Persistent increase of osteoprotegerin levels after cortisol normalization in patients with Cushing's syndrome

Abstract

Objective: Osteoprotegerin (OPG) has been identified as a decoy receptor that inhibits osteoclast differentiation and, more recently, as a paracrine regulator of vascular calcification. OPG is suppressed by glucocorticoids (GC); however, results from experimental and clinical studies are not univocal. The aim of this study was to evaluate OPG and bone metabolism in patients with Cushing's syndrome (CS) before and after cure. Design and methods: Twenty-six patients with CS (all women, mean age: 39.1G11.9 years) and 24 ageand gonadal status-matched healthy women were studied for bone mineral density, bone metabolism, OPG, and receptor activator of nuclear factor-kB ligand at baseline. Twelve patients were also studied 6-18 months after surgery, with persistent normalization of cortisol levels. Results: OPG was significantly higher and osteocalcin (OC) was significantly lower in CS patients than in controls (OPG: 4.17G1.23 vs 2.95G0.79 pmol/l, PZ0.00001; OC: 15.0G6.1 vs 18.8 G6.8 ng/ml, PZ0.04 in CS and controls respectively). After cure, we found no difference in OPG levels, despite a significant increase in OC levels (from 16.4G11 to 37.2G15 ng/ml, PZ0.03). Conclusion: Patients with CS showed increased OPG serum levels that remained unchanged after recovery, despite a restoration of bone formation. We speculate that high levels of OPG could reflect the persistent damage of the GCs on cardiovascular system. European Journal of Endocrinology 162 85-90

TXNIP is highly regulated in bone biopsies from patients with endogenous Cushing's syndrome and related to bone turnover

“…However, although we cannot establish if the TXNIP in bone is increased in active CS, the strong correlation between TXNIP and TRX, as well as the markedly elevated TRX levels compared with control at baseline, may suggest so. The OPG/RANKL system is of major importance for the coordinated coupling principle in bone remodeling (4,23). We found that silencing of TXNIP in hFOB decreased OPG and increased RANKL, indicating that decreased OB expression of TXNIP favors bone resorption.…”

Circulating TRAIL Shows a Significant Post-Partum Decline Associated to Stressful Conditions

“…Interestingly, elevated levels of total cortisol were associated with low levels of TRAIL also in the CB although this association did not reach statistical significance. In addition, a previous study demonstrated that pathological levels of cortisol increase the circulating levels of osteoprogerin, a neutralizing receptor for TRAIL [33]. In relationship with the potential vasoprotective activity of TRAIL [15]–[18], it remains to be established whether the drop of TRAIL after partum associated to stressful conditions represents a risk for future cardiovascular disease, which, anyhow, is rare at the age of the women enrolled in our study.…”

Glucocorticoid‐induced osteoporosis: lessons from Cushing's syndrome

“…Earlier views on its pathogenesis stressed the extraskeletal effects of glucocorticoids, such as hypogonadotrophic hypogonadism, a decrease in intestinal calcium absorption and an increase in renal calcium excretion, resulting in secondary hyperparathyroidism. At variance, several studies found normal PTH levels in patients with CS . The administration of exogenous glucocorticoids and most forms of primary adrenal CS result in decreased secretion of adrenal androgens and oestrogens, and changes in the GH–IGF1 axis and insulin .…”

“…Glucocorticoids increase the expression of receptor activator of nuclear factor‐κB ligand (RANKL), while the expression of osteoprotegerin (OPG) is decreased . Interestingly, however, measurement of circulating RANKL and OPG concentrations does not reflect their bone tissue expression, with OPG levels increased in patients with chronic hypercortisolism and persisting even after successful surgical treatment of CS; the source of increased OPG level in patients with CS is probably the vascular endothelium and may correlate with the increased cardiovascular risk of these patients rather than their bone status …”