Rapamycin: a bone sparing immunosuppressant?
Immunosuppressant therpay is associated with osteoporosis both clinically, post-transplantation, and experimentally. In rats, cyclosporin A (CsA) and FK506 induce a state of high turnover rapid bone loss. After 14 days of administration in immunosuppressive doses, the more recently discovered immunosuppressant, rapamycin, resulted in no change of cancellous bone volume. A longer study over 28 days has now been carried out; contrasting the new drug with CsA and FK506. Sixty, 10-week-old Sprague-Dawley rats were randomly divided into five groups of 12 rats each. The first group served as an aging control. The remaining four groups received, by daily gavage, a combined vehicle placebo, CsA 15 mg/kg, FK506 5 mg/kg, and rapamycin 2.5 mg/kg, respectively. CsA- and FK506-treated rats, but not those treated with rapamycin, demonstrated high turnover osteoporosis with raised serum 1,25(OH)2D (p < 0.05) and elevated serum osteocalcin (p < 0.05). The trabecular bone area was decreased by 66% (p < 0.01) in the CsA group and 56% (p < 0.05) in the FK506-treated group compared with the control animals. The CsA- and the rapamycin-treated groups failed to gain weight and developed severe hyperglycemia (> 20 mmol/l, p < 0.001) by day 14 but which largely resolved by day 28. Unlike the groups treated with CsA and FK506, rapamycin-treated rats had no loss of trabecular bone volume but there was increased modeling and remodeling and a decreased longitudinal growth rate. Rapamycin may thus confer a distinct advantage over the established immunosuppressants in not reducing bone volume in the short term.(ABSTRACT TRUNCATED AT 250 WORDS)
Romero
D F
DF
Department of Endocrinology and Metabolism, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.
Buchinsky
F J
FJ
Rucinski
B
B
Cvetkovic
M
M
Bryer
H P
HP
Liang
X G
XG
Ma
Y F
YF
Jee
W S
WS
Epstein
S
S
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001806:Blood Urea Nitrogen; D015519:Bone Density / Q000187:drug effects*; D002118:Calcium / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D004100:Dihydroxycholecalciferols / Q000097:blood; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D015675:Osteocalcin / Q000097:blood; D010024:Osteoporosis / Q000139:chemically induced*; D010281:Parathyroid Hormone / Q000097:blood; D011090:Polyenes / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D011863:Radioimmunoassay; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D013977:Tibia / Q000187:drug effects / Q000473:pathology
D001786:Blood Glucose; D004100:Dihydroxycholecalciferols; D007166:Immunosuppressive Agents; D010281:Parathyroid Hormone; D011090:Polyenes; D015675:Osteocalcin; D016572:Cyclosporine; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus