Amifostine and Dexrazoxane Enhance the Rapid Loss of Bone Mass and Further Deterioration of Vertebrae Architecture in Female Rats

Abstract

Doxorubicin (DOX) is widely used in combination cocktails for treatment of childhood hematologic cancers and solid tumors. A major factor limiting DOX usage is DOX-induced cardiotoxicity. Dexrazoxane (DXR) is an iron-binding compound and the only approved cardioprotectant for use with DOX. Amifostine (AMF) is a free radical scavenger and approved as a broad-spectrum cytoprotectant. We have shown that when female rats are treated with AMF, AMF + DOX, or AMF + DXR + DOX there is a significant decrease in the right femoral and lumbar vertebral bone mineral density (BMD) (P < 0.05) but not in the left femoral BMD. Furthermore, the relative bone volume (BV/TV) was significantly smaller in the lumbar vertebral bodies of rats treated with AMF (21.1%), AMF + DOX (34.4%), and AMF + DXR + DOX (38.4%), as was the trabecular number (Tb.N) with AMF (15.5%), AMF + DOX (29.9%), and AMF + DXR + DOX (32.3%). AMF + DOX- and AMF + DXR + DOX-treated vertebrae also exhibited deterioration in the microarchitecture of the trabecular bone and spinous processes as ascertained by microcomputerized tomography (micro CT). This information will be useful in designing better cancer combination therapies that do not lead to bone deterioration.

Effect of Dexrazoxane and Amifostine on the Vertebral Bone Quality of Doxorubicin Treated Male Rats

“…1B ). DOX treatment alone led to a significant 24% decrease in the BMC (p<0.01) as previously observed with female rats [ 22 ]. In order to better understand the protective effect of DXR, we decided to treat rats with DOX+DXR.…”

“…AMF and DXR were injected 30 min prior to the DOX injection. The choice of the DOX and AMF concentrations is based on previous work in young rats [ 24 ] and accordingly to our previous work on female rats [ 22 ]. The concentration of DXR was 20-times the concentration of DOX, a ratio previously demonstrated to reduce DOX toxicity in adult rodent [ 25 ].…”

“…The effect of DOX, with or without DXR and/or AMF, on bone in children is not well understood. We have previously shown a significant decrease in the right femoral and lumbar vertebral BMD of female rats treated with AMF, AMF+DOX or AMF+DXR+DOX [ 22 ]. However, the effect of AMF alone or in combination therapies on male vertebrae is not well understood.…”

Skeletal sequelae of cancer and cancer treatment

“…Both in vitro studies and animal studies of doxorubicin have demonstrated that the agent inhibits the proliferation and differentiation of osteoblasts and selectively reduces the rate of bone formation by altering the interaction of parathyroid hormone with the osteoblast receptor [16,20,73,74]. Studies demonstrating doxorubicin's effect on bone's biomechanical properties are limited [69].…”

Inhomogeneity of rat vertebrae trabecular architecture by high‐field 3D μ‐magnetic resonance imaging and variable threshold image segmentation

“…In this study, specimens of rat lumbar vertebrae were analyzed with an apparent spatial resolution of 20 μm 3 using μ‐MRI combined with 3D image analysis. The choice of rat as an experimental animal model is due to the fact that it is frequently used for studies on metabolic bone diseases (23, 24) or for study of the effects of “reduced gravity,” ie, reduced weight, which induces an experimental osteoporosis when the animal is maintained tail‐suspended for long time periods (25–27).…”