Screening for reversible osteoporosis: is cortisol a culprit?

In this issue, Chiodini and colleagues (1) measured the prevalence of subclinical hypercortisolism in 219 consecutive patients 44 to 72 years of age with suspected idiopathic osteoporosis. These individuals had no known secondary cause of osteoporosis, had not received drugs known to influence bone or cortisol, and had no apparent signs or symptoms of cortisol excess (including moon facies, red striae, skin atrophy, or buffalo hump). The investigators screened each patient for hypercortisolism with a 1-mg dexamethasone suppression test and required an abnormal response to the 2-mg, 2-day dexamethasone test, in addition to abnormal urine cortisol levels and midnight cortisol values to establish the diagnosis. Overall, 3.3% of the patients had abnormal responses to these tests. Because the patients did not have clinically recognized hypercortisolism, the authors used the term subclinical hypercortisolism to describe the disorder. The study suggests that hypercortisolism may contribute to few cases of osteoporosis, at least in a restricted subpopulation that is older and has experienced fractures. This editorial addresses several questions raised by this unexpectedly high rate of hypercortisolism. First, are these results believable, given the rarity of the Cushing syndrome? The 3.3% prevalence of subclinical hypercortisolism in patients with suspected idiopathic osteoporosis is surprisingly high. Clinically apparent Cushing syndrome is rare, being diagnosed in 0.7 to 2.4 per 1 million persons annually (2). As a result, until recently, clinically inapparent hypercortisolism has not been considered as an important—and potentially reversible—cause of disorders associated with hypercortisolism. However, studies of patients with diabetes, hypertension, and hirsutism showed a prevalence of the Cushing syndrome of 2% to 4%, 1%, and 0.25%, respectively. In light of these relatively high prevalences and the findings reported by Chiodini and colleagues, it seems reasonable to screen patients with these disorders for hypercortisolism and perhaps even investigate the prevalence of pathogenic Cushing syndrome in patients with other signs of the syndrome, such as osteoporosis (3–5). Subclinical hypercortisolism refers to the dysregulation of the hypothalamic–pituitary–adrenal axis along with clinical characteristics compatible with the Cushing syndrome but not sufficiently suggestive to raise a diagnostic red flag. Usually the patients are middle-age or older and have disorders common in that age group, such as obesity, diabetes, hypertension, and depression. Often these features appeared insidiously, and the physician has not considered hypercortisolism as an etiologic factor. One problem in Chiodini and colleagues’ study stems from the difficulty in validating the diagnosis of subclinical Cushing syndrome. We do not know the best tests for subclinical hypercortisolism. Chiodini and colleagues used abnormal responses to dexamethasone and increased midnight serum or urinary free cortisol levels to identify subclinical hypercortisolism. These abnormalities are present in clear-cut Cushing syndrome, and they therefore indicate cortisol dysregulation. However, people who have nonspecific clinical features but do not have overt Cushing syndrome sometimes have similar abnormalities (6). To measure the sensitivity and specificity of these tests, a gold standard is needed for the diagnosis of subclinical Cushing syndrome. Until one is agreed on, we will have difficulty confirming the diagnosis and should rely on several abnormal tests of adrenal function. Meanwhile, some investigators have relied on post–adrenal surgery hypocortisolism or improvement in clinical features to validate the diagnosis retrospectively (7–10). Unfortunately, not all patients who are obese, have hypertension, or have diabetes improve after surgery, and it is not possible to predict beforehand who will benefit from surgery. Second, do these results suggest a causal relationship between hypercortisolism and reduced bone density? Florid glucocorticoid excess is toxic to bone health. Children can stop growing, and patients can have bone demineralization and necrosis (11). The clinical scenario is usually straightforward: The patient has an unmistakable clinical phenotype of the Cushing syndrome, with recent weight gain, abnormal fat distribution, diabetes, hypertension, hirsutism, depression, stretch marks, and weakness. In these cases, a return to normal glucocorticoid levels allows growth and remineralization of bone (12). The length of time that glucocorticoid levels need to be at a high level in order to cause a toxic effect of cortisol is not known, although recent publications suggest that subtle hypercortisolism may account for osteopenia in both depression and subclinical Cushing syndrome (7, 13). This study suggests a dose-dependent effect of hypercortisolism on bone mineral density, which is an important criterion for a causal relationship. Almost all (about 96%) patients with normal bone density had a normal cortisol response to 1 mg of dexamethasone. In patients with an abnormal response to 1 mg of dexamethasone, the responses to the 2-mg dexamethasone suppression test varied. Patients without suppression after either dose of dexamethasone presumably had more autonomous, abnormal cortisol secretion than those who have suppression after the 2-mg, but not the 1-mg, dexamethasone dose. Within this group, the cortisol responses to the 2-mg dexamethasone test were inversely related to their T-scores, suggesting that more autonomous cortisol secretion was associated with lower bone density. Subclinical hypercortisolism, the most severe abnormality of cortisol dynamics in the study, was found only in patients with the most severe bone disease, as evidenced by osteoporosis and vertebral facture. These data suggest a graded effect of hypercortisolism on bone density. Annals of Internal Medicine Editorial