<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02216721</url>
  </required_header>
  <id_info>
    <org_study_id>FF-2014-267</org_study_id>
    <nct_id>NCT02216721</nct_id>
  </id_info>
  <brief_title>The Effect of Disease-specific Treatment on Bone Turnover Markers in Patients With Primary Aldosteronism</brief_title>
  <official_title>The Effect of Disease-specific Treatment on Bone Turnover Markers in Patients With Primary Aldosteronism</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Malaysia Sarawak</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Malaysia Sarawak</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary aldosteronism (PA) is a disorder of the adrenal gland causing an autonomous&#xD;
      overproduction of mineralocorticoids, leading to arterial hypertension. Although rare, it is&#xD;
      the most frequent cause of secondary hypertension. Early detection is important to avoid end&#xD;
      organ damage, specifically cardiovascular and metabolic morbidity. Recent studies showed a&#xD;
      positive correlation between patients with PA with lower bone density especially at the&#xD;
      spine, with significant improvement post treatment, either medically or surgically. There was&#xD;
      also a positive correlation between high aldosterone renin ratio with higher levels of intact&#xD;
      parathyroid hormone (iPTH) which is responsible for cortical bone loss especially at the&#xD;
      distal forearm.&#xD;
&#xD;
      We hypothesize that our patients with PA have a higher level of iPTH, with lower bone density&#xD;
      especially at the distal forearm, with improvement post treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In 2004, through an animal model study, rats given aldosterone/salt treatment were found to&#xD;
      have reduction in bone mineral density (BMD) and cortical bone strength. This was believed to&#xD;
      be due to hypermagnesuria and hypercalciuria leading to bone loss.&#xD;
&#xD;
      This led to subsequent studies which found the association between PA with low serum ionized&#xD;
      calcium, increased urine calcium and magnesium, raised intact parathyroid hormone (PTH)&#xD;
      levels with subsequent low bone mineral density.&#xD;
&#xD;
      In one small study of 11 patients with confirmed PA taken from a cohort of 188 patients with&#xD;
      adrenal incidentaloma, BMD of vertebral, total and neck of femur was found to be lower than&#xD;
      non-PA patients, with a higher prevalence of vertebral osteoporotic fractures (72.7% among PA&#xD;
      patients vs 20% among non-PA patients). Serum PTH was significantly higher in PA group&#xD;
      compared to non-PA group. Six months of treatment either medically or surgically led to&#xD;
      significant decrease of urinary calcium excretion and PTH in PA group. Lumbar spine BMD&#xD;
      showed significant improvement one year after treatment in 5 patients.&#xD;
&#xD;
      The cross-sectional and interventional data from the GECOH study, which was conducted in a&#xD;
      tertiary center in Austria on patients confirmed to have PA, looked at differences in PTH&#xD;
      levels between patients with PA (n=10) and essential hypertension (EH) (n=182) and found PTH&#xD;
      levels to be significantly higher in PA patients compared with EH group. Treatment with&#xD;
      either adrenalectomy or mineralocorticoid receptor antagonists led to a significant decrease&#xD;
      of PTH concentrations. Both of these studies had no significant differences in serum Vitamin&#xD;
      D level in both cases and controls, as well as pre and post treatment for PA patients.&#xD;
      However in the latter study, PTH reduction was found to be more significant in PA patients&#xD;
      who underwent adrenalectomy compared to patients treated medically with mineralocorticoid&#xD;
      receptor antagonists.&#xD;
&#xD;
      A recent large-scale study on more than 3000 German general adult population showed a&#xD;
      significant but non linear association between aldosterone-renin ratio with plasma PTH&#xD;
      concentrations, especially in subjects with ARR&gt;90th percentile, despite normal Vitamin D&#xD;
      levels. This was believed to be due to the presence of parathyroid receptors type 1 in the&#xD;
      adrenals as well as the parathyroid glands expressing mineralocorticoid receptors. However,&#xD;
      calcium intake status as well as calcium levels were not assessed in this study.&#xD;
&#xD;
      This findings were all echoed in a few other studies which showed a positive association&#xD;
      between PTH levels with PA which was not affected by Vitamin D status.&#xD;
&#xD;
      It is well known that high PTH level is associated with low bone mass and higher osteoporotic&#xD;
      fracture risk due to the stimulation effect of PTH on the osteoclastic and osteoblastic&#xD;
      activity of the bones resulting in the release of calcium and phosphate from the bone.&#xD;
&#xD;
      Up to date, to our knowledge, there has been no study on the association between PA with bone&#xD;
      turnover markers. The use of this sensitive marker as a surrogate indicator of improvement in&#xD;
      bone mass pre and post treatment in patients with PA either medically or surgically is novel.&#xD;
      The relationship between calcium intake in the patients with the bone metabolism and blood&#xD;
      parameters were not looked into previously. In addition, the involvement of peripheral&#xD;
      cortical bone mass (distal radius), which is usually associated with elevated PTH, in this&#xD;
      group of patients has not been studied.&#xD;
&#xD;
      In this study, we aim to:&#xD;
&#xD;
        1. Assess the BMD of vertebrae, total and femoral neck, and distal third radius in PA&#xD;
           patients compared to non-PA.&#xD;
&#xD;
        2. Evaluate the effect of specific treatments on bone turnover markers and BMD in patients&#xD;
           with PA&#xD;
&#xD;
        3. Assess the relationship between BMD and bone turnover markers with serum iPTH, calcium,&#xD;
           magnesium and vitamin D levels.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">May 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Bone mineral density</measure>
    <time_frame>3 months</time_frame>
    <description>Change of bone mineral density 3 months post treatment for primary aldosteronism</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Bone turnover markers</measure>
    <time_frame>3 months</time_frame>
    <description>Change of bone turnover markers 3 months post treatment for primary aldosteronism</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">35</enrollment>
  <condition>Primary Aldosteronism</condition>
  <arm_group>
    <arm_group_label>Non primary aldosteronism</arm_group_label>
    <description>Non primary aldosteronism patients undergoing usual anti hypertensive treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Primary Aldosteronism</arm_group_label>
    <description>Patients with confirmed primary aldosteronism undergoing treatment</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        This is a prospective study conducted in out-patient clinics of a tertiary care center. The&#xD;
        study population consists of patients referred to our centres for endocrine hypertension.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &gt;18 years old&#xD;
&#xD;
          2. Confirmed primary aldosteronism with following criteria i) Aldosterone-renin ratio &gt;&#xD;
             555 SI or 30 (if aldosterone is taken in pmol/L, renin in ng/dL) and ii) Aldosterone&#xD;
             post fludrocortisone suppression test &gt; 166pmol/L or &gt;6ng/dL, or iii) Aldosterone post&#xD;
             saline suppression test &gt;277pmol/L or &gt;10ng/dL&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Patients on medication affecting bone metabolism, eg bisphosphonates, hormonal&#xD;
             replacement therapy, SERM, testosterone, antiandrogen, anticonvulsants, calcium and&#xD;
             Vitamin D&#xD;
&#xD;
          2. Primary aldosteronism post treatment (surgically or medically on spironolactone or&#xD;
             eplerenone)&#xD;
&#xD;
          3. Estimated GFR &lt;30ml/min&#xD;
&#xD;
          4. Severe hepatic failure&#xD;
&#xD;
          5. Severe heart failure&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hospital Universiti Kebangsaan Malaysia</name>
      <address>
        <city>Kuala Lumpur</city>
        <state>WP Kuala Lumpur</state>
        <zip>56000</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Malaysia</country>
  </location_countries>
  <verification_date>November 2015</verification_date>
  <study_first_submitted>August 12, 2014</study_first_submitted>
  <study_first_submitted_qc>August 13, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 15, 2014</study_first_posted>
  <last_update_submitted>November 30, 2015</last_update_submitted>
  <last_update_submitted_qc>November 30, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 2, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Malaysia Sarawak</investigator_affiliation>
    <investigator_full_name>Dr Huai Heng, Loh</investigator_full_name>
    <investigator_title>Dr</investigator_title>
  </responsible_party>
  <keyword>bone mineral density</keyword>
  <keyword>bone turnover markers</keyword>
  <keyword>primary aldosteronism treatment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyperaldosteronism</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02216721
org study id: FF-2014-267
nct id: NCT02216721
lead sponsor: 
has dmc: Yes
Primary aldosteronism (PA) is a disorder of the adrenal gland causing an autonomous
      overproduction of mineralocorticoids, leading to arterial hypertension. Although rare, it is
      the most frequent cause of secondary hypertension. Early detection is important to avoid end
      organ damage, specifically cardiovascular and metabolic morbidity. Recent studies showed a
      positive correlation between patients with PA with lower bone density especially at the
      spine, with significant improvement post treatment, either medically or surgically. There was
      also a positive correlation between high aldosterone renin ratio with higher levels of intact
      parathyroid hormone (iPTH) which is responsible for cortical bone loss especially at the
      distal forearm.

      We hypothesize that our patients with PA have a higher level of iPTH, with lower bone density
      especially at the distal forearm, with improvement post treatment.
In 2004, through an animal model study, rats given aldosterone/salt treatment were found to
      have reduction in bone mineral density (BMD) and cortical bone strength. This was believed to
      be due to hypermagnesuria and hypercalciuria leading to bone loss.

      This led to subsequent studies which found the association between PA with low serum ionized
      calcium, increased urine calcium and magnesium, raised intact parathyroid hormone (PTH)
      levels with subsequent low bone mineral density.

      In one small study of 11 patients with confirmed PA taken from a cohort of 188 patients with
      adrenal incidentaloma, BMD of vertebral, total and neck of femur was found to be lower than
      non-PA patients, with a higher prevalence of vertebral osteoporotic fractures (72.7% among PA
      patients vs 20% among non-PA patients). Serum PTH was significantly higher in PA group
      compared to non-PA group. Six months of treatment either medically or surgically led to
      significant decrease of urinary calcium excretion and PTH in PA group. Lumbar spine BMD
      showed significant improvement one year after treatment in 5 patients.

      The cross-sectional and interventional data from the GECOH study, which was conducted in a
      tertiary center in Austria on patients confirmed to have PA, looked at differences in PTH
      levels between patients with PA (n=10) and essential hypertension (EH) (n=182) and found PTH
      levels to be significantly higher in PA patients compared with EH group. Treatment with
      either adrenalectomy or mineralocorticoid receptor antagonists led to a significant decrease
      of PTH concentrations. Both of these studies had no significant differences in serum Vitamin
      D level in both cases and controls, as well as pre and post treatment for PA patients.
      However in the latter study, PTH reduction was found to be more significant in PA patients
      who underwent adrenalectomy compared to patients treated medically with mineralocorticoid
      receptor antagonists.

      A recent large-scale study on more than 3000 German general adult population showed a
      significant but non linear association between aldosterone-renin ratio with plasma PTH
      concentrations, especially in subjects with ARR>90th percentile, despite normal Vitamin D
      levels. This was believed to be due to the presence of parathyroid receptors type 1 in the
      adrenals as well as the parathyroid glands expressing mineralocorticoid receptors. However,
      calcium intake status as well as calcium levels were not assessed in this study.

      This findings were all echoed in a few other studies which showed a positive association
      between PTH levels with PA which was not affected by Vitamin D status.

      It is well known that high PTH level is associated with low bone mass and higher osteoporotic
      fracture risk due to the stimulation effect of PTH on the osteoclastic and osteoblastic
      activity of the bones resulting in the release of calcium and phosphate from the bone.

      Up to date, to our knowledge, there has been no study on the association between PA with bone
      turnover markers. The use of this sensitive marker as a surrogate indicator of improvement in
      bone mass pre and post treatment in patients with PA either medically or surgically is novel.
      The relationship between calcium intake in the patients with the bone metabolism and blood
      parameters were not looked into previously. In addition, the involvement of peripheral
      cortical bone mass (distal radius), which is usually associated with elevated PTH, in this
      group of patients has not been studied.

      In this study, we aim to:

        1. Assess the BMD of vertebrae, total and femoral neck, and distal third radius in PA
           patients compared to non-PA.

        2. Evaluate the effect of specific treatments on bone turnover markers and BMD in patients
           with PA

        3. Assess the relationship between BMD and bone turnover markers with serum iPTH, calcium,
           magnesium and vitamin D levels.
observational model: Case-Control
time perspective: Prospective
measure: Bone mineral density
time frame: 3 months
description: Change of bone mineral density 3 months post treatment for primary aldosteronism
measure: Bone turnover markers
time frame: 3 months
description: Change of bone turnover markers 3 months post treatment for primary aldosteronism
arm group label: Non primary aldosteronism
description: Non primary aldosteronism patients undergoing usual anti hypertensive treatment
arm group label: Primary Aldosteronism
description: Patients with confirmed primary aldosteronism undergoing treatment
Blood samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Malaysia
responsible party type: Principal Investigator
investigator affiliation: University Malaysia Sarawak
investigator full name: Dr Huai Heng, Loh
investigator title: Dr
mesh term: Hyperaldosteronism