Raised serum levels of interleukin-8 and interleukin-18 in relation to bone metabolism in endogenous Cushing's syndrome

Abstract

Objective: It is well known that patients with endogenous Cushing's syndrome (CS) have decreased bone mass and enhanced risk for osteoporotic fractures, secondary to decreased bone formation and increased bone resorption. Immunological mediators, such as cytokines, have recently been shown to influence bone metabolism, and in the present study we examined serum levels of several cytokines, with known or potential effects on bone homeostasis, in 33 consecutive recruited untreated CS patients and 33 age-, sex-and body mass index-matched healthy controls. Methods: Cytokine levels were measured by enzyme immunoassay and bone mass by dual-energy X-ray absorptiometry. Results: Our main findings were (i) interleukin (IL)-8 and IL-18 levels were significantly increased in CS patients compared with controls. (ii) Levels of both IL-8 and IL-18 were positively correlated to serum cortisol. (iii) For serum levels of the 'classical' resorptive cytokines, i.e. IL-6 and tumor necrosis factor a, no significant differences were found between CS patients and controls. (iv) Raised IL-18 levels were correlated with decreased osteocalcin levels in CS patients. Conclusions: Our results demonstrated that CS patients have markedly elevated levels of the proinflammatory cytokines IL-8 and IL-18 in spite of high levels of the immunosuppressive hormone cortisol. These cytokines may be involved in the pathogenesis of disturbed bone homeostasis in CS.

Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing’s syndrome: A prospective, long-term study

“…In the follow-up period bone area increased significantly in the LS (and a similar trend in TB) throughout the observation period most likely reflecting periosteal apposition of new bone, in accordance with the persistent increase in serum levels of the bone formation marker osteocalcin. Decreased bone area has previously been demonstrated in active CS (5,16), and altered bone area has also been found in other endocrine disorders (37 -39). While we are not aware of any earlier reports showing that successful cure of CS affects bone area, treatment with parathyroid hormone was recently shown to increase vertebral cross-sectional area in postmenopausal women with GC-induced osteoporosis (40).…”

“…CS patients with pituitary adenoma (Cushing's disease) or adrenal cortex adenoma diagnosed in our center between 1994 and 1999 were consecutively recruited to this study, after giving signed informed consent (5,16). The study was approved by the local ethical committee and conducted according to the Declaration of Helsinki II.…”

“…All patients were diagnosed with CS based on a thorough clinical evaluation and biochemical work-up, as previously reported (5). Prior to surgical treatment, a baseline population of 33 CS patients (24 women, 9 men) was systematically evaluated and matched with 33 healthy controls.…”

“…Glucocorticoid (GC)-induced bone loss is a frequent and serious complication in patients with endogenous Cushing's syndrome (CS) (1,(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) as well as in patients on GC therapy (12), leading to an increased risk of low-energy fractures (8, 13 -15). While patients receiving GC therapy usually suffer from a primary disease that may have negative influence on bone mass by itself, CS (i.e.…”

“…Accordingly, fracture risk appears to be highest in the vertebrae and ribs of these patients (8,13,14). In contrast, the effect of GC on skeletal sites with predominantly cortical bone is less well-documented (5,9,16,17). Few reports have assessed restoration of bone mass after treatment of patients with active CS and there is a scarcity of long-term prospective studies (1,3,11,18), reflecting the low incidence of CS (1 -10 per million per year) (19).…”