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    • Welcome to volume two of the the first

    2019-07-01

    Welcome to volume two of the , the first journal devoted to the multidisciplinary management of bone disease in cancer patients. During the past year, the importance of bone oncology in cancer care has continued to increase. This follows the emergence of further clinical data supporting the use of bone targeted treatments in the adjuvant treatment of early breast cancer , the activity of denosumab in delaying the development of bone metastases in castrate resistant prostate cancer and clearer understanding of the risk benefits of denosumab in the prevention of skeletal morbidity in advanced cancer patients with bone metastases. Alongside these important clinical trial results that are already influencing clinical practice, our understanding of the importance of the bone microenvironment and the numerous cellular interactions that take place in the process of metastasis as well as the concept of tumour dormancy has expanded further .
    Introduction Third-generation aromatase inhibitors (letrozole, anastrozole, and exemestane) have now largely replaced tamoxifen as the standard of care for postmenopausal women with hormone receptor-positive breast cancer because of their greater efficacy [1,2]. Aromatase inhibitors block the production of peripheral estradiol precursors and reduce endogenous catalase inhibitor to levels substantially below those naturally occurring in healthy postmenopausal women [3]. Because estrogen is a negative regulator of bone turnover, its depletion during aromatase inhibitor therapy results in increased bone turnover and osteoclast activity, and leads to rapid reduction in bone mineral density and increased risk of fractures [4,5]. Bisphosphonates (BPs) inhibit osteoclast-mediated bone resorption, and thus can reduce or prevent bone loss during aromatase inhibitor therapy. Intravenous (IV) and oral (PO) BPs such as zoledronic acid, pamidronate, clodronate, and ibandronate are approved for reducing the risk of skeletal-related events (SREs) in patients with metastatic bone disease, and have demonstrated efficacy for preventing cancer treatment-induced bone loss in patients with breast cancer [5]. Denosumab, a monoclonal antibody against the receptor activator of nuclear factor kappaB ligand (RANKL), has emerged as an alternative to BPs for reducing the risk of SREs in patients with bone metastases from solid tumors, including breast cancer [6,7]. However, the long-term side-effect profile of denosumab is still unknown, and no guidance currently exists for managing the risk of hypocalcemia. Because denosumab has a short history of clinical use and has not demonstrated anticancer activity, it was not included in this study. A growing body of evidence supports the anticancer benefits of BPs above and beyond their bone-conserving effects. In recent retrospective (N=154,768) and population-based (N=9950) studies in healthy women, BP treatment was associated with reduced risk of breast cancer [8–10]. Preclinical and clinical data suggest that BPs may provide anticancer benefits such as inducing cancer cell apoptosis; inhibiting cancer cell proliferation, migration, invasiveness, and tumor-associated angiogenesis; activating anticancer immune activity; and potential synergy with anticancer agents [5,11–13]. Several pilot clinical studies in women with early breast cancer demonstrated that adding (neo)adjuvant zoledronic acid (4mg every 3–4 weeks) to hormonal therapy or chemotherapy reduced the number of persistent disseminated tumor cells in the bone marrow compared with regular anticancer therapy alone [14–17]. Such reductions in disseminated tumor cells might lead to reduced tumor recurrences in these patients. Two clinical trials that included patients with early breast cancer who were either postmenopausal or premenopausal and received ovarian suppression showed that adding twice-yearly zoledronic acid (4mg) to standard adjuvant endocrine therapy significantly improved disease-free survival (DFS) compared with endocrine therapy alone [18,19]. Moreover, in patients with breast cancer and bone marrow micrometastases, overall survival (OS) improved with adjuvant clodronate compared with placebo [20,21]. In a meta-analysis of randomized, controlled clinical trials of BPs, adjuvant zoledronic acid reduced the risk of breast cancer recurrence; however, overall, adjuvant BPs did not reduce mortality, disease recurrence rates, or relapse rates in this population [22]. Recent results from the Adjuvant Zoledronic acid to redUce REcurrence (AZURE) trial, conducted in women with early breast cancer, showed no significant benefit of adjuvant zoledronic acid in the overall population, whereas significant DFS and OS benefits were observed in a subset of women with established postmenopausal status (i.e., >5 years postmenopause at baseline) [23]. These results suggest that the anticancer effects of BPs may be dependent on a low-estrogen environment.