PATHophysiology of OSteoporosis: Role of Hidden Cortisol Excess and Its Predictors in Bone Fragility

NCT06324084 | Recruiting

• 1 other identifier: 05M201
• Study Type: observational
• Target: 1,500
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Osteoporosis; Bone Fracture; Cortisol Excess

Keywords

Osteoporosis; Cortisol

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (4)

• 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

• Further investigation of bone quality as assessed by Radiofrequency Echographic Multi Spectrometry (REMS)

  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

• Assessment of gut microbiome composition by the analysis of fecal samples

  24 months

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Individuals referred to our outpatients clinics for osteoporosis

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Istituto Auxologico Italiano: lead

Study Sites (5)

Azienda Ospedaliera Universitaria Policlinico "G. Rodolico-San Marco"

Catania, Italy

NOT YET RECRUITING

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Italy

RECRUITING

Istituto Auxologico Italiano IRCCS

Milan, Italy

RECRUITING

Ospedale "Casa Sollievo della Sofferenza" IRCCS

San Giovanni Rotondo, Italy

RECRUITING

Azienda Ospedaliera Universitaria Senese

Siena, Italy

NOT YET RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Serum samples for the assessment of bone turnover markers Blood samples for the assessment of circulating microRNAs 24-hour urinary samples for the assessment of 24-hour urinary free cortisol/free cortisone ratio DNA isolated from blood samples for the determination of 11ßHSD1, GR and B2AR gene polymorphisms Fecal samples for the analysis of gut microbiome composition

MeSH Terms

Conditions

Osteoporosis; Fractures, Bone; ACTH Syndrome, Ectopic

Condition Hierarchy (Ancestors)

Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Wounds and Injuries; Paraneoplastic Endocrine Syndromes; Paraneoplastic Syndromes; Neoplasms

Study Officials

• Iacopo Chiodini, Professor

  ASST Ospedale Niguarda, Milan, Italy

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elisa Cairoli, MD PhD

CONTACT

+3902691111; e.cairoli@auxologico.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2024
• First Posted: March 21, 2024
• Study Start: April 24, 2023
• Primary Completion: October 24, 2024
• Study Completion: April 24, 2025
• Last Updated: March 21, 2024

Record last verified: 2024-03

Locations

IT (5)