engleski

Breast carcinoma treatmant induced bone loss: interplay of Wnt inhibitors and lifestyle parameters

Breast cancer (BC) is the most prevalent cancer in women wordwide. The treatment of BC is multidisciplinary and includes surgery, radiation, chemotherapy and adjuvant endocrine therapy in cases of hormone receptor(HR)- positive BC. In 60–80% of the cases, BC cells express the estrogen receptor (ER), the progesterone receptor (PR) or co-express both (3) and, thus, are candidates for adjuvant endocrine therapy, with either selective ER modulators (SERMs) or third generation aromatase inhibitors (AIs). All these therapies aim to deprive cancer cells of estrogens and their growth-promoting effects (4). Whereas tamoxifen, a SERM, competitively blocks ER signaling in BC cells, AIs suppress the conversion of androgens to estrogens, thereby suppressing residual estrogen levels in postmenopausal women. AIs are the first choice treatment in postmenopausal women with HR-BC (4). As a result of earlier diagnosis, more efficacious treatments, and longer survival, more patients than ever are receiving long-term treatment for BC. According to the study of Hadji et al. in 2009, AI induced bone loss (AIBL) occurs at a rate of at least 2-fold higher than bone loss seen in healthy, age- matched postmenopausal women, resulting in a significantly higher fracture incidence (5). Hadji et al. concluded that adjuvant AIs therapy depletes residual estrogen and is associated with rapid bone loss, and the increased fracture risk is distinctly different from that observed in postmenopausal osteoporosis (5). Similar findings in the ATAC (Arimidex, Tamoxifen, alone or in combination) bone subprotocol by Eastell et al. in 2008, confirmed that adjuvant anastrozole therapy for postmenopausal women with early BC led to accelerated bone loss (6). This reduction in bone mineral density (BMD) associated with AI occurs in 35-47% of patients, but it is important to emphasize that this loss is asimptomatic (untill fractures occur) and that 82% of fractures occur in women who do not have osteoporosis, according to the WHO classification (T scores < -2.5 SD). Since fractures can not be predicted only on the basis of BMD measurement, it is necessary to identify sensitive and quantitative biomarkers of bone remodeling. Therapeutic interventions may also be needed for women whose T scores are above thresholds. Bone turnover is a physiological process tightly controlled by a complex system of signaling pathways regulating both osteoclast and osteoblast function. While osteoclastic differentiation and activity is regulated by RANKL-OPG signaling pathway (7), Wingless-type (Wnt) signaling is one of the main regulators of osteoblast activity. Wnt ligand binding to its receptor promotes osteoblast differentiation (8). Activation of this bone anabolic pathway is prevented by Wnt inhibitors such as sclerostin and dickkopf1 (DKK1). While sclerostin is almost exclusively expressed in osteocytes (9), DKK1 is secreted by a variety of different cells and tissues including BC cells (10). AIs effects on sclerostin and DKK1 as Wnt inhibitors of bone anabolic pathway are still unclear. The aim of this study was to determine the levels of Wnt inhibitors in AIs treated patients and to investigate their association with (BMD) and lifestyle parameters.

Osteoporosis, Drugs / Reactions, Cancer, Laboratory tests, Comparative studies, Chemotherapy, Absorptiometry / Bone densitometry, Oncology, Breast, Bones

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