br Methods br Results br Discussion
Discussion Bisphosphonates reduce skeletal morbidity in patients with advanced cancers involving bone and have become a recommended component of the multidisciplinary treatment of MBD . However, bone-health benefits have not generally translated into significantly improved OS in phase III trials [3–5]. These individual placebo-controlled trials were not powered to evaluate OS differences and included groups of patients with low SRE rates (e.g., patients with MBD in the skull)  or aggressive metastases in vital SC 144 that may have contributed substantially to mortality. A bone-targeted therapy would be less likely to influence the clinical course of disease in such patients. In the overall phase III MBD trial population, there was only a 5% nonsignificant improvement in OS with ZOL treatment. Nonetheless, the results herein suggest a beneficial effect of ZOL on survival (up to 24 months and in addition to SRE prevention) in patients with MBD and baseline characteristics associated with aggressive disease and/or poor prognosis. These characteristics include parameters associated with aggressive bone disease – namely, high baseline NTX, prior SREs at baseline – or parameters indicating a poor overall condition (e.g., low albumin levels and impaired PS). In particular, the survival benefit in patients with high NTX was observed in multiple analytic models regardless of how other covariates were categorised, and is biologically plausible given the antiresorptive ability of bisphosphonates. Cancer-induced osteolysis is the main therapeutic target for bisphosphonates and, consistent with other targeted therapy approaches, measurement of target activity may help identify patient populations with the greatest likelihood of benefit from treatment. Furthermore, the larger survival benefit with ZOL in patients with NTX>100nmol/mmol Cr (versus a smaller trend in patients with NTX>64nmol/mmol Cr) suggests a dose-response effect. Interestingly, several of the characteristics associated with potential OS benefits from ZOL have been also associated with poor clinical outcomes in earlier studies in patients with advanced cancers. High baseline NTX is associated with increased risks of SREs and death , and low albumin levels have emerged as negative prognostic indicators in a variety of advanced cancers [19–23,31]. Factors such as hypoalbuminaemia and poor PS might also impact treatment decisions (e.g., by exacerbating the side effects of chemotherapy or by hindering access to in-clinic treatment), thereby influencing clinical outcomes. The strong associations between such “poor-prognosis” variables and the probability of OS benefits from ZOL suggest that bone-directed therapy continues to provide benefits even in patients with the most advanced disease; moreover, such patients might derive even greater benefits from ZOL. Consistent with recent results from the MRC Myeloma IX trial , the survival benefits associated with ZOL in the present analyses appeared independently of SRE prevention. If the observed improvements in OS with ZOL treatment were completely attributable to preventing potentially life-limiting SREs , the survival benefits would not be sustained in models including SRE incidence as a competing time-dependent variable. The consistent maintenance of the OS benefits of ZOL in models adjusting for SREs suggests that ZOL, in addition to preventing treatment interruption and cessation because of SREs and the associated decreases in PS, may exert anticancer effects in some patient subsets. Of note, the survival impact is greatest in those patients with NSCLC and OST, whose survival is typically short and for whom a delay in anticancer treatment of a few weeks may have more bearing on subsequent outcome. Denosumab, an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL), has demonstrated comparable or superior efficacy versus ZOL for reducing SREs in head-to-head clinical trials in patients with MBD from solid tumours [32–34]. Nonetheless, OS was similar between treatment arms [32–34], suggesting that SRE prevention alone may be insufficient to alter survival. Although correlative analyses are yet to be reported, these trials prospectively collected bone marker data at baseline and 13 weeks, and present an opportunity to investigate whether the correlations between elevated osteolysis levels and survival benefits with antiresorptives are generally applicable.