title: Fish oil in comparison to folinic acid for protection against adverse effects of methotrexate chemotherapy on bone.
abstract: Methotrexate (MTX) chemotherapy is known to cause bone loss which lacks specific preventative treatments, although clinically folinic acid is often used to reduce MTX toxicity in soft tissues. This study investigated damaging effects of MTX injections (0.75 mg/kg/day for 5 days) in rats and potential protective benefits of fish oil (0.25, 0.5, or 0.75 ml/100 g/day) in comparison to folinic acid (0.75 mg/kg) in the tibial metaphysis. MTX treatment significantly reduced height of primary spongiosa and volume of trabecular bone while reducing density of osteoblasts. Consistently, MTX reduced osteogenic differentiation but increased adipogenesis of bone marrow stromal cells, accompanied by lower mRNA expression of osteogenic transcription factors Runx2 and Osx, but an up-regulation of adipogenesis-related genes FABP4 and PPAR-γ. MTX also increased osteoclast density, bone marrow osteoclast formation, and mRNA expression of proinflammatory cytokines IL-1, IL-6, TNF-α, and RANKL/OPG ratio in bone. Fish oil (0.5 or 0.75 ml/100 g) or folinic acid supplementation preserved bone volume, osteoblast density, and osteogenic differentiation, and suppressed MTX-induced cytokine expression, osteoclastogenesis, and adipogenesis. Thus, fish oil at 0.5 ml/100 g or above is as effective as folinic acid in counteracting MTX-induced bone damage, conserving bone formation, suppressing resorption and marrow adiposity, suggesting its therapeutic potential in preventing bone loss during MTX chemotherapy.
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, 5001, Australia.
authors.forename: Rethi
authors.initials: R
authors.lastname: Raghu Nadhanan
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Fan
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Su
authors.forename: Peter R C
authors.initials: PR
authors.lastname: Howe
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001847:Bone Diseases / Q000139:chemically induced / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005395:Fish Oils / Q000008:administration & dosage*; D002955:Leucovorin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D010006:Osteoblasts / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014803:Vitamin B Complex / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D005395:Fish Oils; D014803:Vitamin B Complex; D002955:Leucovorin; D008727:Methotrexate
keywords: bone loss; bone marrow adiposity; cancer chemotherapy; fish oil; folinic acid