La valutazione del turnover osseo in pazienti affette da carcinoma della mammella con metastasi ossee: analisi delle diverse possibili componenti

Introduction: Breast cancer patients (BC) with bone metastatic disease are characterized by very high levels of bone turnover. CTX and NTX levels in these patients have a significant prognostic value as to the following risk of skeletal related events (SRE), which is negative if these markers are high and positive if they are normalized by therapy with zoledronic acid (ZOL). CTX high levels are usually ascribed to the presence of bone metastatic disease and so the positive prognostic results correlating with the normalization of bone turnover are usually considered the effect of ZOL on bone metastatic disease. Actually many factors should be considered in the analysis of the components which may contribute to the elevation of bone resorption markers (bone metastases, aromatase inhibitors therapy(AI), menopause, hypovitaminosis D). Aim of the study: analyzing the main components of bone turnover (CTX) in breast cancer patients with bone metastatic disease, comparing the three major determinants of elevated bone turnover in these patients (bone metastases, aromatase inhibitors therapy and postmenopausal status). Material and Methods: The population was constituted by 407 women belonging to three different groups: 304 patients affected by postmenopausal osteoporosis (PMO group); 73 patients with non-metastatic breast cancer treated with aromatase inhibitors since at least one year (AIM- group) and 30 patients with breast cancer and bone metastatic disease also treated since at least one year with aromatase inhibitors (AIM+ group). The three groups had similar anthropometric characteristics. Nobody had ever assumed any therapy such bisphosphonates or other anti-osteoporotic therapies. All patients were treated with cholecalciferol 300.000 IU daily for two consecutive days. After 2 weeks (T0), patients were infused with zoledronic acid 5 mg (ZOL). Bone metabolic parameters such as CTX, PTH, 25 (OH)VIT.D and calcium, were measured at basal level (T0) and after 1 week (T7). Risults: At TO, AIM+ patients had CTX levels significantly higher than the patients in the AIM- and PMO groups. In all groups CTX levels were markedly increased compared to the premenopausal range (0.130-0.390 ng/ml). Comparing the different CTX levels in the three groups, we found at T0, that in the AIM+ group about the 60% of CTX (0.620 ng/ml) resulted from the non–metastatic bone tissue (due to postmenopausal status and AI therapy: about 50% and 12% respectively) with the 40% (0.410 ng/ml) that could derive from the metastatic remodeling. At T7, after ZOL infusion, CTX levels resulted normalized in all patients, returning in the premenopausal range. However while in non-metastatic patients the CTX reduction was almost complete (-89% in PMO and -93% in AIM-) in the AIM+ group the reduction was significantly smaller (-73%; p 0.002 vs AIM- e PMO). Moreover, after ZOL infusion, since the almost complete suppression of extra-metastatic bone turnover, the 78% of CTX levels (0.170 ng/ml) could be considered as expression of the activity of the metastatic bone in the AIM+ patients. Conclusions: Our data show that: 1) Bone turnover elevation in patients with bone metastatic breast cancer derives mainly from extra-metastatic bone, being influenced by the postmenopausal status and the aromatase inhibitors therapy; 2) CTX changes after ZOL treatment are likely due to the effect on the benign component of bone turnover so leading to interpret in a new way the data regarding the positive prognostic effects obtained by ZOL on SRE and overall survival; 3) CTX changes after ZOL treatment, even if occurring in the normality range, could be expression of the activity of bone metastatic disease.