Animal models are important tools to study the development of bone metastases and to evaluate strategies for their prevention and treatment. We here describe a new model in which tumour inoculation is achieved by injection of cancer cells into the femoral artery. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within 18 days after inoculation, with a success rate of 95-100% and no additional comorbidity. In untreated animals, osteolyses expanded continuously at a growth rate of 4.7-8.2 mm 2 /4 days, causing extensive destruction of resident bone structures by the tumour, significant loss of tibial bone density and a transient rise in urinary bone resorption markers. Continuous daily treatment with ibandronate (10 g/kg) inhibited further growth of fully established metastases and reduced the mean osteolytic growth rate to 0.03 mm 2 /4 days. In lesions <6 mm bisphosphonate treatment resulted in a negative growth rate (-0.33 to -0.81 mm 2 /4 days). When ibandronate was started 3 days prior to tumour cell inoculation, the development of osteolytic lesions was substantially reduced (take rate only 17%) and bone density and structure were mostly preserved. We conclude that the intra-arterial approach used in this new model of metastatic bone disease results in site-specific osteolytic lesions with high take rates, steady tumour growth and no additional morbidity. While serial bone marker assessments did not prove useful to monitor osteolytic growth, our studies provide in vivo evidence that ibandronate treatment induces tumour remission by reversal of tumour growth. © Bone metastases are frequent complications of many malignant tumours, particularly of breast, prostate and lung cancers. 1,2 Animal models are important tools to study the mechanisms involved in the development of metastatic bone disease and to evaluate in vivo strategies for its prevention and treatment. 3 Most current animal models utilise suspensions from malignant cell lines that are brought to the skeleton either via direct 4 -6 or indirect inoculation. With intracardial injections, 3,7-11 cells are inoculated at a relatively high tumour dose and, in most models, malignant dissemination occurs into both skeletal and visceral peripheries, resulting in varying degrees of animal comorbidity (e.g., cachexia, paraplegia). Direct inoculation of tumour cells into the bone marrow leads to site-specific osteolyses, but these models lack the processes associated with extravasation of tumour cells, while the injection itself causes bone damage that might result in nonspecific wound responses. [12][13][14][15] Furthermore, all currently characterised animal models of metastatic bone disease use either syngeneic tumours or human xenografts in small animals ( e.g., mice) or syngeneic tumours in larger animals (e.g., rats). While small-animal models are often restricted to end-point analyses or radiographic follow-up, studies in larger animals allow the longitudinal assessment of bone turnover by s...

Background: Using a nude rat model of site-specific metastatic bone disease (MBD), we developed a semiquantitative histological score for rapid assessment of lytic lesions in bone. This provides additional information to conventional histological measurement by clarifying the extent and location of metastatic infiltration and the tumor growth pattern. The score can also be used to assess the action of bisphosphonates on bone metastases. Materials and Methods: Male nude rats (n = 12 per group) were inoculated with the human breast cancer cell line MDA-MB-231 via the femoral artery. Following appearance of radiographically visible osteolytic lesions on day 18, the animals received phosphate-buffered saline (PBS; controls) or ibandronate (IBN, 10 µg P/kg) daily until day 30. Whole body radiographs were obtained on days 18 and 30, and osteolytic areas (OA) were determined by radiographic computer-based analysis (CBA). On day 30, MBD was assessed in both tibias using conventional histological CBA and the new scoring system. Results: Metastatic tumor area correlated with the total sum of the new score in both PBS- (r = 0.762) and IBN-treated animals (r = 0.951; p < 0.001). OA correlated well with the total sum in both groups (r = 0.845 and 0.854, respectively; p < 0.001). Conclusion: Significant reduction of bone marrow and cortical infiltration of tumor cells with IBN suggested local control of metastases.

We have been observing 2 groups of 50 female patients with occult or clinical breast cancer each of whom was initially treated at the Gynaecologic Hospital of the University of Erlangen-Nürnberg between 1975 and 1978. During the follow-up period, 2 patients out of the group of occult cancer and 13 out of the group of clinical carcinoma died of their primary disease. Four women out of the group of occult cancer and 3 from the group of "clinical carcinoma" have developed recurrences. The differences in survival times according to Kaplan-Meier are immense, even if they are not significant owing to the small number of patients. But it is difficult to obtain and to evaluate larger groups of patients and longer follow-up periods due to the low percentage of occult cancer (7.7 to 10.5% only). There are 30 women out of the group of occult breast cancer living without relapse after an observation period up to 15 years. 27 patients out of the group of "clinical cancer" have not shown any evidence of recurrence up to now. This small difference after such a long follow-up period can be explained by the general life expectancy and by the age at initial treatment.