Bone Vol. 19, No. 2 August 1996:81-88 ELSEVIER ORIGINAL ARTICLES Skeletal Response to Corticosteroid Deficiency and Excess in Growing Male Rats M. LI, 1 Y. SHEN, 1 B. P. HALLORAN, 2 B. D. BAUMANN, l K. MILLER, 2 and T. J. WRONSKI 1 1 Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA 2 Endocrine Unit, VA Medical Center and Department of Medicine, University of California, San Francisco, CA, USA The study was designed to investigate bone histomorphomet- ric changes induced by corticosteroid deficiency and supple- mentation at different dose levels in the rat skeleton. Male rats were adrenalectomized (ADX) or sham-operated and divided into six groups. At 2 days after surgery, sham- operated control rats (CON + PLA) and one group of ADX rats (ADX + PLA) were implanted subcutaneously (sc) with placebo pellets. ADX rats in the remaining four groups (ADX + C25, ADX + C50, ADX + C100, and ADX + C300) were implanted sc with corticosterone pellets designed to release 25, 50, 100, or 300 mg of the hormone over a 60 day period. Each ADX rat was also implanted sc with an aldosterone pellet (2.5 mg) similarly designed to release its contents over the same time period. All rats were killed at 3 weeks after implantation of pellets. Terminal blood samples were col- lected for serum biochemistry and the proximal tibial me- taphyses (PTM), tibial diaphyses, and first lumbar vertebrae (LV) were processed undecalcified for quantitative bone his- tomorphometry. A dose-dependent increase in serum corti- costerone concentration was observed in ADX rats implanted with hormone pellets. In comparison to CON + PLA rats, ADX + PLA rats had lower cancellous bone volume associ- ated with a stimulation in longitudinal bone growth, an in- crease in mineral apposition rate, and a trend for increased osteoclast and osteoblast surfaces in PTM. In contrast, can- cellous bone of ADX + C25 rats was preserved at nearly the CON + PLA level. However, the higher doses of corticoste- rone increased cancellous bone mass, but decreased longitu- dinal bone growth and all indices of bone resorption and formation in a dose-dependent manner in PTM. Similar can- cellous bone changes were observed in the LV of corticoste- rone-treated rats, with the exception of a lack of an hormonal effect on cancellous bone mass. In the tibial diaphysis, corti- costerone inhibited periosteal bone formation in a dose- dependent manner, but did not affect cortical bone mass. The results indicate that corticosteroid deficiency induces cancel- lous osteopenia, whereas supplementation with a near physi- ologic dose of the hormone prevents this bone loss in ADX rats. Furthermore, corticosteroid excess inhibits bone growth and bone turnover in a dose-dependent manner, but does not induce cancellous osteopenia in growing male rats. (Bone 19:81-88; 1996) Address for correspondence and reprints: Dr. M. Li, Department of Physiological Sciences, Box 100144, JHMHC, University of Florida, Gainesville, FL 32610. Key Words: Adrenalectomy; Corticosterone; Bone histomor- phometry; Cancellous bone; Cortical bone; Rat. Introduction It is well established that corticosteroid excess may lead to bone loss and subsequent spontaneous fractures in humans. 3"3° These deleterious effects of corticosteroids on the skeleton are thought to be due to decreased bone formation and increased bone re- sorption. 8 Many studies have been performed in different ani- mals such as rats, rabbits, beagles, and ewes to seek a suitable animal model that mimics osteopenia and disordered bone me- tabolism in patients treated with corticosteroids. 6'9'16"2°'29"3°'33"34 Unfortunately, none of the animal models have been widely ac- cepted. Regarding rodents, previous studies of bone changes in rats treated with corticosteroids have been conflicting. For ex- ample, bone mass has been reported to be normal, 2° increased, 17 or decreased 13"21 in corticosteroid-treated rats. These conflicting results may be due in part to use of different doses of cortico- steroids. For example, high doses of the hormone increased can- cellous bone mass but decreased cortical bone mass in rats, 17'26'37 whereas lower doses had little effect. 17'2° Neverthe- less, even in vitro studies with cultured rat bones have been inconsistent as similar doses of the hormone reportedly stimu- lated a4 or inhibited 36 osteoclastic bone resorption. Furthermore, most in vivo studies were performed with a single dose of cor- ticosteroids in rats with intact adrenal glands. A dose response study in rats without endogenous corticosteroids is desirable to better define the skeletal effects of the hormone. Therefore, the current study was designed to determine the effects of cortico- steroid supplementation at different doses ranging from near physiologic to supraphysiologic at several bone sites in growing, adrenalectomized rats. Materials and Methods The experimental animals were 56 male Sprague-Dawley rats (Charles River Laboratory, Wilmington, MA) that were approxi- mately 7 weeks of age. They were randomized into six groups with nearly identical mean body weights (200 g) at the beginning of the study. All rats were anesthetized with an intraperitoneal (ip) injec- tion of ketamine hydrochloride and xylazine at doses of 50 and 10 mg/kg body weight (BW), respectively. Bilateral adrenalec- tomies (ADX) were performed in five groups using a dorsal approach. 39 One group was subjected to sham surgeries in which the adrenal glands were exposed but not removed. All rats were © 1996 by Elsevier Science Inc. 81 8756-3282/96/$15.00 All rights reserved. PII $8756-3282(96)00170-6