Ignite Creation Date:
2024-05-06 @ 8:16 PM
Last Modification Date:
2024-10-26 @ 3:24 PM
Study NCT ID:
NCT06324084
Status:
RECRUITING
Last Update Posted:
2024-03-21
First Post:
2024-03-07
Brief Title:
PATHophysiology of OSteoporosis Role of Hidden Cortisol Excess and Its Predictors in Bone Fragility
Sponsor:
Istituto Auxologico Italiano
Organization:
Istituto Auxologico Italiano
Study Overview
Official Title:
Pathophysiology of Osteoporosis Role of Hidden Cortisol Excess and Its Predictors in Bone Fragility PNRR-MAD-2022-12375951
Status:
RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PATHOS
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 osteoporoticosteopenic 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 osteopenicosteoporotic 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
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 osteoporoticosteopenic 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 osteopenicosteoporotic 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
Detailed Description:
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 02-2 but it has been reported up to 99 and 176 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 andor 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
In all patients who have been included in the study and who have given the informed consent to participate in the study 1 mg overnight dexamethasone suppression test F-1mgDST will be performed In all subjects with F-1mgDST 18 mcgdL cortisol levels after two-day low dose 2 mgday dexamethasone suppression test F-2mgx2dDST will be measured
Patients with F-2mgx2dDST above 18 mcgdL will be considered affected with HidHyCo and will be managed following the available guidelines for hypercortisolism
The HidHyCo prevalence in osteopenicosteoporotic patients and its 95 interval confidence will be calculated
Moreover in all recruited patients the following vital and anthropometric parameters will be recorded blood pressure heart rate weight height body mass index BMI abdominal circumference and waist-to-hip ratio Moreover the following variables will be collected familiar history of fragility fracture smoking habit main comorbidities history of falls previous clinical fragility fractures ongoing pharmacological treatment in particular type and number of antihypertensive lipid lowering anti-diabetic and anti-osteoporotic drugs previous anti-osteoporotic treatments in females regularity of menses or age of menopause and in males testosterone levels Questionnaires for assessing daily calcium intake and physical activity will be administered to all patients At the time of enrolment the results of first tier investigations according to national guidelines ie serum erythrocyte sedimentation rate complete blood count serum protein electrophoresis serum calcium levels serum phosphate levels total alkaline phosphatase serum creatinine 24-h urinary calcium will be also registered Moreover other calcium-phosphate metabolism parameters ie serum ionized calcium serum parathyroid hormone serum 25-OH-vitamin D serum ß-CrossLaps bone alkaline phosphatase and routine determinations ie fasting glucose insulin glycated haemoglobin total cholesterol low density lipoprotein high density lipoprotein triglycerides transaminases will be recorded if available
According to the good clinical practice in all patients bone mineral density will be assessed by dual-energy X-ray Absorptiometry Hologic or Lunar bone densitometers and the presence of asymptomatic vertebral fractures will be checked by conventional spinal radiographs using the semi-quantitative visual assessment described by Genant et al defined as a reduction of 20 in anterior middle or posterior vertebral height
The investigators will compare the clinical and biochemical characteristics of osteoporoticosteopenic patients with HidHyCo and those without HidHyCo The sample size has been calculated in order to have an adequate number of HidHyCo cases to determine the characteristics of osteoporotic patients suggestive for the presence of HidHyCo Since HidHyCo may be estimated to have at least a 3 prevalence in osteoporotic patients a sample of 1500 osteoporotic patients should be adequate to find no less than 45 HidHyCo cases
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 subtle cortisol excess on bone health and the potential role of the genetic background and of the gut microbiome
In patients found to be affected with HidHyCo and in age- sex- and BMI-matched patients without HidHyCo with a case-control ratio of 12 the investigators will
i assess bone turnover markers and new potential serum markers of bone status such as those involved in the Wnt-ßcatenin signaling ii perform Radiofrequency echographic multi spectrometry REMS a non-ionizing skeleton technique performed employing a new dedicated echographic device EchoStation Echolight Spa Lecce Italy to further investigate bone quality characteristics that are not included in DXA-measured BMD such as the Fragility Score FS
iii assess circulating microRNAs miRNAs ie small non coding single-stranded RNAs that have emerged as important post transcriptional regulators of gene expression expression profile iv assess cortisol peripheral activation as expressed by the 24-hour urinary free cortisolfree cortisone ratio ie the higher the R-UFFUFE the higher tissues exposure to active glucocorticoids measured by liquid chromatography-tandem mass spectrometry and its relationship with the polymorphic variants of the 11beta-hydroxysteroid dehydrogenase type 1 11ßHSD1 gene v assess cortisol sensitivity expressed by the polymorphisms of the glucocorticoid receptor GR gene from DNA isolated from peripheral blood vi assess beta-2 adrenergic activity regulated by the polymorphism rs1800544 of the beta-2 adrenergic receptor B2AR gene from DNA isolated from peripheral blood which could have an impact on cortisol effect due to the multiple interactions between the sympathetic and the hypothalamic-pituitary-adrenal systems via adrenoceptors vii assess gut microbiome composition using fecal samples To avoid the confounding effect of bone-active drugs i ii and iii will not be assessed in patients on treatment with bone-active drugs but exclusively in naïve-treatment patients or in patients not recently treated over 12 months previously for oral bisphosphonates and teriparatide and over 24 months previously for intravenous bisphosphonates and denosumab
The HidHyCo case finding is of utmost importance since an underlying condition of HidHyco is associated with an increased risk of osteoporosis and fragility fractures and can decrease the response to bone-active drugs Conversely the resolution of cortisol excess can result in the improvement of bone strength and in the reduction of fracture risk However HidHyCo is by definition an occult condition until its presence is suspected on the basis of particular characteristics of the underlying disease
Based on preliminary data it is possible to assume that HidHyCo is present in a not negligible percentage of osteopenicosteoporotic patients
The investigators hypothesize a 3 HidHyCo prevalence in the osteoporotic population The presence of osteoporosis associated with a poorly controlled hypertension andor diabetes or with a history of cardiovascular events osteopenia with comorbidities or the presence of fragility fractures in the presence of not osteoporotic bone density in an eugonadal state andor on osteoporotic treatment with bone-active drugs may be the variables potentially associated with an increased probability of having HidHyCo
By testing our sample of osteoporotic patients for HidHyCo the investigators aim at obtaining information regarding the pre-test probability of a single individual of having a subtle cortisol excess and if feasible at developing a clinical model for the identification in outpatient osteoporosis clinics of subjects worthy of HidHyCo testing thus avoiding a mass screening
Moreover the evaluation of circulating miRNAs expression profile can help to distinguish primary osteoporosis and secondary osteoporosis due to subtle cortisol excess
From a pathophysiological point of view the condition of HidHyCo in our patients differently from the exogenous hypercortisolism may represent a pure form of slight cortisol excess without the confounding effect of the diseases for which therapeutic glucocorticoids are given Therefore the assessment of bone involvement in HidHyCo patients may consent to evaluate the pure role of glucocorticoid excess on bone metabolism and bone quality as expressed for example by the markers of bone turnover and of the Wnt-ß-catenin signaling and by the REMS parameters respectively
In addition the glucocorticoid secretion and sensitivity evaluation in our osteoporotic population can also consent us to study the impact of cortisol peripheral activation and of the polymorphisms of 11ßHSD1 GR and B2AR genes in modulating the skeletal sensitivity and damage to the subtle cortisol excess
If the importance of these parameters for bone health was confirmed it would be possible to personalize the clinical workup on the basis of the individual risk of fracture and to try to counteract in selected patients the adverse effects of the relatively increased cortisol secretion with the 11ßHSD1 inhibitors Indeed some studies showed that the inhibition of the 11ßHSD1 may protect bone against the deleterious effects of glucocorticoids
Finally investigators will obtain information on whether or not microbiome composition differs between osteoporotic patients with and without HydHyCo This information could suggest new pathophysiological mechanisms underlying the relationship between cortisol excess and bone fragility
If there were interactions between these factors microbiome and cortisol milieu on the clinical outcomes of bone fragility investigators might suggest the gut as a novel therapeutic target for preventing the adverse systemic effects of cortisol excess as suggested by experimental observations Overall information from this study will make possible to unmask the presence of HidHyCo in patients evaluated for osteoporosis andor bone fragility and to personalize the clinical management of these patients in relation to the genetic background the GC sensitivity and the microbiome composition
The HidHyCo prevalence in the general population is estimated to be 02-2 but it has been reported up to 99 and 176 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 andor 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
In all patients who have been included in the study and who have given the informed consent to participate in the study 1 mg overnight dexamethasone suppression test F-1mgDST will be performed In all subjects with F-1mgDST 18 mcgdL cortisol levels after two-day low dose 2 mgday dexamethasone suppression test F-2mgx2dDST will be measured
Patients with F-2mgx2dDST above 18 mcgdL will be considered affected with HidHyCo and will be managed following the available guidelines for hypercortisolism
The HidHyCo prevalence in osteopenicosteoporotic patients and its 95 interval confidence will be calculated
Moreover in all recruited patients the following vital and anthropometric parameters will be recorded blood pressure heart rate weight height body mass index BMI abdominal circumference and waist-to-hip ratio Moreover the following variables will be collected familiar history of fragility fracture smoking habit main comorbidities history of falls previous clinical fragility fractures ongoing pharmacological treatment in particular type and number of antihypertensive lipid lowering anti-diabetic and anti-osteoporotic drugs previous anti-osteoporotic treatments in females regularity of menses or age of menopause and in males testosterone levels Questionnaires for assessing daily calcium intake and physical activity will be administered to all patients At the time of enrolment the results of first tier investigations according to national guidelines ie serum erythrocyte sedimentation rate complete blood count serum protein electrophoresis serum calcium levels serum phosphate levels total alkaline phosphatase serum creatinine 24-h urinary calcium will be also registered Moreover other calcium-phosphate metabolism parameters ie serum ionized calcium serum parathyroid hormone serum 25-OH-vitamin D serum ß-CrossLaps bone alkaline phosphatase and routine determinations ie fasting glucose insulin glycated haemoglobin total cholesterol low density lipoprotein high density lipoprotein triglycerides transaminases will be recorded if available
According to the good clinical practice in all patients bone mineral density will be assessed by dual-energy X-ray Absorptiometry Hologic or Lunar bone densitometers and the presence of asymptomatic vertebral fractures will be checked by conventional spinal radiographs using the semi-quantitative visual assessment described by Genant et al defined as a reduction of 20 in anterior middle or posterior vertebral height
The investigators will compare the clinical and biochemical characteristics of osteoporoticosteopenic patients with HidHyCo and those without HidHyCo The sample size has been calculated in order to have an adequate number of HidHyCo cases to determine the characteristics of osteoporotic patients suggestive for the presence of HidHyCo Since HidHyCo may be estimated to have at least a 3 prevalence in osteoporotic patients a sample of 1500 osteoporotic patients should be adequate to find no less than 45 HidHyCo cases
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 subtle cortisol excess on bone health and the potential role of the genetic background and of the gut microbiome
In patients found to be affected with HidHyCo and in age- sex- and BMI-matched patients without HidHyCo with a case-control ratio of 12 the investigators will
i assess bone turnover markers and new potential serum markers of bone status such as those involved in the Wnt-ßcatenin signaling ii perform Radiofrequency echographic multi spectrometry REMS a non-ionizing skeleton technique performed employing a new dedicated echographic device EchoStation Echolight Spa Lecce Italy to further investigate bone quality characteristics that are not included in DXA-measured BMD such as the Fragility Score FS
iii assess circulating microRNAs miRNAs ie small non coding single-stranded RNAs that have emerged as important post transcriptional regulators of gene expression expression profile iv assess cortisol peripheral activation as expressed by the 24-hour urinary free cortisolfree cortisone ratio ie the higher the R-UFFUFE the higher tissues exposure to active glucocorticoids measured by liquid chromatography-tandem mass spectrometry and its relationship with the polymorphic variants of the 11beta-hydroxysteroid dehydrogenase type 1 11ßHSD1 gene v assess cortisol sensitivity expressed by the polymorphisms of the glucocorticoid receptor GR gene from DNA isolated from peripheral blood vi assess beta-2 adrenergic activity regulated by the polymorphism rs1800544 of the beta-2 adrenergic receptor B2AR gene from DNA isolated from peripheral blood which could have an impact on cortisol effect due to the multiple interactions between the sympathetic and the hypothalamic-pituitary-adrenal systems via adrenoceptors vii assess gut microbiome composition using fecal samples To avoid the confounding effect of bone-active drugs i ii and iii will not be assessed in patients on treatment with bone-active drugs but exclusively in naïve-treatment patients or in patients not recently treated over 12 months previously for oral bisphosphonates and teriparatide and over 24 months previously for intravenous bisphosphonates and denosumab
The HidHyCo case finding is of utmost importance since an underlying condition of HidHyco is associated with an increased risk of osteoporosis and fragility fractures and can decrease the response to bone-active drugs Conversely the resolution of cortisol excess can result in the improvement of bone strength and in the reduction of fracture risk However HidHyCo is by definition an occult condition until its presence is suspected on the basis of particular characteristics of the underlying disease
Based on preliminary data it is possible to assume that HidHyCo is present in a not negligible percentage of osteopenicosteoporotic patients
The investigators hypothesize a 3 HidHyCo prevalence in the osteoporotic population The presence of osteoporosis associated with a poorly controlled hypertension andor diabetes or with a history of cardiovascular events osteopenia with comorbidities or the presence of fragility fractures in the presence of not osteoporotic bone density in an eugonadal state andor on osteoporotic treatment with bone-active drugs may be the variables potentially associated with an increased probability of having HidHyCo
By testing our sample of osteoporotic patients for HidHyCo the investigators aim at obtaining information regarding the pre-test probability of a single individual of having a subtle cortisol excess and if feasible at developing a clinical model for the identification in outpatient osteoporosis clinics of subjects worthy of HidHyCo testing thus avoiding a mass screening
Moreover the evaluation of circulating miRNAs expression profile can help to distinguish primary osteoporosis and secondary osteoporosis due to subtle cortisol excess
From a pathophysiological point of view the condition of HidHyCo in our patients differently from the exogenous hypercortisolism may represent a pure form of slight cortisol excess without the confounding effect of the diseases for which therapeutic glucocorticoids are given Therefore the assessment of bone involvement in HidHyCo patients may consent to evaluate the pure role of glucocorticoid excess on bone metabolism and bone quality as expressed for example by the markers of bone turnover and of the Wnt-ß-catenin signaling and by the REMS parameters respectively
In addition the glucocorticoid secretion and sensitivity evaluation in our osteoporotic population can also consent us to study the impact of cortisol peripheral activation and of the polymorphisms of 11ßHSD1 GR and B2AR genes in modulating the skeletal sensitivity and damage to the subtle cortisol excess
If the importance of these parameters for bone health was confirmed it would be possible to personalize the clinical workup on the basis of the individual risk of fracture and to try to counteract in selected patients the adverse effects of the relatively increased cortisol secretion with the 11ßHSD1 inhibitors Indeed some studies showed that the inhibition of the 11ßHSD1 may protect bone against the deleterious effects of glucocorticoids
Finally investigators will obtain information on whether or not microbiome composition differs between osteoporotic patients with and without HydHyCo This information could suggest new pathophysiological mechanisms underlying the relationship between cortisol excess and bone fragility
If there were interactions between these factors microbiome and cortisol milieu on the clinical outcomes of bone fragility investigators might suggest the gut as a novel therapeutic target for preventing the adverse systemic effects of cortisol excess as suggested by experimental observations Overall information from this study will make possible to unmask the presence of HidHyCo in patients evaluated for osteoporosis andor bone fragility and to personalize the clinical management of these patients in relation to the genetic background the GC sensitivity and the microbiome composition
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None