Childhood cancer chemotherapy–induced bone damage: pathobiology and protective effects of resveratrol and other nutraceuticals

Abstract

Intensive cancer chemotherapy causes significant bone loss, for which the mechanisms remain unclear and effective treatments are lacking. This is a significant issue particularly for childhood cancers, as the most common ones have a >75% cure rate following chemotherapy; there is an increasing population of survivors who live with chronic bone defects. Studies suggest that these defects are the result of reduced bone from increased marrow fat formation and increased bone resorption following chemotherapy. These changes probably result from altered expression/activation of regulatory molecules or pathways regulating skeletal cell formation and activity. Treatment with methotrexate, an antimetabolite commonly used in childhood oncology, has been shown to increase levels of proinflammatory/pro-osteoclastogenic cytokines (e.g., enhanced NF-κB activation), leading to increased osteoclast formation and bone resorption, as well as to attenuate Wnt signaling, leading to both decreased bone and increased marrow fat formation. In recent years, understanding the mechanisms of action and potential health benefits of selected nutraceuticals, including resveratrol, genistein, icariin, and inflammatory fatty acids, has led to preclinical studies that, in some cases, indicate efficacy in reducing chemotherapy-induced bone defects. We summarize the supporting evidence.

Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Protects Against Adriamycin and Cyclophosphamide Chemotherapy-Induced Bone Marrow Damage in Female Rats

“…Since anthracycline-based combination chemotherapy remains to be the backbone for treating breast cancer nowadays, it is vital to develop preventive strategies for alleviating bone marrow and bone toxicities that may affect quality of life post chemotherapy. Recently, several nutraceuticals (including LCn3PUFA) have been found to have some efficacies to promote bone health under physiological conditions or during methotrexate chemotherapy [ 21 ]. Consumption of LCn3PUFA has been suggested to attenuate aging-related bone loss and preventing bone loss in ovariectomized models [ 8 , 10 ].…”

Comparative Histological Study on the Protective Effect of Folinic Acid versus Fish Oil on the Growing Bone of Methotrexate-Treated Young Rats

“…In the current study, H&E-stained sections of MTXtreated group showed marked reduction in thickness of growth plate cartilage and marked reduction in chondrocytes number within the proliferative zone. These findings were explained by [16] who reported that MTX treatment was shown to decrease chondrogenesis, accompanied by increased apoptosis of chondrocytes in the growth plate cartilage. Also, significant reduction in the growth plate thickness following MTX treatment, as compared to the control, was reported by [17] .…”

“…However, the use of FA is controversial, as its overuse can reduce MTX treatment effects and cause cancer relapses. Thus, developing safe/effective solutions for MTX-induced bone defects is required for pediatric oncology [16] .…”

Roles of apoptotic chondrocyte‐derived CXCL12 in the enhanced chondroclast recruitment following methotrexate and/or dexamethasone treatment

“…Although intensifying use of chemotherapeutic agents such as methotrexate (MTX) and glucocorticoids including dexamethasone (DEX) has achieved great success in the management of pediatric malignancies, high prevalence of chemotherapy‐associated bone growth impairments has been found in cancer patients and/or survivors which could persist into adulthood and is with significant clinical burden (Crofton et al, 2000; Fan et al, 2011; Haddy et al, 2001; Su et al, 2017). For example, patients of acute lymphoblastic leukemia (ALL), the most common pediatric cancer, have an over 80% of survival rate following multiagent chemotherapy involving the combination treatment of MTX and DEX (Mitchell et al, 2009).…”