Immunosuppressant use without bone loss--implications for bone loss after transplantation.
Cyclosporine A (CsA) is associated with posttransplantation bone disease. Immunosuppressant drugs such as sirolimus (SRL), which are more potent and less deleterious than CsA, are being developed. Previous experiments have shown that SRL although immunosuppressive, is relatively bone sparing. The use of low doses of CsA and SRL in combination has displayed in vivo synergism. This study was initiated to examine the effect of low-dose CsA and SRL on bone metabolism, thereby hopefully providing a bone sparing immunosuppressive regimen for transplant recipients. One hundred and nineteen rats were divided into groups: basal, vehicle, CsA high dose, CsA low dose, SRL low dose, and combination low-dose CsA and SRL. The basal group was killed on day 0 for histomorphometry. The experimental groups were weighed and bled on days 0, 28, 56, and 84 and were killed on day 84 for histomorphometry. Serial assays for blood urea nitrogen (BUN), creatinine, and osteocalcin were performed. Osteocalcin was raised on days 28 and 56 in the high dose CsA group. Histomorphometry showed osteopenia with high-dose CsA. Low-dose CsA was relatively bone sparing, while low-dose SRL and combined low-dose CsA did not cause bone loss. In conclusion, the synergistic combination of low-dose CsA and SRL has the potential of providing both bone sparing and immunosuppressive benefits.
Goodman
G R
GR
Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.
Dissanayake
I R
IR
Sodam
B R
BR
Gorodetsky
E
E
Lu
J
J
Ma
Y F
YF
Jee
W S
WS
Epstein
S
S
D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D001862:Bone Resorption / Q000097:blood / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D016377:Organ Transplantation / Q000009:adverse effects*; D015675:Osteocalcin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D013977:Tibia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D007166:Immunosuppressive Agents; D015675:Osteocalcin; D016572:Cyclosporine; D003404:Creatinine; D020123:Sirolimus