The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency.
OBJECTIVE
Optimization of physiological replacement of glucocorticoid in patients with adrenal insufficiency is controversial. The present study was undertaken to compare the relative impact of three different regimes of glucocorticoid replacement in patients with adrenal insufficiency on parameters of bone turnover and insulin sensitivity.


PATIENTS
Six female and three male patients with adrenal insufficiency and 17 female and 14 male control subjects participated.


DESIGN
This was an open study conducted in a university teaching hospital. Schedule 1 (S1) consisted of hydrocortisone 10 mg with breakfast and 5 mg with lunch. S2 was similar to S1 with the addition of 5 mg hydrocortisone with the evening meal. S3 utilized dexamethasone 0.1 mg/15 kg body weight given per day with breakfast only. Each schedule was given for at least 4 weeks in random sequence to nine patients with adrenal insufficiency.


METHODS
Blood was obtained at 0900 h (fasting) and at 1300 h for measurement of the ionized calcium (Cai), PTH, 25-hydroxyvitamin D and the bone formation markers intact osteocalcin and amino-terminal propeptide of type 1 procollagen (PINP). Timed urine collections were made under standardized conditions, that is while fasting between 0700 and 0900 h (basal) and between 0900 and 1300 h for measurement of the bone resorption markers, free deoxypyridinoline (FDPD) and cross-linked N-telopeptide of type 1 collagen (NTX). Blood was drawn for measurement of fasting plasma glucose and serum insulin levels. Insulin (0.075 IU/kg) was administered i.v. while the patient was fasting prior to the first glucocorticoid replacement dose on each study day. Plasma glucose was measured before and 3, 6, 9, 12 and 15 min after insulin administration to calculate the glucose disappearance rate (Kitt). Insulin resistance (IR) and beta-cell function were estimated using the homeostasis model assessment (HOMA). Glucocorticoid dosage was given according to the various schedules at approximately 0930 h.


RESULTS
During all three treatment schedules the serum Cai level was significantly lower than that seen in control subjects. PTH levels in patients taking the three replacement schedules and in normal subjects were similar. Serum 25-hydroxyvitamin D levels were not suppressed in the patients during any of the three treatment schedules. The bone resorption marker urinary FDPD under basal conditions was significantly lower during S3 (dexamethasone) than during either hydrocortisone schedules, S1 or S2. Urinary NTX values were not significantly different in the three study groups. The bone formation markers intact osteocalcin and PINP were similar in the three replacement schedules. The indices of IR and beta-cell function tended to be higher during treatment with dexamethasone than with S1 or S2 but did not achieve statistical significance.


CONCLUSIONS
These data indicate that all three replacement schedules were associated with low serum ionized calcium levels without evidence of a compensatory increase in PTH levels. These findings are consistent with direct or indirect suppression of the bone remodelling cycle and suppression of PTH levels. Bone turnover in patients with adrenal insufficiency treated with schedule 3, dexamethasone, was associated with lower bone turnover than patients treated with hydrocortisone schedules 1 or 2. While indices of insulin sensitivity measured during schedules 1, 2 and 3 did not achieve statistical significance, there was an obvious trend for greater insulin resistance to occur with schedules 3 using dexamethasone.