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Editorial |
Division of Endocrinology, Metabolism and Genetics Department of Medicine University of Kansas School of Medicine Kansas City, Kansas 66160
Address all correspondence and requests for reprints to: Barbara P. Lukert, M.D., F.A.C.P., Division of Endocrinology, Metabolism and Genetics, Department of Medicine, University of Kansas School of Medicine, 3901 Cambridge, Kansas City, Kansas 66160. E-mail: blukert{at}kumc.edu.
The physiological replacement of corticosteroids presents a difficult challenge. Replacing thyroid hormone is relatively straightforward because the half-life of T4 is long (days) and TSH secretion is not pulsatile; therefore, measuring TSH provides a reliable assessment of response. In comparison, the half-life of steroid hormones is relatively short (hours compared with days for T4), and ACTH secretion is pulsatile and cannot be used to monitor adequacy of glucocorticoid replacement. Adjusting the dose to suppress ACTH produces features of Cushing’s syndrome in patients with Addison’s disease. Avoiding overreplacement is problematic whether one is treating congenital adrenal hyperplasia (CAH), Addison’s disease, or pituitary insufficiency.
The relationship between excessive glucocorticoid replacement and osteoporosis has been reported repeatedly. Serum osteocalcin (a marker of bone formation) was suppressed and rose by 19% in a group of patients in whom the cortisol dose was reduced on the basis of peak cortisol and urine free cortisol measurements (1). Glucocorticoids cause rapid decline in bone mass through a variety of effects including inhibition of calcium absorption, suppression of gonadal hormone, and adrenal androgen secretion and, most importantly, direct effects on bone (2). Bone resorption is increased early after exposure to glucocorticoids due to enhanced expression of RANK ligand (RANK-L), collagenase-3, and colony-stimulating factor-1, and to inhibition of osteoprotegerin production by osteoblasts with consequent induction of osteoclastogenesis (3). Bone resorption eventually decreases due to a decline in the number of mature osteoblasts resulting in a decrease in osteoblastic signals required for osteoclastogenesis. The most profound and enduring effect of glucocorticoids is inhibition of bone formation secondary to a decrease in the number and activity of osteoblastic cells. The number of osteoblasts declines due to a decrease in differentiation of osteoblasts and a consequent increase in adipocytes along with an increase in apoptosis of mature osteoblasts and osteocytes (2). Osteoblast activity is reduced by glucocorticoid regulation of the IGF axis. Glucocorticoids inhibit transcription of IGF-I and IGF-binding protein-5, both of which normally promote bone formation (4, 5). Additional factors contributing to glucocorticoid-induced inhibition of bone formation include decreased activity of TGF-ß and enhanced expression of dickkopf-1, which inhibits Wnt signaling (6, 7). All these glucocorticoid-induced alterations in bone metabolism cause the most rapid rates of bone loss observed in clinical medicine with the consequence of vertebral fractures in 30–50% of patients exposed to glucocorticoid excess.
A report in this issue of JCEM (8) presents a unique cross-sectional long-term follow-up of bone mineral density (BMD) in women with salt-losing and simple-virilizing forms of 21-hydroxylase deficiency. Five of 11 (45%) of the salt-losing patients and two of the 15 (13%) of simple-virilizing patients were osteopenic. None of the patients were osteoporotic. These investigators found that BMD was not significantly correlated with body mass index as previously expected but was highly correlated with adrenal androgen levels, particularly in postmenopausal women who had the lowest levels of dehydroepiandrosterone (DHEA) and DHEA sulfate and the lowest T-scores when BMD was measured. Although this is a small study, its unique aspect is the long duration of follow-up with 12 of the subjects followed through menopause.
The valuable lessons to be learned from this work may be to recognize the need for finding ways of predicting which patient will be most susceptible to the adverse effect of glucocorticoids on bone and the need for biochemical markers for monitoring glucocorticoid adequacy vs. excess.
Clinicians have long observed significant interindividual variation in susceptibility to the development of features of Cushing’s syndrome in patients being treated with glucocorticoids. The effects on bone appear to be as variable as the propensity for inducing changes in appearance and body habitus. It is presently impossible to predict which individual will develop osteoporosis-related fractures while being treated with glucocorticoids. For example, epidemiological studies have shown that even very small doses of prednisone (2.5 mg) increase the risk for fractures in both men and women with normal adrenal function, and the risk increases progressively with age (9). Overzealous replacement in growing adolescents, with the consequent suppression of bone modeling at a time that is crucial for achieving peak bone mass, is equally disturbing and may have a significant impact on the risk for fractures as an adult.
Sensitivity to glucocorticoids could be regulated by individual differences in absorption of the orally administered hormone, distribution or metabolism of the steroid, the number of and affinity of glucocorticoid receptors, or the amount and binding of nuclear cofactors. The most frequently prescribed glucocorticoids are cortisone and hydrocortisone (cortisol), prednisone and prednisolone, for replacement in Addison’s disease and CAH. Prednisone and prednisolone are synthetic derivatives of cortisone and cortisol, respectively. Cortisone must be converted to cortisol and prednisone to prednisolone to become metabolically active. The conversion of the inactive to the active steroid requires the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). 11ß-HSD2 inactivates cortisol to cortisone and prednisolone to prednisone. 11ß-HSD1 (but not 11ß-HSD2) is expressed in osteoblasts and influences osteoblastic differentiation and activity when exposed to glucocorticoids (10). Furthermore, the activity of this enzyme increases with aging. This may partially explain the increasing risk for fractures with age observed in epidemiological studies of steroid-treated subjects. The enzyme is also induced by glucocorticoids; i.e. the higher the steroid level, the higher the 11ß-HSD1 expression. Estrogen had no effect on 11ß-HSD1 activity in cultured osteoblasts (10). Variability in bone loss, in the face of similar extracellular levels of glucocorticoids, may be due at least in part to individual differences in 11ß-HSD1 expression in osteoblasts. This concept is supported by a recent study in which healthy males were given prednisolone, 5 mg twice daily, for 7 d (10). The extent of the fall in bone formation markers in this study was highly correlated with urinary measures of 11ß-HSD1 activity.
The problem for the clinician is the lack of objective criteria for determining adequate, but not excessive, doses of glucocorticoids. This is somewhat easier in patients with CAH than in those with primary or secondary adrenal insufficiency. In patients with CAH, measuring 17OH-progesterone and DHEA can be a guide. Although mineralocorticoid replacement can be assessed by measuring serum electrolytes, plasma renin activity, and atrial natriuretic peptide in patients with adrenal insufficiency, the assessment of glucocorticoid replacement depends on clinical observation of the early changes of Cushing’s syndrome and laborious and inconvenient laboratory assessment such as frequent measurements of serum cortisol levels over a 24-h period and/or measuring 24-h urine cortisol (1, 11, 12). Using these methods of assessment as many as 75% of patients treated for adrenal insufficiency were found to be taking supraphysiological doses of glucocorticoids (2). In current practice, the clinician must rely on surrogate markers of glucocorticoid excess rather than definitive end points. Studies using frequent serum and urine determinations have shown that the usual replacement doses of hydrocortisone 20 mg in the morning and 10 mg in evening are excessive. These doses were based on the thought that daily cortisol production was 12–15 mg/m2·d. More recent studies measure production at 5–7 mg/m2·d, which equates to a replacement dose of oral hydrocortisone equivalent to 10–12 mg/m2·d (12). Even with careful adjustment of dose, we can never mimic the circadian rhythm of normal pituitary/adrenal function.
There is clearly a need for reliable surrogate markers to monitor the adequacy of glucocorticoid doses. Prospective studies looking at the ability of candidate markers such as 11ß-DHS1 activity, osteocalcin, and/or critical timing of serum measurement of cortisol to assist in finding a dose of cortisol/prednisolone that will prevent the consequences of glucocorticoid excess still need to be done. Until then, physicians who manage patients with CAH should carefully monitor 17-OH progesterone and DHEA levels to avoid oversuppression of adrenal androgens. In patients with primary or secondary adrenal insufficiency, attempts to avoid overreplacement will require careful clinical observation for physical signs and, in the more challenging cases, frequent assessment of serum cortisol levels over a 24-h period or measuring 24-h urine cortisol. BMD should be monitored every 1–2 yr to identify patients who are losing bone and require treatment with an antiresorptive or anabolic agent to minimize the risk for osteoporosis-related fractures.
Footnotes
Abbreviations: BMD, Bone mineral density; CAH, congenital adrenal hyperplasia; DHEA, dehydroepiandrosterone; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase.
Received December 15, 2005.
Accepted January 3, 2006.
References
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