duration of treatment, and the impact of chemotherapy. The B-34 study from the US Study Group for Adjuvant Breast and Bowel Surgery (NSABP) compared the efficacy of adjuvant clodronate disodium therapy with placebo in patients with stage I and II breast cancer. A total of 3323 patients were enrolled with a median follow-up of 8.4 years. Although their final results failed to show a difference in overall disease-free survival, they did show some advantage in older patients (4). The reporter, Prof. Paterson, concluded that clodronate disodium is easy to administer as a low-toxicity oral bisphosphonate, and three previous studies have also shown some benefit in elderly patients. Disodium clodronate is approved for use in Europe and Canada, but is not currently approved by the FDA in the United States. The last trial reported was the GAIN study from Germany. The trial looked at the efficacy of dose-dense epirubicin, paclitaxel and cyclophosphamide sequential chemotherapy according to a quadruple schedule, as well as epirubicin combined with cyclophosphamide sequential paclitaxel combined with capecitabine with concomitant adjuvant ibandronate. Ibandronate as an oral bisphosphonate has been approved for the prevention and treatment of osteoporosis in postmenopausal women in the United States. A total of 3,023 women were randomized from June 2004 to August 2008. The results showed that the 3-year disease-free survival rate was 87.6% in the ibandronate group and 87.2% in the control observation group, (p=0.59). The 3-year overall survival rates were also very similar in both groups, 94.7% and 94.1% in the ibandronate and observation groups, respectively, p=0.80. There was also no difference in disease-free survival between the two groups in all subgroup analyses. Based on the results of the ABCSG-12 study, the use of zoledronic acid for adjuvant therapy in premenopausal women is expected to be the new norm, and the mechanism of action may be related to the antitumor effect of the drug on the bone marrow microenvironment. the ZO-FAST trial showed that the use of zoledronic acid for adjuvant therapy in postmenopausal patients with early breast cancer also resulted in a disease-free survival and overall survival advantage, but this index was not the initial design goal and therefore cannot support the use of zoledronic acid for adjuvant therapy. Therefore, the use of zoledronic acid as standard adjuvant therapy for postmenopausal patients cannot be supported. The mechanism of action of bisphosphonates in breast cancer is complex, and further confirmation will require larger multicenter clinical studies.