This article reports the final five-year results from the Z-FAST study, which evaluated zoledronic acid, administered either upfront (started at the same time as letrozole) or delayed (initiated with a decrease in lumbar spine total hip T score to ≤2 or at the time of a non-traumatic fracture, or if an asymptomatic vertebral fracture was identified at the month 36 follow-up), in women with early breast cancer.  The authors note that aromatase inhibitor (AI) therapy has been associated with progressive bone loss and subsequent fractures.  As many postmenopausal women with breast cancer are likely to be routinely treated with several years of AI therapy, effective bone-loss prevention strategies need to be implemented.

A total of 602 postmenopausal women with early, hormone receptor-positive breast cancer receiving adjuvant letrozole 2.5mg daily for five years were randomised to receive open-label treatment with either upfront (n=301) or delayed (n=301) zoledronic acid (4mg IV every six months).  The primary endpoint was change in lumbar spine bone mineral density (BMD) at month 12; secondary endpoints included changes in BMD at various sites and bone turnover markers at 2, 3 and 5 years, and fracture incidence at 3 years.  Interim results have been previously reported (see link below for details).

Approximately 25% of the delayed group had received treatment with zoledronic acid by five years.  The main results at this final follow-up were as follows:

• The adjusted mean difference in BMD was 8.9% (95% CI 7.4-10.5%) with the upfront group and 6.7% (5.5-8.0%) in the delayed group

• Fracture rates were 9.3% in the upfront group and 11% in the delayed group (p=0.3803) and recurrence rates (estimated using the Kaplan-Meier method) were 9.8% and 10.5% (p=0.6283), respectively

• The incidence of serious adverse events was similar between the groups (27.7% upfront and 23.7% delayed); 3.0% and 1.0% respectively were deemed to be related to the study drug.  

• Osteonecrosis of the jaw (ONJ) was reported by investigators as study drug-related in two patients in the upfront group (both had zoledronic acid treatment permanently discontinued); neither case was confirmed. 

• Renal failure (grade 3-4) was reported in one upfront patient and no patients in the delayed group.  Three patients experienced renal impairment (grade 1-2) in the upfront group believed to be study drug-related; no cases of renal impairment in the delayed group were suspected to be study drug-related.

Although the authors suggest that upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, there was no statistically significant difference between the groups in fracture rates (although this was a secondary endpoint and the study was not adequately powered to detect any differences between the groups with respect to this).  The authors discuss their findings in relation to those of other research groups, and debate the data on the effects of zoledronic acid on disease recurrence and survival in breast cancer.