Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats
- 298 Downloads
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.
KeywordsBreast cancer chemotherapy Bone loss Marrow cellularity Marrow adiposity Osteoclast
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.
- 1.Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D, Group. Hs (2001) Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol 19:943–953PubMedGoogle Scholar
- 3.Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E (2003) Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol 14:833–842CrossRefPubMedGoogle Scholar
- 6.Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick R, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B, Study. ZEBCRA (2002) Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628–4635CrossRefPubMedGoogle Scholar
- 15.Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O’Brien P, Shepherd LE (2010) Cyclophosphamide, epirubicin, and Fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by Paclitaxel versus Doxorubicin and cyclophosphamide followed by Paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol 28:77–82CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Farquhar C, Marjoribanks J, Basser R, Hetrick S, Lethaby A (2005) High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Database Syst Rev, CD003142Google Scholar
- 33.Berliere M, Dalenc F, Malingret N, Vindevogel A, Piette P, Roche H, Donnez J, Symann M, Kerger J, Machiels JP (2008) Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel. BMC Cancer 8:56CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Fujita K, Iwasaki M, Ochi H, Fukuda T, Ma C, Miyamoto T, Takitani K, Negishi-Koga T, Sunamura S, Kodama T, Takayanagi H, Tamai H, Kato S, Arai H, Shinomiya K, Itoh H, Okawa A, Takeda S (2012) Vitamin E decreases bone mass by stimulating osteoclast fusion. Nat Med 18:589–594CrossRefPubMedGoogle Scholar
- 42.Jones LC, Hungerford DS (2012) Bone marrow adipocytes: Friend or foe. J Bone Joint Surg Br 94B:60Google Scholar