Einfluss einer polizyklischen Chemotherapie mit 4-6 Zyklen Adriamycin/Cyclophosphamid auf die Knochendichte und Knochenstruktur von praemenopausalen Patientinnen mit primaerem Mammakarzinom.

Breast cancer and osteoporosis are two of the most frequent diseases, affecting about 5-6 Mio. women in Germany. The use of adjuvant chemotherapy in breast cancer patients has been shown to improve disease-free and overall survival. A consensus conference 2006 on adjuvant chemotherapy for breast cancer has specified that adjuvant combination chemotherapy is standard care for premenopausal breast cancer patients with histologically involved axillary nodes. As overall survival and disease-free survival of these patients improve, the long term consequences of therapy need to be assessed. One major long-term consequence of therapy with cytotoxic agents is early ovarian dysfunction, which seems to be dose and age dependent. Permanent chemotherapy-induced ovarian failure occurs in 63-85% of women treated with anthracycline- and cyclophosphamide-containing regimes. These patients may experience osteopenia and some of them will be at higher risc for subsequent osteoporosis. To test the hypothesis, that breast cancer patients who develop chemotherapy-induced ovarian failure may experience accelerated bone loss, a prospective evaluation of bone mineral density assessed by DXA, Quantitative Ultrasonometrie (QUS) and biochemical indices of skeletal turnover was performed in premenopausal women with breast cancer before and during the first year of adjuvant chemotherapy. In our examination the results of 53 premenopausal patients, who became amenorrheic during chemotherapy where compared with age-, sex-, weight- and hight-matched controls. Patients must have been treated with surgery plus adjuvant chemotherapy with or without radiation therapy. Adjuvant chemotherapy consisted of 4-6 cycles of adriamycin and cyclophosphamid. Controls were healthy women who underwent bone-density measurement for screening purposes. The baseline evaluation was scheduled within 2 weeks before the start of adjuvant chemotherapy. The tests were repeated at 6 and 12 month. All women were menstruating normally when first treated for breast cancer and all were free of disease at the time of investigation. BMD was assessed by dual energy X-ray absorptiometry (DXA) using DPX-L (GE/Lunar) and was measured at the proximal femur (femoral neck and trochanter) and the total spine (L1-L4). The QUS-values at the Calcaneus were assessed using Achilles plus (GE/Lunar). The Ultrasound-values at the Phalanges have been measured with the Bone-Profiler (Igea). Additionally we assessed the markers of bone turnover like for example the bone-specific alkaline phosphatase and the Cross Laps. 53 breast cancer patients who became menopausal as a result of chemotherapy participated in the study. In the breast cancer patients significant decreases concerning the QUS-values at the Calcaneus (BUA: p=0,068; SOS: p=0,006; SI agerel.: p<0,001 und SIy: p<0,001) and the Phalanges (AD-SoS,T-Score, Z-Score and tf with p<0,001) were observed through 12 month. In contrast there were no significant differences in the QUS-values in matched controls. Additionally after 12 month the BMD values decreased significantly in the amenorrheic breast cancer group (all measured values p<0,001; except BMD femoral neck: p=0,019). Significant increases in bone-specific alkaline phosphatase (p=0,001), PINP (p=0,004), ICTP (p=0,002) and Cross Laps (p=0,001) were observed in the women who developed ovarian failure at 6 and 12 month. This prospective study suggests first that premenopausal women who experience chemotherapy-induced ovarian failure develop rapid and significant decreases in the QUS-values measured at the Calcaneus and the Phalanges that are detectable within 6 months after starting chemotherapy. In addition to that our results show a significant decrease in BMD of the spine and the femur within 12 month after adjuvant breast cancer treatment with chemotherapeutic agents. Significant decreases in bone mineral-density and increases in markers of bone turnover were detectable after only 6 month, what suggests, that bone loss already begins during adjuvant chemotherapy. The results of this study show that women who develop chemotherapy-induced ovarian failure undergo accelerated and highly significant bone mineral loss, which can be detected by QUS and BMD measurements and may lead to a development of osteoporosis at a relativly early age. Our results support a role for monitoring bone density in premenopausal women with breast cancer undergoing an adjuvant chemotherapy as well as recommending adequate calcium and vitamin D intake and moderate exercise. Interventions to reduce bone loss are at high priority in women who develop chemotherapy-induced ovarian failure.