Effects of Alendronate and Alfacalcidol on Preventing Bone Loss in Chemotherapy-treated Soft-tissue Sarcoma

Background/Aim: Cancer treatment-induced bone loss (CTIBL) increases fracture risk and impairs quality of life, but little is known about CTIBL in soft-tissue sarcoma. This study aimed to investigate whether alendronate and alfacalcidol prevent doxorubicin-induced bone loss in a mouse model of soft-tissue sarcoma. Materials and Methods: Sarcoma S-180II cells were transplanted subcutaneously into 10-week-old female BALB/c mice using an air-pouch model. After tumor engraftment, mice received weekly intraperitoneal doxorubicin and were allocated to one of four groups: vehicle control, alendronate, alfacalcidol, and alendronate plus alfacalcidol. Alendronate was administered subcutaneously twice weekly, and alfacalcidol was administered orally three times weekly. Mice were euthanized 2 or 4 weeks after tumor transplantation. Body weight, tumor weight and volume, femoral microstructure by micro-computed tomography, histomorphometric indices by tartrate-resistant acid phosphatase (TRAP) staining and osteocalcin immunostaining, and receptor activator of nuclear factor-κB ligand (RANKL) and runt-related transcription factor 2 (RUNX2) expression were evaluated. Results: Body weight and tumor parameters did not differ among groups. At 2 weeks, combination therapy had significantly increased trabecular bone volume fraction, thickness, and number compared with the vehicle control. At 4 weeks, alendronate alone and combination therapy had preserved trabecular bone volume and number and reduced trabecular separation; combination therapy resulted in higher bone-volume fraction and trabecular number than alendronate alone. Cortical bone area and thickness were also greater in all drug-treated groups than in the control at 4 weeks. TRAP staining showed significant suppression of osteoclast-related indices in the alendronate- and combination-treated groups, whereas no significant differences were observed in osteocalcin, RANKL, or RUNX2 expression. Conclusion: Alendronate may prevent doxorubicin-associated bone loss in soft-tissue sarcoma, primarily by directly suppressing residual osteoclast activity in vivo.