title: The short- and long-term effects of methotrexate on the rat skeleton.
abstract: Both clinical and laboratory studies have shown that the chemotherapy drug, Methotrexate (MTX), has adverse short-term effects on bone. There are no studies that demonstrate the long-term response of bone to MTX. The purpose of this study was to determine the short- and long-term effects of MTX on bone volume, turnover, mineralization and strength. Three-month-old Sprague-Dawley rats were randomly assigned to a control (CTL) or MTX group and were given either daily MTX or saline injections for two separate 5-day courses (5 on/9 off/5 on). Fluorochrome compounds were injected prior to killing to label actively mineralizing bone surfaces. One CTL and MTX group were killed at 30, 80 and 170 days after treatment. Both femurs and tibiae were harvested for cancellous and cortical bone histomorphometry and biomechanical testing (torsion). Standard cancellous and cortical histomorphometric parameters were measured from undecalcified, methyl-methacrylate-embedded sections from the right proximal tibia and tibial and femoral diaphyses. The contralateral femur and tibia were torsionally loaded to failure and standard mechanical parameters were measured. All bone responses were statistically analyzed using a two-way ANOVA followed by Duncan's multiple comparison procedure (significance: p = 0.05). Cancellous bone volume was significantly lower in the MTX-treated group at 80 and 170 days. Cancellous mineralizing surface and longitudinal bone growth were significantly depressed at all time points yet mineral apposition rate was only depressed at the 170-day point. Cancellous osteoclast surface was increased at all time points for the MTX-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Orthopaedics, Oregon Health Sciences University, School of Medicine, Portland, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Wheeler
authors.forename: R A
authors.initials: RA
authors.lastname: Vander Griend
authors.forename: T J
authors.initials: TJ
authors.lastname: Wronski
authors.forename: G J
authors.initials: GJ
authors.lastname: Miller
authors.forename: E E
authors.initials: EE
authors.lastname: Keith
authors.forename: J E
authors.initials: JE
authors.lastname: Graves
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D005269:Femur / Q000187:drug effects / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000633:toxicity*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D016610:Tissue Embedding
chemical_list: D008727:Methotrexate