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Doxorubicin Therapy Causes Additional Bone Loss in Preclinical Osteolytic Breast Cancer Model
Abstracts / Bone 46 (2010) S9–S83
treatment. This trial was sponsored by Roche Pharma AG, Grenzach, Germany. Protocol number: ML18508, www.roche-trials.com. doi:10.1016/j.bone.2010.01.073
71. Renal safety of ibandronate in the treatment of myeloma patients Raoul Bergner1, Breuer Jochen1, Michael Uppenkamp1, Andreas Sandermann2, Martin Hoffmann1 1 Medizinische Klinik A, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany 2 WiSP Wissenschaftlicher Service Pharma GmbH, Langenfeld, Germany Introduction: Treatment of myeloma (MY) bone disease with bisphosphonates (BP) is standard of care. But renal toxicity due to BP treatment tends to be a major problem in MY patients, especially. Patients with reduced renal function (RF) and patients who had switched BP drugs are at highest risk. Toxicity appears typically after few month of treatment. We evaluated safety data about RF from MY patients, who were treated with ibandronate (IBD). The patients were stratified according to pretreatment and RF.Methods: In a prospective noninterventional study (NIS) about safety and efficacy of IBD in breast cancer patients it turned out that unintentionally MY patients were also included. Out of 3528 documented patients 93 MY patients were identified. We evaluated the data from these MY patients separately. The patients were subdivided in 4 groups according to their RF: GFR>90 (1), 60-90 (2), 30-59 (3) and <30 (4) ml/min. Since pretreatment with or without BP could be of influence, patients were analysed according to former pretreatment: no BP (I), IBD (II), and other BP (III). The kidney function was calculated every month over a period of six month. Results: 93 patients were available for evaluation. In 87 patients RF was documented over a minimum of 5 months. The initial RF was (1) n = 11, (2) n = 34, (3) n = 36 and (4) n = 12, respectively. There were no differences in renal function according to their pre-treatment. A total number of 620 infusions were documented. The IBD dosage was 6 mg in 89% of all infusions, 4 mg in 4%, 3 mg in 2% and 2 mg in 5%, respectively. In the subgroups (1-4) RF was stable over time (mean GFR+//0-SD ; difference over the time [ml/min]: (1): 116,8+//0-20,9; -3,38; (2): 74,7+//0-8.4; 2,04; (3): 46,1+//0-8,1; 3,7; (4): 20,4+//0-7; 13,37; all changes n.s.), but there was a trend for improved RF in patients with GFR < 30 ml/min. The mean changes were similar in all groups irrespectively of the pretreatment. In 8 patients the treatment was terminated prematurely, due to disease progression (n = 3), death due to MY during study period (n = 2). Two patients were lost by follow up and one patient declined further treatment. Discussion: The data of this NIS suggest, that there is no evidence for renal toxicity of IBD in MY patients in all stages of renal function. Patients with worse kidney function (stage 4) had a trend of improvement of RF over the study period, however, the changes were not significant due to the limited number of patients. doi:10.1016/j.bone.2010.01.074
72. Doxorubicin Therapy Causes Additional Bone Loss in Preclinical Osteolytic Breast Cancer Model Swati Biswas, Austin Ayers, Anwesa Chakrabarti, Steve Munoz, Joshua Johnson, Gregory Mundy Cancer Biology/ Center for Bone BIology, Vanderbilt University, Nashville, Tennessee, United States
S35
Breast cancer patients often suffer from osteolytic bone metastasis and subsequent bone loss. This is a major problem for these patients leading to higher risk of pathological fractures, nerve compression and pain. Breast cancer patients are often treated with chemotherapeutic drugs such as doxorubicin. Doxorubicin is known to cause long-term bone damage in patients with childhood cancers. Doxorubicin decreased alkaline phosphatase activity in mouse osteoblast cell lines (MC3T3), suggesting a potential mechanism for bone loss. Additionally, therapeutic doses of doxorubicin decreased osteoblast activity, bone mineralization and resulted in 60% reduction in bone formation in rat, suggesting that, these adverse effects may also occur in cancer patients undergoing chemotherapy. Therefore, the effect of doxorubicin on osteolytic bone metastasis needs to be evaluated. Female nude mice were injected with MDA-MB-231 cells via left cardiac ventricle. Doxorubicin (5 mg/Kg) treatment was initiated 1 day after the tumor cell injection via the left cardiac ventricle and continued once every week until the end of the experiment. Osteolytic bone lesion formation was monitored by weekly X-ray (Faxitron). Bone volume was assessed by microCT analysis. Faxitron imaging of the tumor bearing animals revealed that doxorubicin treatment resulted in increased osteolysis (control 1999 ± 1136, doxorubicin 16143 ± 5438, P = 0.002) in tumor-bearing mice. Tibia samples were harvested after two weeks and microCT analysis of the tibiae revealed that doxorubicin treatment significantly decreased bone volume, which was rescued by anti-TGFβ antibody 1D11 (BV/TV: control 0.09 ± 0.04, doxorubicin 0.06 ± 0.01, doxorubicin +1D11 0.107 ± 0.3. Taken together, we conclude that, doxorubicin therapy may account for additional bone loss in patients with osteolytic bone disease and an anti-TGFβ therapy may be effective in controlling that bone loss. doi:10.1016/j.bone.2010.01.075
73. Oncostatin M leads to opposite effects on the proliferation of different primary bone tumors Emmanuelle David, Bénédicte Brounais, Dominique Heymann, Francoise Rédini, Frederic Blanchard Inserm U957, Nantes, France Osteosarcoma, Chondrosarcoma and Ewing sarcoma represent the majority of primary bone tumors and their treatment has to be improved. They all derive from bone mesenchymal stem cells, but Ewing sarcoma are not much differentiated compared to osteosarcoma and chondrosarcoma. Ewing sarcoma cells are characterized by a chromosomal translocation, EWS-FLI1, which behave as an oncogene. Oncostatin M (OSM), a cytokine from the IL-6 family, inhibits the proliferation of osteoblasts and osteosarcoma through activation of the transcription factor STAT3 and induction of the cell cycle inhibitor p21WAF1. The aim of this study was to define the activity of OSM on Chondrosarcoma and Ewing sarcoma in comparison to other IL-6 type cytokines. OSM inhibited the proliferation of 5 on 6 chondrosarcoma cell lines by a mechanism independent of p21 and associated with the blockade of the cells in S/G2/M phase of the cell cycle. This inhibition of proliferation was confirmed in vivo in the Swarm rat model of chondrosarcoma as we observed a decrease in the tumoral growth after intra-tumor injection of an adenovirus encoding murine OSM. In contrast, OSM induced the proliferation of 5 on 9 Ewing sarcoma cell lines by inducing the quiescent cells in G0 (Ki67-) to get into the cell cycle (Ki67+, cells mainly in S phase). All the cell lines expressed the OSM receptor subunits (gp130, OSMR and LIFR) and these receptors were functional (activation of STAT3 and ERK1/2). On all the cell lines tested, the effects on proliferation
treatment. This trial was sponsored by Roche Pharma AG, Grenzach, Germany. Protocol number: ML18508, www.roche-trials.com. doi:10.1016/j.bone.2010.01.073
71. Renal safety of ibandronate in the treatment of myeloma patients Raoul Bergner1, Breuer Jochen1, Michael Uppenkamp1, Andreas Sandermann2, Martin Hoffmann1 1 Medizinische Klinik A, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany 2 WiSP Wissenschaftlicher Service Pharma GmbH, Langenfeld, Germany Introduction: Treatment of myeloma (MY) bone disease with bisphosphonates (BP) is standard of care. But renal toxicity due to BP treatment tends to be a major problem in MY patients, especially. Patients with reduced renal function (RF) and patients who had switched BP drugs are at highest risk. Toxicity appears typically after few month of treatment. We evaluated safety data about RF from MY patients, who were treated with ibandronate (IBD). The patients were stratified according to pretreatment and RF.Methods: In a prospective noninterventional study (NIS) about safety and efficacy of IBD in breast cancer patients it turned out that unintentionally MY patients were also included. Out of 3528 documented patients 93 MY patients were identified. We evaluated the data from these MY patients separately. The patients were subdivided in 4 groups according to their RF: GFR>90 (1), 60-90 (2), 30-59 (3) and <30 (4) ml/min. Since pretreatment with or without BP could be of influence, patients were analysed according to former pretreatment: no BP (I), IBD (II), and other BP (III). The kidney function was calculated every month over a period of six month. Results: 93 patients were available for evaluation. In 87 patients RF was documented over a minimum of 5 months. The initial RF was (1) n = 11, (2) n = 34, (3) n = 36 and (4) n = 12, respectively. There were no differences in renal function according to their pre-treatment. A total number of 620 infusions were documented. The IBD dosage was 6 mg in 89% of all infusions, 4 mg in 4%, 3 mg in 2% and 2 mg in 5%, respectively. In the subgroups (1-4) RF was stable over time (mean GFR+//0-SD ; difference over the time [ml/min]: (1): 116,8+//0-20,9; -3,38; (2): 74,7+//0-8.4; 2,04; (3): 46,1+//0-8,1; 3,7; (4): 20,4+//0-7; 13,37; all changes n.s.), but there was a trend for improved RF in patients with GFR < 30 ml/min. The mean changes were similar in all groups irrespectively of the pretreatment. In 8 patients the treatment was terminated prematurely, due to disease progression (n = 3), death due to MY during study period (n = 2). Two patients were lost by follow up and one patient declined further treatment. Discussion: The data of this NIS suggest, that there is no evidence for renal toxicity of IBD in MY patients in all stages of renal function. Patients with worse kidney function (stage 4) had a trend of improvement of RF over the study period, however, the changes were not significant due to the limited number of patients. doi:10.1016/j.bone.2010.01.074
72. Doxorubicin Therapy Causes Additional Bone Loss in Preclinical Osteolytic Breast Cancer Model Swati Biswas, Austin Ayers, Anwesa Chakrabarti, Steve Munoz, Joshua Johnson, Gregory Mundy Cancer Biology/ Center for Bone BIology, Vanderbilt University, Nashville, Tennessee, United States
S35
Breast cancer patients often suffer from osteolytic bone metastasis and subsequent bone loss. This is a major problem for these patients leading to higher risk of pathological fractures, nerve compression and pain. Breast cancer patients are often treated with chemotherapeutic drugs such as doxorubicin. Doxorubicin is known to cause long-term bone damage in patients with childhood cancers. Doxorubicin decreased alkaline phosphatase activity in mouse osteoblast cell lines (MC3T3), suggesting a potential mechanism for bone loss. Additionally, therapeutic doses of doxorubicin decreased osteoblast activity, bone mineralization and resulted in 60% reduction in bone formation in rat, suggesting that, these adverse effects may also occur in cancer patients undergoing chemotherapy. Therefore, the effect of doxorubicin on osteolytic bone metastasis needs to be evaluated. Female nude mice were injected with MDA-MB-231 cells via left cardiac ventricle. Doxorubicin (5 mg/Kg) treatment was initiated 1 day after the tumor cell injection via the left cardiac ventricle and continued once every week until the end of the experiment. Osteolytic bone lesion formation was monitored by weekly X-ray (Faxitron). Bone volume was assessed by microCT analysis. Faxitron imaging of the tumor bearing animals revealed that doxorubicin treatment resulted in increased osteolysis (control 1999 ± 1136, doxorubicin 16143 ± 5438, P = 0.002) in tumor-bearing mice. Tibia samples were harvested after two weeks and microCT analysis of the tibiae revealed that doxorubicin treatment significantly decreased bone volume, which was rescued by anti-TGFβ antibody 1D11 (BV/TV: control 0.09 ± 0.04, doxorubicin 0.06 ± 0.01, doxorubicin +1D11 0.107 ± 0.3. Taken together, we conclude that, doxorubicin therapy may account for additional bone loss in patients with osteolytic bone disease and an anti-TGFβ therapy may be effective in controlling that bone loss. doi:10.1016/j.bone.2010.01.075
73. Oncostatin M leads to opposite effects on the proliferation of different primary bone tumors Emmanuelle David, Bénédicte Brounais, Dominique Heymann, Francoise Rédini, Frederic Blanchard Inserm U957, Nantes, France Osteosarcoma, Chondrosarcoma and Ewing sarcoma represent the majority of primary bone tumors and their treatment has to be improved. They all derive from bone mesenchymal stem cells, but Ewing sarcoma are not much differentiated compared to osteosarcoma and chondrosarcoma. Ewing sarcoma cells are characterized by a chromosomal translocation, EWS-FLI1, which behave as an oncogene. Oncostatin M (OSM), a cytokine from the IL-6 family, inhibits the proliferation of osteoblasts and osteosarcoma through activation of the transcription factor STAT3 and induction of the cell cycle inhibitor p21WAF1. The aim of this study was to define the activity of OSM on Chondrosarcoma and Ewing sarcoma in comparison to other IL-6 type cytokines. OSM inhibited the proliferation of 5 on 6 chondrosarcoma cell lines by a mechanism independent of p21 and associated with the blockade of the cells in S/G2/M phase of the cell cycle. This inhibition of proliferation was confirmed in vivo in the Swarm rat model of chondrosarcoma as we observed a decrease in the tumoral growth after intra-tumor injection of an adenovirus encoding murine OSM. In contrast, OSM induced the proliferation of 5 on 9 Ewing sarcoma cell lines by inducing the quiescent cells in G0 (Ki67-) to get into the cell cycle (Ki67+, cells mainly in S phase). All the cell lines expressed the OSM receptor subunits (gp130, OSMR and LIFR) and these receptors were functional (activation of STAT3 and ERK1/2). On all the cell lines tested, the effects on proliferation