Incidentaloma, glucocorticoid excess and low bone mineral density: a coincidence?

The paper by L TauchmanovaA et al. published in this issue of the Journal leads to the discussion of several aspects of the management of patients suspected of being exposed to glucocorticoid excess (1). The ®rst point to be considered is that there is no doubt, nowadays, that glucocorticoid (GC) excess, whether exogenous or endogenous, leads to rapid bone loss early after the start of GC therapy and, by extrapolation, presumably early in the course of excessive adrenal secretion. It increases dramatically the risk of fragility fractures (2). Osteoporosis (OP) had already been observed by H Cushing in his princeps description of the syndrome which, since then, bears his name. The mechanisms of glucocorticoid-induced osteoporosis (GC-OP) are multiple, but not yet fully understood. Grossly, GC-OP is the consequence of decreased bone formation and increased bone resorption, the former being more marked than the latter (3). Both act synergistically to provoke bone fragility. Increased bone resorption may be the consequence of some degree of secondary hyperparathyroidism (4), only partially explained by a GC-induced sensitization to parathyroid hormone (PTH) action of the target cells. Secondary hyperparathyroidism mainly results from the decrease in intestinal calcium absorption, probably induced by some acquired resistance to 1,25(OH)2 vitamin D3, and, to a lesser extent, by an increase in urinary calcium excretion, both concurring additively to a trend leading to the lowering of serum calcium. Moreover, GCs inhibit osteoblastic function, as can be seen in dynamic histomorphometry (4) and which is patently illustrated by the dramatic decrease in the plasma osteocalcin level, a marker of osteoblastic function, immediately after GC exposure, with fast recovery in the hours to days following complete withdrawal of GCs (5). Another mechanism for the development of GC-OP could be an increased apoptosis of osteoblasts and osteocytes, both cells so crucial for bone formation and maintenance of bone integrity (6). So far, most of the clinical studies dealing with the bone effect of GCs have been conducted in patients with exogenous GC excess given as therapy for disorders like rheumatoid arthritis and systemic lupus erythematosus, which may themselves affect bone turnover and bone mineral density (BMD). In Cushing's syndrome, however, similar alterations of bone turnover and BMD have been observed (7). The complexity of the mechanisms potentially leading to GC-OP can help to understand why, at least in some patients, even very low doses of endogenous or exogenous GCs might be deleterious to bone and lead to an increased risk of vertebral and non-vertebral fractures (8). Histomorphometrically, with doses up to 10 mg there is a thinning of bone trabeculae with long-term maintenance of interconnectivity (9±11), as opposed to postmenopausal OP in which perforations of trabeculae occur rapidly, leading to a rapid degradation of bone microarchitecture. With higher GC doses, however, irreversible trabecular discontinuity is observed (10, 11). If extrapolated to what happens in incipient Cushing's syndrome, it seems, therefore, mandatory to diagnose as early as possible any excessive endogenous secretion of GC, in order to prevent a dramatic bone loss and the destruction of bone architecture. This is an easy task if the results of testing the hypothalamic± pituitary±adrenal axis are clearcut. Indeed, several reports have observed recovery of bone mineral density after withdrawal of GCs or after curative therapy of overt Cushing's syndrome (12). This should encourage practitioners to check systematically the bone mineral density not only in patients chronically on GC therapy (any dosage) but also in patients in whom endogenous glucocorticoid excess is suspected. The second point is how to measure BMD. It looks a more ancillary issue, as far as the choice of the technique is concerned, if only a cross-sectional (as opposed to longitudinal) BMD measurement is envisaged. Currently, dual energy X-ray absorptiometry (DXA) is the more widely accepted procedure, well validated for longitudinal trials. The risk-de®nitions for postmenopausal osteoporosis with their expression as T-scores, proposed by a World Health Organisation (WHO) group, are based on this technique (13). However, these de®nitions are only validated for Caucasian postmenopausal women, and are not directly applicable to males nor to secondary osteoporosis. Ultrasound techniques have also been developed. They are able to measure various sites of the skeleton like calcaneus, tibia, and the phalanges of the ®ngers. Some further developments are expected. However, each manufacturer develops his own apparatus with its proper characteristics, potentially leading ISSN 0804-4643 European Journal of Endocrinology (2001) 145 237±239