Journal of Bone and Mineral Metabolism

, Volume 34, Issue 3, pp 277–290 | Cite as

Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats

  • Chiaming Fan
  • Kristen R. Georgiou
  • Ross A. McKinnon
  • Dorothy M. K. Keefe
  • Peter R. C. Howe
  • Cory J. Xian
Original Article

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.

Keywords

Breast cancer chemotherapy Bone loss Marrow cellularity Marrow adiposity Osteoclast 

Notes

Acknowledgments

This project was funded in parts by the National Health Medical Research Council (NHMRC) of Australia and the University of South Australia. CJ Xian is a senior research fellow of NHMRC Australia. The authors thank Dr. Alice Lee for the advice on serum ALP assay.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan 2015

Authors and Affiliations

  • Chiaming Fan
    • 1
  • Kristen R. Georgiou
    • 1
  • Ross A. McKinnon
    • 1
    • 2
  • Dorothy M. K. Keefe
    • 1
    • 3
    • 4
  • Peter R. C. Howe
    • 5
  • Cory J. Xian
    • 1
  1. 1.School of Pharmacy and Medical Sciences, and Sansom Institute for Health ResearchUniversity of South AustraliaAdelaideAustralia
  2. 2.Flinders Centre for Innovation in Cancer, School of MedicineFlinders UniversityBedford ParkAustralia
  3. 3.SA Cancer ServiceSA Cancer Clinical Network, SA HealthAdelaideAustralia
  4. 4.Centre of Cancer MedicineUniversity of AdelaideAdelaideAustralia
  5. 5.Clinical Nutrition Research Centre, School of Biomedical Sciences and PharmacyUniversity of NewcastleCallaghanAustralia

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