title: Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats.
abstract: The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation.
authors.affiliation: School of Pharmacy and Medical Sciences, and Sansom Institute for Health Research, University of South Australia, City East Campus, GPO Box 2471, Adelaide, SA, 5001, Australia.
authors.forename: Chiaming
authors.initials: C
authors.lastname: Fan
authors.affiliation: School of Pharmacy and Medical Sciences, and Sansom Institute for Health Research, University of South Australia, City East Campus, GPO Box 2471, Adelaide, SA, 5001, Australia.
authors.forename: Kristen R
authors.initials: KR
authors.lastname: Georgiou
authors.affiliation: School of Pharmacy and Medical Sciences, and Sansom Institute for Health Research, University of South Australia, City East Campus, GPO Box 2471, Adelaide, SA, 5001, Australia.|Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Bedford Park, SA, 5042, Australia.
authors.forename: Ross A
authors.initials: RA
authors.lastname: McKinnon
authors.affiliation: School of Pharmacy and Medical Sciences, and Sansom Institute for Health Research, University of South Australia, City East Campus, GPO Box 2471, Adelaide, SA, 5001, Australia.|SA Cancer Service, SA Cancer Clinical Network, SA Health, Adelaide, SA, 5000, Australia.|Centre of Cancer Medicine, University of Adelaide, Adelaide, SA, 5000, Australia.
authors.forename: Dorothy M K
authors.initials: DM
authors.lastname: Keefe
authors.affiliation: Clinical Nutrition Research Centre, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia.
authors.forename: Peter R C
authors.initials: PR
authors.lastname: Howe
authors.affiliation: School of Pharmacy and Medical Sciences, and Sansom Institute for Health Research, University of South Australia, City East Campus, GPO Box 2471, Adelaide, SA, 5001, Australia. cory.xian@unisa.edu.au.
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
mesh_terms: D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology; D015251:Epirubicin / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000494:pharmacology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil
keywords: Bone loss; Breast cancer chemotherapy; Marrow adiposity; Marrow cellularity; Osteoclast