Cyclosporin A in the oophorectomized rat: Unexpected severe bone resorption

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Abstract
Local factors, such as interleukin-1, may mediate the accelerated bone remodeling in the acute estrogen-deficient rat. Cyclosporin A (CsA), which in vitro inhibits some of these local factors, was administered to oophorectomized (OX) rats in an attempt ot modify this high turnover state. Three groups of 15 rats were studied. Group A was sham operated, group B was OX, and group C was OX and received CsA (15 mg/kg per day) by gavage commencing 4 days postoophorectomy for 28 days. Estradiol levels were determined to confirm oophorectomy. Blood was sampled on days −7, 0, 7, 14, 21, and 28 for ionized calcium (Ca2+), 1,25-(OH)2-vitamin D, PTH, and bone gla protein (BGP). Rats received tetracycline hydrochloride for bone histomorphometric labeling. All results were compared to group A. Body weight was increased in group B (p < 0.003) but not in group C. There was no difference in Ca2+ or PTH between the groups. BGP levels were higher in group B by day 28 (p < 0.05); BGP levels were increased in group C from days 7–28 (p < 0.002). 1,25-(OH)2-vitamin D was significantly increased in group C (p < 0.0001) but not in group B. Tibial bone histomorphometry revealed increased measurements of bone formation and osteoclast number without a loss of bone volume (BV/TV) in group B. Group C showed a dramatic increase in bone turnover with significant loss of BV/TV (p < 0.001). In conclusion, CsA in the OX rat resulted in unexpected enhanced bone remodeling with high BGP levels and severe bone resorption. These changes may be due to CsA alone or may be modified by oophorectomy.