Cyclosporin A (CsA) administered to the oophorectomized (Ox) rat exacerbates the high turnover
osteopenia associated with
estrogen deficiency.
17 beta-estradiol replacement
therapy prevent this bone loss. The aim of this study was to see whether an
estrogen-like compound,
Raloxifene analog (
LY117018 HCL, Ral) could likewise ameliorate CsA-induced
osteopenia in the Ox rat. Sixty 6-month-old Sprague-Dawley rats, divided into five groups, underwent
oophorectomy. One group acted as a basal group and the others received either vehicle (group B), CsA 15 mg/kg/day (group C), Ral 3 mg/kg/day (group D), or CsA 15 mg/kg/day and Ral 3 mg/kg/day (group E) for 28 days by gavage. A sixth
sham operated group of 12 rats received vehicle only (group A). Rats were weighed and bled on days 0, 14, and 28 for measurement of ionized
calcium,
glucose,
osteocalcin (BGP),
17 beta-estradiol, and
1,25-dihydroxyvitamin D3 (
1,25[OH]2D3). Tibiae were removed on day 28 for bone histomorphometry after double
tetracycline and
calcein labeling.
Oophorectomy caused a significant gain in weight in groups B and C which was prevented by Ral in groups D and E. Randomized
blood glucose levels and
1,25(OH)2D3 levels were elevated in both CsA-treated groups. Blood ionized
calcium levels were lower in vehicle (group B) compared with
sham (group A) on day 28. Ox (group B) had significantly higher serum BGP levels compared with
sham-operated rats. Serum BGP levels were further elevated in group C compared with vehicle and were lowered in both Ral-treated groups to vehicle levels by day 28. Bone histomorphometry revealed a high turnover
osteopenia with increased parameters of bone formation and resorption and loss of cancellous bone volume postoophorectomy (group B). CsA (group C) exacerbated the effects of
oophorectomy. Ral (group D) completely prevented the high turnover
osteopenia caused by
oophorectomy and was able to attenuate substantially the effects of CsA in the Ox rat (group E). Ral
therapy ameliorated CsA-induced
osteopenia in the Ox rat and might prove a useful agent in preventing bone loss in postmenopausal women receiving CsA.