Structural skeletal impairment induced by immunosuppressive therapy in rats: cyclosporine A vs tacrolimus.
The exact role of immunosuppressive drugs in the development of osteoporosis and pathologic fractures frequently reported in patients following organ transplantation is still not known. In two experiments, the effects of immunosuppressive drugs were studied on growing rats allocated randomly into five groups of eight rats each which received either FK506 (1.5 mg/kg or 3 mg/kg) or cyclosporine A (15 mg/kg or 30 mg/kg) for 28 days by daily oral gavage. In experiment I ( n=40), bone mineral content (BMC) of the femur by dual energy X-ray absorptiometry (DXA), and bone ash weight were measured. In experiment II ( n=40), stereologic measurements of decalcified tibiae were carried out. The BMC and ash weight values of the whole femur were significantly lower both in the low- and high-dose FK506 groups as well as in the high-dose CsA group. Decalcified sections showed lower volume density of trabecular bone of the tibial metaphysis in both CsA-treated groups and in the high-dose FK506 group. Furthermore, the volume density of the hypertrophic zone volume of the growth plate was higher in high-dose CsA-treated rats. Our data demonstrate that both CsA and FK506 have adverse effects on bone and that high doses of CsA or FK506 alter both cortical and trabecular bone with subsequent osteopenia. In addition, CsA-treated groups showed histological changes in some aspect resembling rickets/osteomalacia.
Abdelhadi
Mohamed
M
Center for Metabolism and Endocrinology, Department of Surgery, Karolinska Institutet, Huddinge University Hospital, 141 86 Huddinge, Sweden.
Ericzon
Bo-Göran
BG
Hultenby
Kjell
K
Sjöden
Göran
G
Reinholt
Finn P
FP
Nordenström
Jörgen
J
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects*; D002118:Calcium / Q000097:blood; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects*; D004838:Epiphyses / Q000187:drug effects; D006132:Growth Plate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008297:Male; D009929:Organ Size; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000009:adverse effects*; D014508:Urea / Q000097:blood
D015415:Biomarkers; D007166:Immunosuppressive Agents; D010281:Parathyroid Hormone; D010710:Phosphates; D016572:Cyclosporine; D014508:Urea; D003404:Creatinine; D000469:Alkaline Phosphatase; D002118:Calcium; D016559:Tacrolimus