Damaging effects of chronic low-dose methotrexate usage on primary bone formation in young rats and potential protective effects of folinic acid supplementary treatment

Autor: Tetyana Shandala, Chiaming Fan, Cory J. Xian, Bruce K. Foster, Johanna C. Cool, Michaela Scherer, Heather Tapp
Přispěvatelé: Fan, Chiaming, Cool, Johanna C, Scherer, Michaela A, Foster, Bruce K, Shandala, Tetyana, Tapp, Heather, Xian, Cory J
Rok vydání: 2009
Předmět:
Male
Aging
Physiology
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Leucovorin
Osteoclasts
Cell Count
folinic ascid
methotrexate chemotherapy
Rats
Sprague-Dawley
Osteogenesis
growth plate
Growth Plate
osteoclast precursor
Bone growth
Stem Cells
Librarianship and Information Studies
Osteoblast
Organ Size
Dose–response relationship
medicine.anatomical_structure
bone marrow osteoprogenitor cells
medicine.drug
musculoskeletal diseases
Cell Physiology
medicine.medical_specialty
Histology
Bone Marrow Cells
Orthopaedics
Protective Agents
Bone and Bones
osteogenesis
Folinic acid
Chondrocytes
Osteoclast
Internal medicine
medicine
Animals
osteoclastogenesis
Chemotherapy
Osteoblasts
Dose-Response Relationship
Drug
business.industry
Rats
Methotrexate
Endocrinology
Primary bone
Dietary Supplements
business
Zdroj: Bone. 44:61-70
ISSN: 8756-3282
DOI: 10.1016/j.bone.2008.09.014
Popis: Methotrexate (MTX) is a most commonly used anti-metabolite in cancer treatment and as an anti-rheumatic drug. While MTX chemotherapy at a high dose is known to cause bone growth defects in growing bones, effects of its chronic use at a low dose on growing skeleton remain less clear. Here, we examined effects on bone growth of long-term MTX chemotherapy at a low dose in young rats, and potential protective effects of supplementary treatment with antidote folinic acid (given ip at 1 mg/kg 6 h after MTX). After two cycles of 5 once-daily MTX injections (at 0.75 mg/kg, 5 days on/9 days off/5 days on), histological analysis showed that MTX at this dose caused significant reduction in heights of growth plate and primary spongiosa bone on day 22 compared to controls (P < 0.05). In contrast, a similar dosing regimen but at a lower dose (0.4 mg/kg) caused only slight or no reduction in heights of both regions. However, after the induction phase at this 0.4 mg/kg dosing, continued use of MTX at a low dose (once weekly at 0.2 mg/kg) caused a reduction in primary spongiosa height and bone volume on weeks 9 and 14, which was associated with an increased osteoclast formation and their bone surface density as well as a decreased osteoblast bone surface density in the primary spongiosa. Folinic acid supplementation was shown able to prevent the MTX effects in the primary spongiosa. These results suggest that acute use of MTX can damage growth plate and primary bone at a high dose, but not at a low dose. However, long-term use of MTX at a low dose can reduce primary bone formation probably due to decreased osteoblastic function but increased osteoclastic formation and function, and supplementary treatment with folinic acid may be potentially useful in protecting bone growth during long-term low-dose MTX chemotherapy. Refereed/Peer-reviewed
Databáze: OpenAIRE
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