Lack of change of cancellous bone volume with short-term use of the new immunosuppressant rapamycin in rats.
Immunosuppressants have adverse effects on bone mineral metabolism in animal and human studies, with corticosteroids producing low-turnover osteopenia, and cyclosporin-A (CsA) producing high-turnover osteopenia. Rapamycin (RAPA) is a new immunosuppressant reported to be at least 10 times more potent than CsA, and acts via a different pathway to CsA and the other new immunosuppressant FK506. This study investigated the effects of RAPA on bone mineral metabolism in the rat. Forty-two, 10-week-old, male Sprague Dawley rats were divided into three groups, and treated according to the following protocol: group A (control) received RAPA vehicle by daily gavage for 14 days (n = 12); group B (high dose RAPA) received RAPA 2.5 mg/kg/day by daily gavage for 14 days (n = 15); group C (low dose RAPA) received RAPA 1.25 mg/kg/day by daily gavage for 14 days (n = 15). Rats were weighed and bled on days 0, 7, and 14 for measurement of blood ionized calcium, bone Gla protein (BGP), parathyroid hormone (PTH), and 1,25(OH)2D. Tibial bone histomorphometry was determined on day 14 after double-calcein labeling. Weight gain was similar in the two groups treated with RAPA compared with control animals. High-dose RAPA (group B) transiently depressed serum BGP levels on day 7, with elevated blood ionized calcium levels on day 7, and lowered 1,25(OH)2D levels on day 14. Serum PTH levels were unchanged. Low-dose RAPA (group C) did not affect calciotropic hormones.(ABSTRACT TRUNCATED AT 250 WORDS)
Joffe
I
I
Division of Endocrinology and Metabolism, Albert Einstein Medical Center, Philadelphia, Pennsylvania 19141.
Katz
I
I
Sehgal
S
S
Bex
F
F
Kharode
Y
Y
Tamasi
J
J
Epstein
S
S
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects*; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D015675:Osteocalcin / Q000097:blood; D010281:Parathyroid Hormone / Q000097:blood; D011090:Polyenes / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus
D001786:Blood Glucose; D007166:Immunosuppressive Agents; D010281:Parathyroid Hormone; D011090:Polyenes; D015675:Osteocalcin; D003404:Creatinine; D002117:Calcitriol; D002118:Calcium; D020123:Sirolimus