TY - JOUR
T1 - Damaging effects of chronic low-dose methotrexate usage on primary bone formation in young rats and potential protective effects of folinic acid supplementary treatment
AU - Fan, Chiaming
AU - Cool, Johanna C.
AU - Scherer, Michaela
AU - Foster, Bruce K.
AU - Shandala, Tetyana
AU - Tapp, Heather
AU - Xian, Cory J.
N1 - Funding Information:
Contract grant sponsors: Bone Growth Foundation, WCH Foundation, NHMRC Australia.
Funding Information:
This project was funded in part by The Bone Growth Foundation (to BKF and CJX), Women's and Children's Hospital Foundation (to CJX and BKF), NHMRC Australia (to CJX and BKF), and a PhD Scholarship from the Faculty of Health Sciences of The University of Adelaide (South Australia) (to CMF).
PY - 2009/1
Y1 - 2009/1
N2 - 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. Crown
AB - 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. Crown
KW - Bone marrow osteoprogenitor cells
KW - Folinic acid
KW - Growth Plate
KW - Methotrexate chemotherapy
KW - Osteoclast precursor
KW - Osteoclastogenesis
KW - Osteogenesis
UR - http://www.scopus.com/inward/record.url?scp=57449112967&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2008.09.014
DO - 10.1016/j.bone.2008.09.014
M3 - Article
C2 - 18976724
AN - SCOPUS:57449112967
SN - 8756-3282
VL - 44
SP - 61
EP - 70
JO - Bone
JF - Bone
IS - 1
ER -