Abstract
Cyclophosphamide (CTX) as an alkylating agent is used for treating a range of tumor types and allergic diseases. However, high-dose application may induce rapid bone loss and increase the risk of osteoporotic fractures. Eldecalcitol (ED-71), a clinically approved active vitamin D analog, has been approved for osteoporosis treatment. It potently inhibited bone resorption while maintaining osteoblastic function in estrogen-deficient and high-turnover osteoporosis in model rats. The aim of the present study was to clarify the treatment effect of ED-71 on bone loss in a well-established rat model of osteoporosis with CTX administration. After 15 days of CTX treatment, ED-71 was administered, while estradiol valerate (E2V) was used as a positive control. At 2 and 4 weeks after ED-71 or E2V administration, rats were sacrificed and fixed. The tibiae were extracted for histochemical analysis using hematoxylin and eosin staining and immunohistochemistry. When compared with the untreated control group, the CTX group displayed clear osteoporotic features, including a decreased number of bone trabeculae and increased trabecular separation. ED-71 and E2V successfully rescued CTX-induced bone loss. The ED-71 group displayed denser and increasingly mature trabecular bone than the E2V group. Furthermore, ED-71 administration led to significant suppression of tartrate-resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase 9 (MMP9), alkaline phosphatase (ALP) and Osteopontin (OPN), which was less pronounced than in E2V administration but was similar to the values exhibited in the normal control group. These results indicated that ED-71 had a moderate and increased effect on bone turnover compared with E2V. Therefore, the present study suggests that ED-71 is a potential inhibitor of CTX-induced osteoporosis, successfully rescuing bone loss without excessively suppressing bone turnover, and may be a suitable treatment for preventing bone loss in patients receiving CTX.