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.

Evaluation of Toxic Effects of Chemotherapeutic Drugs on Normal Jaw Bones Using Osteopontin: An Experimental Study.

“…Consistent with a multiplicity of functions for OPN, it is involved specifically in both the forming and resorption of bone. That is why its suppression causes defects in process of bone remodeling (Fan et al, 2016) In The result of present work came in line with the study of Xian et al (2008) who found that MTX had no obvious effects on apoptosis but only some moderate damaging effects on proliferation of osteoblasts and preosteoblasts in bone with moderate changes in osteoblastic cell density along trabecular surface in comparing to 5-FU.…”

Chemotherapy‐induced loss of bone and muscle mass in a mouse model of breast cancer bone metastases and cachexia

“…Our data shows that a clinically relevant dose of carboplatin in healthy mice induces trabecular bone loss (decrease in Tb.BV/TV, Tb.N, and Conn.D and an increase in Tb.Sp in the distal femur and proximal tibia of mice treated with carboplatin). These findings are supported by studies that reported combination chemotherapy treatment of 5-fluorouracil, cyclophosphamide, and epirubicin caused trabecular bone loss in rats [ 28 ] and that Folfiri (5-fluorouracil, leucovorin and irinotecan) caused loss of muscle and bone mass [ 14 ]. Additionally, data suggests that cisplatin, another platinum-based chemotherapy drug, induces a decrease in Tb.BV/TV in the proximal tibia of rats [ 12 ].…”

Effects of Resveratrol Supplementation on Methotrexate Chemotherapy‐Induced Bone Loss

“…Osteoblast density was obtained by counting cuboidal mononuclear cells along the trabecular surface in six sequential images along primary spongiosa, and expressed as osteoblast number per mm 2 trabecular bone area. TRAP+ multinuclear osteoclasts were counted under light microscopy and expressed as cells per mm 2 trabecular bone area in the secondary spongiosa as described [31,32]. Adipocytes within bone marrow area were counted in four random images within the lower secondary spongiosa region, and expressed as adipocyte number per mm 2 marrow area [7,10].…”