Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model

Abstract

Wistar-Lewis rats received therapeutic doses of doxorubicin or methotrexate daily for five days, were pulse-labeled with a fluorescent compound (calcein) on the seventh and thirteenth days, and were killed fourteen days after initiation of the protocol. Proximal tail vertebrae were then evaluated histomorphometrically, and the effects of the chemotherapeutic agents on trabecular bone were quantitated with respect to changes in total bone mass, new-bone formation, and resorption. Short-term administration of methotrexate caused a 26.9 per cent reduction in net trabecular bone volume and doxorubicin, an 11.5 per cent decrease. Both drugs significantly and profoundly diminished bone-formation rates by nearly 60 per cent. The toxic effect on osteoblasts was also reflected in reduced volume and thickness of osteoid, but the total numbers of osteoblasts and the per cent of trabecular surface covered by bone-forming cells were not affected. The numbers of osteoclasts and the extent of their activity were not clearly different from those in untreated rats, but rates of resorption were not determined. The effects of chronic treatment with these chemotherapeutic agents on intact, fractured, and transplanted bone and the biomechanical significance of these changes has not yet been evaluated.

Clinical relevance: Chemotherapeutic agents have an adverse effect on normal physiological bone turnover, especially osteoblastic activity, and would also be expected to alter fracture-healing and bone-allograft incorporation by these same mechanisms. Knowledge of these changes and efforts to favorably affect the remodeling cycle must address these specific defects before bone allografts can be reliably used and fracture-healing can be improved concomitant with chemotherapy.