Methotrexate inhibition of bone mineral density increase in growing rabbits: prevention by folinic acid.
OBJECTIVE
Methotrexate (MTX) action on bone metabolism is as yet not completely understood. The results of clinical studies are controversial, since it is difficult to distinguish the side effects of MTX from those of the primary disease. This study assessed the effect of MTX, with and without folinic acid supplementation, on bone mineral density in growing normal rabbits.


METHODS
Three groups of young NZW growing female rabbits were treated with: saline (n = 6) or MTX (0.25 mg/kg/week, n = 5) or MTX (same dose as above) plus folinic acid (0.25 mg/kg/week, n = 6) for a period of 3 months. The dose, duration and frequency of MTX administration were similar to the treatment of RA patients. The animals were submitted to dual-energy absorptiometry densitometry (HologicQDR 2000) before and after treatment; total body and L4-L5 BMD were evaluated. Histomorphometric analysis (L4 vertebrae) was also performed.


RESULTS
Growing control rabbits showed increased total body BMD from a baseline of 0.180 +/- 0.006 to 0.198 +/- 0.007 gm/cm2 (mean +/- S.E.M, p < 0.006). In contrast, no increase in BMD (0.182 +/- 0.006 versus a baseline of 0.184 +/- 0.004, ns) was observed in the group treated with MTX, while the addition of folinic acid resulted in an increase in BMD values similar to controls, from a baseline of 0.181 +/- 0.004 to 0.198 +/- 0.003, p < 0.02), thus preventing adverse MTX bone effects. Average percent variations in BMD were +7.7%, -1% and +8.4% respectively. Spine (L4-L5) BMD showed analogous results, in line with the histomorphometric data.


CONCLUSIONS
These results strongly support a deleterious action of MTX on bone metabolism, which is prevented by folinic acid supplementation. The potential clinical implications of our data are particularly significant for paediatric therapy.
Laurindo
I M
IM
Division of Rheumatology, Department of Internal Medicine, School of Medicine, University of São Paulo, Brazil. monocyte@lim17.fm.usp.br
Mendes
F L
FL
Novaes
G S
GS
Mello
S B
SB
Falco
V
V
Jorgetti
V
V
D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D005260:Female; D002955:Leucovorin / Q000494:pharmacology*; D008727:Methotrexate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011817:Rabbits
D002955:Leucovorin; D008727:Methotrexate