17 beta-estradiol prevents osteopenia in the oophorectomized rat treated with cyclosporin-A.
Cyclosporin-A (CsA) administered to the oophorectomized rat exaggerates the high turnover osteopenia associated with oophorectomy alone. This study investigated whether 17 beta-estradiol replacement could influence the development of osteopenia in the oophorectomized rat treated with CsA. Ninety female Sprague-Dawley rats, approximately 300 g in weight, were divided into 6 groups of 15 each and treated according to the following protocol: group A were sham operated (control), group B underwent oophorectomy (Ox), group C underwent Ox and received CsA (15 mg/kg, by daily gavage) for 28 days (Ox and CsA), group D underwent Ox and received CsA and a 0.1 mg 17 beta-estradiol pellet (EP) implanted sc (Ox, CsA, and EP), group E underwent Ox and received EP (Ox and EP), and group F, which was intact and nonoperated, received CsA (CsA). Rats were weighed and bled on days -7, 0, 7, 14, 21, and 28 for measurement of blood ionized calcium, bone Gla protein (BGP), 17 beta-estradiol, and PTH. Bone histomorphometry was determined after double tetracycline labeling. On day 28, serum 17 beta-estradiol was undetectable in groups B (Ox) and C (Ox and CsA), and similar to group A (control) in groups D (Ox, CsA, and EP), E (Ox and EP), and F (CsA). Oophorectomy resulted in a significant gain in weight in groups B (Ox) and C (Ox and CsA), which was prevented by 17 beta-estradiol in groups D (Ox, CsA, and EP) and E (Ox and EP). On day 28, serum BGP levels were higher in groups B (Ox; 73.58 +/- 3.63 ng/ml), C (Ox and CsA; 85.05 +/- 9.88), and F (CsA; 81.35 +/- 3.4) compared to group A (control; 46.07 +/- 5.52; P less than 0.05), while 17 beta-estradiol in groups D (Ox, CsA, and EP; 38.65 +/- 2.85) and E (Ox and EP; 41.89 +/- 1.89) prevented this rise (P = 0.01). BGP levels in group C (Ox and CsA) were higher on days 14 and 21 compared to group B (Ox). Groups D (Ox, CsA, and EP) and E (Ox and EP) had elevated blood ionized calcium levels from day 7 onward. Serum PTH levels were unchanged. Histomorphometric analyses of tibial metaphyses revealed increased parameters of bone formation and resorption, with significant loss of bone volume, in groups B (Ox; 12.03 +/- 1.40%) and C (Ox and CsA; 11.43 +/- 2.20) vs. group A (control; 24.36 +/- 2.37; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Joffe
I
I
Division of Endocrinology and Metabolism, Albert Einstein Medical Center, Philadelphia, Pennsylvania 19141.
Katz
I
I
Jacobs
T
T
Stein
B
B
Takizawa
M
M
Liu
C
C
Berlin
J
J
Epstein
S
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000517:prevention & control*; D001862:Bone Resorption / Q000517:prevention & control; D002118:Calcium / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains
D010281:Parathyroid Hormone; D015675:Osteocalcin; D004958:Estradiol; D016572:Cyclosporine; D002118:Calcium