Combination breast cancer chemotherapy with doxorubicin and cyclophosphamide damages bone and bone marrow in a female rat model

• Published in: Breast cancer research and treatment Vol. 165; no. 1; pp. 41 - 51
• Main Authors: Fan, Chiaming, Georgiou, Kristen R., Morris, Howard A., McKinnon, Ross A., Keefe, Dorothy M. K., Howe, Peter R., Xian, Cory J.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2017; Springer; Springer Nature B.V
• Subjects: Adipocytes - drug effects; Adipocytes - metabolism; Adipocytes - pathology; Adipogenesis; Adipose tissue; Alkaline phosphatase; Alkaline Phosphatase - blood; Animals; Anthracycline; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - toxicity; Bone cancer; Bone density; Bone growth; Bone loss; Bone marrow; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - pathology; Breast cancer; Calcifediol - blood; Cancellous bone; Cancer research; Cancer therapies; Cells, Cultured; Cellular Microenvironment; Chemotherapy; Cyclophosphamide; Cyclophosphamide - administration & dosage; Cyclophosphamide - toxicity; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - toxicity; Drug Administration Schedule; Fatty Acid-Binding Proteins - genetics; Fatty Acid-Binding Proteins - metabolism; Female; Femur - drug effects; Femur - metabolism; Femur - pathology; Gene expression; Inflammation; Injection; Injections, Intravenous; Intravenous administration; Medicine; Medicine & Public Health; Metaphysis; Oncology; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteocytes; Osteocytes - drug effects; Osteocytes - metabolism; Osteocytes - pathology; Osteogenesis; Phosphatases; PPAR gamma - genetics; PPAR gamma - metabolism; Preclinical Study; Rats, Sprague-Dawley; RNA; Rodents; Serum levels; Tibia - drug effects; Tibia - metabolism; Tibia - pathology; Time Factors; Tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Vitamin D3; Bone marrow damage; Osteoclasts; Breast cancer chemotherapy; Bone turnover; Bone loss; Bone marrow adiposity
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-017-4308-3

Purpose Anthracyclines (including doxorubicin) are still the backbone of commonly used breast cancer chemotherapy regimens. Despite increasing use of doxorubicin and cyclophosphamide (AC) combinations for treating breast cancer, their potential to cause adverse skeletal effects remains unclear. Methods This study examined the effects of treatments with the AC regimen on bone and bone marrow in adult female rats. Results AC treatment for four cycles (weekly intravenous injection of 2 mg/kg doxorubicin and 20 mg/kg cyclophosphamide) resulted in a reduced volume of trabecular bone at the metaphysis, which was associated with reduced serum levels of 25-hydroxy vitamin D3 and alkaline phosphatase. Reductions in densities of osteocytes and bone lining cells were also observed. In addition, bone marrow was severely damaged, including a severe reduction in bone marrow cellularity and an increase in marrow adipocyte content. Accompanying these changes, there were increases in mRNA expression of adipogenesis regulatory genes (PPARγ and FABP4) and an inflammatory cytokine (TNFα) in metaphysis bone and bone marrow. Conclusions This study indicates that AC chemotherapy may induce some bone loss, due to reduced bone formation, and bone marrow damage, due to increased marrow adiposity. Preventive strategies for preserving the bone and bone marrow microenvironment during anthracycline chemotherapy warrant further investigation.