Effects of Resveratrol Supplementation on  Methotrexate Chemotherapy‐Induced Bone Loss

Abstract

Intensive cancer chemotherapy is known to cause bone defects, which currently lack treatments. This study investigated the effects of polyphenol resveratrol (RES) in preventing bone defects in rats caused by methotrexate (MTX), a commonly used antimetabolite in childhood oncology. Young rats received five daily MTX injections at 0.75 mg/kg/day. RES was orally gavaged daily for seven days prior to, and during, five-day MTX administration. MTX reduced growth plate thickness, primary spongiosa height, trabecular bone volume, increased marrow adipocyte density, and increased mRNA expression of the osteogenic, adipogenic, and osteoclastogenic factors in the tibial bone. RES at 10 mg/kg was found not to affect bone health in normal rats, but to aggravate the bone damage in MTX-treated rats. However, RES supplementation at 1 mg/kg preserved the growth plate, primary spongiosa, bone volume, and lowered the adipocyte density. It maintained expression of genes involved in osteogenesis and decreased expression of adipogenic and osteoclastogenic factors. RES suppressed osteoclast formation ex vivo of bone marrow cells from the treated rats. These data suggest that MTX can enhance osteoclast and adipocyte formation and cause bone loss, and that RES supplementation at 1 mg/kg may potentially prevent these bone defects.

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

“…In MTX-treated group, a statistically significant increase in the mean value of RANKL/OPG ratio was reported, as compared to the other experimental groups. These findings are in accordance with [17] who suggested the important role of this osteoclastogenic factor in promoting osteoclasts formation and bone resorption, following MTX-chemotherapy. Moreover, [22] demonstrated that, MTX could increase osteoclasts density and reduce osteogenic differentiation; accompanied by reduction in mRNA expression of osteogenic factors.…”

“…Moreover, [22] demonstrated that, MTX could increase osteoclasts density and reduce osteogenic differentiation; accompanied by reduction in mRNA expression of osteogenic factors. Similarly, [17] observed, upregulation of RANKL/OPG ratio and proinflammatory cytokines such as TNF-α, IL-1 and IL-6 in MTX-treated rats.…”

“…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] .…”

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

“…The above‐mentioned study, moreover, highlighted potential differential concentration effects of resveratrol on bone health in normal rats versus MTX‐treated rats, showing that while resveratrol at 10 mg/kg/day did not affect bone health in normal rats (which is consistent with a report that resveratrol at 20 mg/kg/day was not harmful in healthy rats), it aggravated bone damage in MTX‐treated rats (in contrast to no aggravated effects at 1 mg/kg of resveratrol) . The differential concentration effects could be related to a possible drug interaction (between resveratrol and MTX) on bone tissue.…”

“…The efficacy of resveratrol to prevent MTX chemotherapy–induced bone defects was recently explored . In young rats treated acutely with MTX, resveratrol supplementation at 1 mg/kg was found to preserve the growth plate structure and the endochondral bone growth function, maintain expression of genes involved in osteogenesis, decrease expression of adipogenic and osteoclastogenic factors, and thus attenuate bone marrow adiposity and inhibit MTX‐induced osteoclast formation in the bone marrow of treated rats.…”