Pathophysiology of Osteoporosis: Role of Hidden Cortisol Excess and Its Predictors in Bone Fragility (PNRR-MAD-2022-12375951)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 1,500
- 试验地点
- 5
- 主要终点
- Prevalence of hidden hypercortisolism in osteoporosis
研究概览
简要总结
Osteoporosis is a chronic skeletal disease which leads to a decrease in bone strength which increases the risk of fractures.
Clinically overt hypercortisolism leads to hypertension, central obesity, diabetes and osteoporosis. More recently, even the condition of mild and asymptomatic hypercortisolism has been associated with increased prevalence of chronic complications of cortisol excess and mortality. In patients with osteoporosis this form of hypercortisolism may remain occult (hidden hypercortisolism, HidHyCo).
Although asymptomatic, however, this subtle cortisol excess is associated with an increased risk of osteoporosis and fragility fractures.
Moreover, HidHyCo prevalence seems to be increased in osteoporotic patients. The HidHyCo case finding is of utmost importance. However, given the high prevalence of bone fragility and the relatively low diagnostic accuracy of the currently available tests for the HidHyCo detection, a mass screening for HidHyCo is considered unthinkable. As now, no guidelines are available for addressing the HidHyCo screening in osteoporosis.
Therefore, the aims of the present study are the following: i) to assess the HidHyCo prevalence in a sample of osteoporotic patients; ii) to compare the clinical characteristics between osteoporotic/osteopenic patients with HidHyCo and those without HidHyCo in order to determine the clinical characteristics more frequently associated with the HidHyCo presence and to identify those osteoporotic patients worthy of HidHyCo screening; iii) to further investigate bone quality and turnover in HidHyCo patients, to characterize HidHyco patients from a molecular and genetic point of view and to evaluate the pathogenetic mechanisms explaining the negative effects of endogenous cortisol excess on bone health in these patients and the potential role of the genetic background and of the gut microbiome.
The HidHyCo could be present in a not negligible percentage of osteopenic/osteoporotic patients. In these patients, osteoporosis and, if present, other comorbidities can improve by the surgical resection of the adrenal or pituitary adenoma if feasible, or by the use of drugs able to modulate cortisol secretion or glucocorticoid sensitivity. Moreover, the case-finding could be reserved in those patients at higher risk of having HidHyCo, therefore, reducing the costs of a scarcely specific mass screening.
详细描述
Clinically overt hypercortisolism leads to hypertension, diabetes and osteoporosis. More recently, even the condition of mild and asymptomatic hypercortisolism has been described to be associated with increased prevalence of chronic complications of cortisol excess and mortality. In patients with osteoporosis this form of hypercortisolism may remain occult (hidden hypercortisolism, HidHyCo).
The HidHyCo prevalence in the general population is estimated to be 0.2-2%, but it has been reported up to 9.9% and 17.6% in patients with low bone mineral density and with fragility fracture, respectively. However, given the high prevalence of bone fragility and the relatively low specificity of the available tests for the HidHyCo detection, screening all osteoporotic patients for HidHyCo is considered unthinkable and no guidelines are available for addressing the HidHyCo screening in osteoporosis.
At present, data regarding the osteoporosis characteristics more frequently associated with HidHyCo have been not reported, even though some data suggest that the coexistence of osteopenia with hypertension treated with at least 2 drugs or with not well controlled hypertension and/or diabetes or with a history of cardiovascular events may increase the probability of HidHyCo.
Moreover, scarce and discordant data are available on the pathogenesis of the bone damage due to a subtle cortisol excess and on the possible role of individual bone sensitivity to cortisol and of microbiome composition.
Therefore, the aims of the current project are the following: i) to assess the prevalence of HidHyCo, ii) to determine the characteristics predictive of the presence of this condition in patients with apparently primary osteoporosis, iii) to evaluate the pathogenetic mechanisms explaining the negative effects of this slight cortisol excess on bone and the potential role of the genetic background and of the gut microbiome.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •pregnancy/breastfeeding, sleep apnea, prepuberal onset of hypertension, hormonal hypersecreting adrenal mass,signs/symptoms of hypercortisolism;
- •already known secondary osteoporosis with the exception of hypercalciuria;
- •drugs influencing the bone metabolism with the exception of diuretics, anti-diabetics and anticoagulants;
- •conditions associated with increased hypothalamic-pituitary-adrenal (HPA) axis activity, severe autoimmune/rheumatologic and hematologic diseases, alcoholism, chronic kidney disease (glomerular filtration rate <60 ml/min);
- •drugs influencing the HPA axis activity or the dexamethasone metabolism.
结局指标
主要结局
Prevalence of hidden hypercortisolism in osteoporosis
时间窗: 18 months
To evaluate the prevalence of hidden hypercortisolism in patients with osteoporosis or osteopenia plus the comorbidities possibly associated with cortisol excess.
Statistical comparison of the clinical and biochemical characteristics of osteoporotic/osteopenic patients with HidHyCo and those without HidHyCo to identify the characteristics predictive of the presence of HidHyCo in osteoporosis
时间窗: 18 months
The patients with HidHyCo (Patient Group) and those without HidHyCo (Control Group) will be compared as far as the following independent variables (taken as single variable or in combination) is concerned: i) lumbar and/or femoral BMD; ii) presence of fragility fracture; iii) presence of hypertension treated with at least 2 drugs or of not well controlled hypertension, iv) presence of diabetes; v) number of anti-hypertensive and/or antidiabetic drugs; vi) presence of a history of cardiovascular events ; vii) biochemical parameters. The investigators will evaluate if one or more independent variables will be associated with the presence of HidHyCo after adjusting for confounding factors. The sensitivity and specificity of the independent variables (singularly taken or in combination), which will be found to be different between the two groups in predicting the presence of HidHyCo, will be calculated.
次要结局
- Further investigation of bone quality as assessed by Radiofrequency Echographic Multi Spectrometry (REMS)(24 months)
- Further investigation of bone turnover in HidHyCo patients, as assessed by serum osteocalcin, CrossLaps, bone alkaline phosphatase and amino-terminal propeptide of type 1 procollagen (P1NP) and additional new potential serum markers of bone status.(24 months)
- Assessment of gut microbiome composition by the analysis of fecal samples(24 months)
- Characterization of HidHyco patients from a molecular and genetic point of view by the determination of circulating microRNAs, peripheral glucocorticoid activity and the polymorphic variants of the 11ßHSD1, GR and B2AR gene.(24 months)