Osteoporosis Clinical Trial
— PATHOSOfficial title:
Pathophysiology of Osteoporosis: Role of Hidden Cortisol Excess and Its Predictors in Bone Fragility (PNRR-MAD-2022-12375951)
NCT number | NCT06324084 |
Other study ID # | 05M201 |
Secondary ID | |
Status | Recruiting |
Phase | |
First received | |
Last updated | |
Start date | April 24, 2023 |
Est. completion date | April 24, 2025 |
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.
Status | Recruiting |
Enrollment | 1500 |
Est. completion date | April 24, 2025 |
Est. primary completion date | October 24, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 75 Years |
Eligibility | Inclusion Criteria (one of the following): - presence of osteoporosis (i.e. lumbar and/or femoral BMD T-score < -2.5 and/or Z-score < -2.0 and/or fragility fracture of hip, spine, wrist, humerus, malleolus or ribs); - presence of osteopenia (i.e. lumbar and/or femoral BMD T-score between -1.0 and -2.5) in addition to hypertension treated with at least 2 drugs or not well controlled hypertension (sustained blood pressure above 150/100 mmHg) and/or diabetes and/or to a history of cardiovascular events (such as deep vein thrombosis, coronary heart disease, myocardial infarction, stroke). Exclusion Criteria: - 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. |
Country | Name | City | State |
---|---|---|---|
Italy | Azienda Ospedaliera Universitaria Policlinico "G. Rodolico-San Marco" | Catania | |
Italy | Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico | Milan | |
Italy | Istituto Auxologico Italiano IRCCS | Milan | |
Italy | Ospedale "Casa Sollievo della Sofferenza" IRCCS | San Giovanni Rotondo | |
Italy | Azienda Ospedaliera Universitaria Senese | Siena |
Lead Sponsor | Collaborator |
---|---|
Istituto Auxologico Italiano |
Italy,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Prevalence of hidden hypercortisolism in osteoporosis | To evaluate the prevalence of hidden hypercortisolism in patients with osteoporosis or osteopenia plus the comorbidities possibly associated with cortisol excess. | 18 months | |
Primary | 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 | 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. |
18 months | |
Secondary | 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. | In patients with HidHyCo and in age-, sex- and BMI-matched patients without HidHyCo investigators will assess bone turnover by measuring serum osteocalcin, CrossLaps, bone alkaline phosphatase and amino-terminal propeptide of type 1 procollagen (P1NP) and additional new potential serum markers of bone status, such as those involved in the Wnt-ßcatenin signaling (e.g. sclerostin, DKK-1 and ß-catenin levels) using commercially available kits. | 24 months | |
Secondary | Further investigation of bone quality as assessed by Radiofrequency Echographic Multi Spectrometry (REMS) | Radiofrequency Echographic Multi Spectrometry (REMS), a non-ionizing skeleton technique performed employing a new dedicated echographic device (EchoStation, Echolight Spa, Lecce, Italy) will be performed to further investigate bone characteristics that are not included in DXA-measured bone mineral density. | 24 months | |
Secondary | 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. | To characterize HidHyco patients from a molecular and genetic point of view investigators will assess the circulating microRNAs (i.e. small non coding single-stranded RNAs that have emerged as important post transcriptional regulators of gene expression) expression profile, the cortisol peripheral activation, as expressed by the 24-hour urinary free cortisol/free cortisone ratio, measured by liquid chromatography-tandem mass spectrometry and its relationship with the polymorphic variants of the 11beta-hydroxysteroid dehydrogenase type 1 (11ßHSD1) gene, the cortisol sensitivity, expressed by the polymorphisms of the glucocorticoid receptor (GR) gene from DNA isolated from peripheral blood, the beta-2 adrenergic activity, regulated by the polymorphism (rs1800544) of the beta-2 adrenergic receptor (B2AR) gene from DNA isolated from peripheral blood. | 24 months | |
Secondary | Assessment of gut microbiome composition by the analysis of fecal samples | To determine the gut microbiome composition in HidHyCo patients for the identification of the potential role of the gut microbiome in the determination of the negative effects of endogenous subtle cortisol excess on bone health. | 24 months |
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