Sex Differences in Presentation but Not in Outcome for ACTH-Dependent Cushing's Syndrome

Sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity, is caused by loss of the SOST gene product, sclerostin. The localization in bone and the mechanism of action of sclerostin are not yet known, but it has been hypothesized that it may act as a bone morphogenetic protein (BMP) antagonist. We show here that SOST/sclerostin is expressed exclusively by osteocytes in mouse and human bone and inhibits the differentiation and mineralization of murine preosteoblastic cells (KS483). Although sclerostin shares some of the actions of the BMP antagonist noggin, we show here that it also has actions distinctly different from it. In contrast to noggin, sclerostin did not inhibit basal alkaline phosphatase (ALP) activity in KS483 cells, nor did it antagonize BMP-stimulated ALP activity in mouse C2C12 cells. In addition, sclerostin had no effect on BMP-stimulated Smad phosphorylation and direct transcriptional activation of MSX-2 and BMP response element reporter constructs in KS483 cells. Its unique localization and action on osteoblasts suggest that sclerostin may be the previously proposed osteocyte-derived factor that is transported to osteoblasts at the bone surface and inhibits bone formation.

The relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from seven cohort studies of approximately 42,000 men and women. Current and past use of corticosteroids was an important predictor of fracture risk that was independent of prior fracture and BMD. The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk. We studied 42,500 men and women from seven prospectively studied cohorts followed for 176,000 patient-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, Dubbo Osteoporosis Epidemiology Study (DOES), and prospective cohorts at Sheffield, Rochester, and Gothenburg. The effect of ever use of corticosteroids, BMD, age, and sex on all fracture, osteoporotic fracture, and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted beta coefficients. Previous corticosteroid use was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture when adjusted for BMD. Relative risk of any fracture ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years. For osteoporotic fracture, the range of relative risk was 2.63-1.71, and for hip fracture 4.42-2.48. The estimate of relative risk was higher at younger ages, but not significantly so. No significant difference in risk was seen between men and women. The risk was marginally and not significantly upwardly adjusted when BMD was excluded from the model. The risk was independent of prior fracture. In the three cohorts that documented current corticosteroid use, BMD was significantly reduced at the femoral neck, but fracture risk was still only partly explained by BMD. We conclude that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD. Its identification on an international basis validates the use of this risk factor in case-finding strategies. Copyright 2004 American Society for Bone and Mineral Research

The European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS). Baseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%). Proportion of men in the ECT-CS group was higher than in the other groups (P<0.05). The ADR-CS group was older than the PIT-CS (P<0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P<0.05 and P<0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P<0.01). Reduced libido was more prevalent in men than women (P<0.01). Prevalence of spine osteoporosis was higher in men than women (P<0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P<0.001 and 34 vs 23% for ribs; P<0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P<0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P<0.05). Overall, weight gain was more common in women than men (P<0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups. The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.