<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/NCT02213276</url>
  </required_header>
  <id_info>
    <org_study_id>2014-e1</org_study_id>
    <nct_id>NCT02213276</nct_id>
  </id_info>
  <brief_title>The Effect of Glucose on Bone - Direct og Indirect?</brief_title>
  <acronym>GLUBONE</acronym>
  <official_title>The Effect of Glucose on Bone - Direct or Indirect?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aarhus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Aarhus</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Diabetes is associated with an increased risk of bone fractures, but current predictors of&#xD;
      bone fracture seem to underestimate this risk. It is commonly known that increased levels of&#xD;
      certain biochemical bone markers predict low-energy fractures, but the pattern of these&#xD;
      markers in diabetics still show heterogeneity and inconsistency. Part of the pathology of&#xD;
      diabetes is a high blood glucose level, and this can potentially influence bone turnover and&#xD;
      thereby bone markers. Chronic inflammation in patients with inflammatory bowel disease is&#xD;
      shown to increase bone resorption, and the same may be the case in diabetics. The purpose of&#xD;
      this project is to investigate whether glucose has a direct effect on bone markers or an&#xD;
      indirect effect through intestinal hormones or inflammatory processes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      Previous studies have shown that Diabetes Mellitus type I (DMI) and II (DMII) is associated&#xD;
      with an increased risk of bone fracture. Paradoxically DMII patients have higher Bone Mineral&#xD;
      Density (BMD) than average, while DMI patients have lower BMD than average. Even the low BMD&#xD;
      of DMI cannot fully explain the extent of fractures found. Known risk factors and BMD&#xD;
      underestimate the risk of fracture amongst DM patients using the 10 year fracture risk tool&#xD;
      'Fracture Risk Assessment Tool' (FRAX). It is well-known that increased levels of biochemical&#xD;
      bone markers predict low-energy fractures. However bone markers in DM patients show both&#xD;
      heterogeneity and inconsistency. Because of this, the predictive value of bone markers is&#xD;
      still uncertain in DM patients. Part of the pathology of DM is a higher blood glucose level&#xD;
      than found in non-diabetics. This high level of blood glucose could potentially influence&#xD;
      bone turnover and thereby bone markers. It is, however, still uncertain whether glucose per&#xD;
      se influences the fracture risk of DM patients. Among young healthy individuals, an Oral&#xD;
      Glucose Tolerance Test (OGTT) reduces the concentration of both resorptive and formative bone&#xD;
      markers. This reduction can be counteracted by the somatostatin analogue, octreotide.&#xD;
      Therefore the effect of glucose on bone markers may be indirect and linked to gut hormone&#xD;
      release. It may also be caused by a direct effect on osteocytes or a change in the chemical&#xD;
      configuration of bone markers, which render them undetectable by standard assays. To examine&#xD;
      this, we have conducted preliminary in vitro trials where glucose was added to serum. This&#xD;
      does not change the level of bone markers and it is therefore unthinkable that glucose per se&#xD;
      affects the assay or causes changed bone marker configuration. The effect of an Intravenous&#xD;
      Glucose Tolerance Test (IVGTT) on bone markers has never been examined. Subcutaneous and&#xD;
      parenteral injection of the gut hormone glucagon-like peptide 2 (GLP-2) dose-dependently&#xD;
      reduces resorptive bone markers, while parenteral GLP-2 entails no change in formative bone&#xD;
      markers. This shows that GLP-2 has an uncoupled effect on bone turnover, where resorption is&#xD;
      inhibited, and formation remains the same.&#xD;
&#xD;
      There is an association between bone turnover, inflammation and glucose. Chronic inflammation&#xD;
      in patients with inflammatory bowel disease increases bone resorption through an increase in&#xD;
      the Receptor Activator of Nuclear factor Kappa beta Ligand/Osteoprotegrin (RANKL/OPG) ratio,&#xD;
      and the same may be the case in DMII. Human endothelial cells augment production of the&#xD;
      inflammatory marker MCP-1 when glucose levels are continuously elevated. RANKL also induces&#xD;
      MCP-1 production in human osteoclasts. An in vitro trial shows, that at blood glucose level&#xD;
      of 24 mM, osteoblasts increases expression of RANKL, production of inflammatory markers,&#xD;
      including MCP-1, and expression of mRNA for the formative bone marker osteocalcin. It has not&#xD;
      yet been examined whether MCP-1 correlates with formative and resorptive bone markers in&#xD;
      vivo. It is therefore still uncertain whether glucose has a direct effect on bone turnover or&#xD;
      an indirect effect via. either GLP-2 or inflammatory processes.&#xD;
&#xD;
      Aim&#xD;
&#xD;
      The aim of this project is to examine whether IVGTT reduces bone marker levels in the same&#xD;
      degree as OGTT does. Also, we examine whether the effect of the glucose load is direct or&#xD;
      indirect through either GLP-2 or inflammatory processes reflected by inflammatory markers.&#xD;
&#xD;
      Perspective&#xD;
&#xD;
      This project will determine whether the effect of glucose on bone markers is direct or&#xD;
      indirect. This knowledge can then be used to explore whether glucose is 'the missing link' in&#xD;
      the present fracture prediction score for DM patients.&#xD;
&#xD;
      Methods&#xD;
&#xD;
      In this project 12 healthy male subjects will undergo both oral glucose tolerance test and&#xD;
      intra venous glucose tolerance test. During the tests bone markers will be measured at&#xD;
      different time intervals and compared to each other. Using these methods it is possible to&#xD;
      distinguish whether glucose acts directly on bone and bone markers or through an intestinal&#xD;
      or inflammatory pathway. Subjects will be recruited from advertising. After signing a consent&#xD;
      form, subjects will fill out a questionaire concerning lifestyle (smoking, alcohol, diet and&#xD;
      exercise), previous fracture and familiar disposition to DM, osteoporosis and thyroid&#xD;
      disease. Bloodpressure, height and weight will be measured.&#xD;
&#xD;
      Statistics&#xD;
&#xD;
      Paired t-test and repeated measurement analysis will be used for the statistical analyses, as&#xD;
      well as linear and logistical regression for adjustment for potential confounders.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>August 2014</start_date>
  <completion_date type="Anticipated">July 2017</completion_date>
  <primary_completion_date type="Anticipated">July 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The resorptive bone marker S-CTX.</measure>
    <time_frame>Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).</time_frame>
    <description>This outcome will be measured for both the oral glucose tolerance test and the intravenous glucose tolerance test, in order to detect differences in bone marker status.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The formative bone marker S-P1NP</measure>
    <time_frame>Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).</time_frame>
    <description>This outcome will be measured for both the oral glucose tolerance test and the intravenous glucose tolerance test, in order to detect differences in bone marker status.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>S-NTX</measure>
    <time_frame>Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).</time_frame>
    <description>Same as for primary outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>S-OC</measure>
    <time_frame>Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).</time_frame>
    <description>Same as for primary outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>RANKL.</measure>
    <time_frame>Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).</time_frame>
    <description>Same as for primary outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory markers.</measure>
    <time_frame>Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).</time_frame>
    <description>Same as for primary outcomes.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Glucose Infusion</condition>
  <condition>Bone Markers</condition>
  <condition>Inflammatory Markers</condition>
  <arm_group>
    <arm_group_label>Healthy males</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT).</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Oral Glucose Tolerance Test (OGTT)</intervention_name>
    <description>At baseline participants are asked to drink a glucose solution consisting of 75 grams of glucose dissolved in 250 ml of water. Meanwhile and 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours later, blood is collected from an intravenous access, in order to asses primary and secondary outcomes.</description>
    <arm_group_label>Healthy males</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Intravenous Glucose Tolerance Test (IVGTT)</intervention_name>
    <description>In this intervention, the participant needs to have two intravenous accesses. In one we infuse an adjustable 20% glucose solution, and try to mimic the glucose profile found in the oral glucose tolerance test. In order to do this, blood glucose is measured every 5 minutes. At baseline and 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours later, blood is collected from another intravenous access, in order to asses primary and secondary outcomes.</description>
    <arm_group_label>Healthy males</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy males&#xD;
&#xD;
          -  Aged 20 - 50 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Chronic diseases, including diabetes, but not allergies&#xD;
&#xD;
          -  Daily medication use&#xD;
&#xD;
          -  Daily dietary supplement use&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Department of Endocrinology and Internal Medicine</name>
      <address>
        <city>Aarhus</city>
        <state>Aarhus C</state>
        <zip>8000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>August 7, 2014</study_first_submitted>
  <study_first_submitted_qc>August 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 11, 2014</study_first_posted>
  <last_update_submitted>June 9, 2015</last_update_submitted>
  <last_update_submitted_qc>June 9, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">June 10, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Glucose infusion</keyword>
  <keyword>Bone markers</keyword>
  <keyword>Inflammatory markers</keyword>
  <!-- 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/NCT02213276
org study id: 2014-e1
nct id: NCT02213276
lead sponsor: 
has dmc: No
Diabetes is associated with an increased risk of bone fractures, but current predictors of
      bone fracture seem to underestimate this risk. It is commonly known that increased levels of
      certain biochemical bone markers predict low-energy fractures, but the pattern of these
      markers in diabetics still show heterogeneity and inconsistency. Part of the pathology of
      diabetes is a high blood glucose level, and this can potentially influence bone turnover and
      thereby bone markers. Chronic inflammation in patients with inflammatory bowel disease is
      shown to increase bone resorption, and the same may be the case in diabetics. The purpose of
      this project is to investigate whether glucose has a direct effect on bone markers or an
      indirect effect through intestinal hormones or inflammatory processes.
Background

      Previous studies have shown that Diabetes Mellitus type I (DMI) and II (DMII) is associated
      with an increased risk of bone fracture. Paradoxically DMII patients have higher Bone Mineral
      Density (BMD) than average, while DMI patients have lower BMD than average. Even the low BMD
      of DMI cannot fully explain the extent of fractures found. Known risk factors and BMD
      underestimate the risk of fracture amongst DM patients using the 10 year fracture risk tool
      'Fracture Risk Assessment Tool' (FRAX). It is well-known that increased levels of biochemical
      bone markers predict low-energy fractures. However bone markers in DM patients show both
      heterogeneity and inconsistency. Because of this, the predictive value of bone markers is
      still uncertain in DM patients. Part of the pathology of DM is a higher blood glucose level
      than found in non-diabetics. This high level of blood glucose could potentially influence
      bone turnover and thereby bone markers. It is, however, still uncertain whether glucose per
      se influences the fracture risk of DM patients. Among young healthy individuals, an Oral
      Glucose Tolerance Test (OGTT) reduces the concentration of both resorptive and formative bone
      markers. This reduction can be counteracted by the somatostatin analogue, octreotide.
      Therefore the effect of glucose on bone markers may be indirect and linked to gut hormone
      release. It may also be caused by a direct effect on osteocytes or a change in the chemical
      configuration of bone markers, which render them undetectable by standard assays. To examine
      this, we have conducted preliminary in vitro trials where glucose was added to serum. This
      does not change the level of bone markers and it is therefore unthinkable that glucose per se
      affects the assay or causes changed bone marker configuration. The effect of an Intravenous
      Glucose Tolerance Test (IVGTT) on bone markers has never been examined. Subcutaneous and
      parenteral injection of the gut hormone glucagon-like peptide 2 (GLP-2) dose-dependently
      reduces resorptive bone markers, while parenteral GLP-2 entails no change in formative bone
      markers. This shows that GLP-2 has an uncoupled effect on bone turnover, where resorption is
      inhibited, and formation remains the same.

      There is an association between bone turnover, inflammation and glucose. Chronic inflammation
      in patients with inflammatory bowel disease increases bone resorption through an increase in
      the Receptor Activator of Nuclear factor Kappa beta Ligand/Osteoprotegrin (RANKL/OPG) ratio,
      and the same may be the case in DMII. Human endothelial cells augment production of the
      inflammatory marker MCP-1 when glucose levels are continuously elevated. RANKL also induces
      MCP-1 production in human osteoclasts. An in vitro trial shows, that at blood glucose level
      of 24 mM, osteoblasts increases expression of RANKL, production of inflammatory markers,
      including MCP-1, and expression of mRNA for the formative bone marker osteocalcin. It has not
      yet been examined whether MCP-1 correlates with formative and resorptive bone markers in
      vivo. It is therefore still uncertain whether glucose has a direct effect on bone turnover or
      an indirect effect via. either GLP-2 or inflammatory processes.

      Aim

      The aim of this project is to examine whether IVGTT reduces bone marker levels in the same
      degree as OGTT does. Also, we examine whether the effect of the glucose load is direct or
      indirect through either GLP-2 or inflammatory processes reflected by inflammatory markers.

      Perspective

      This project will determine whether the effect of glucose on bone markers is direct or
      indirect. This knowledge can then be used to explore whether glucose is 'the missing link' in
      the present fracture prediction score for DM patients.

      Methods

      In this project 12 healthy male subjects will undergo both oral glucose tolerance test and
      intra venous glucose tolerance test. During the tests bone markers will be measured at
      different time intervals and compared to each other. Using these methods it is possible to
      distinguish whether glucose acts directly on bone and bone markers or through an intestinal
      or inflammatory pathway. Subjects will be recruited from advertising. After signing a consent
      form, subjects will fill out a questionaire concerning lifestyle (smoking, alcohol, diet and
      exercise), previous fracture and familiar disposition to DM, osteoporosis and thyroid
      disease. Bloodpressure, height and weight will be measured.

      Statistics

      Paired t-test and repeated measurement analysis will be used for the statistical analyses, as
      well as linear and logistical regression for adjustment for potential confounders.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: The resorptive bone marker S-CTX.
time frame: Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).
description: This outcome will be measured for both the oral glucose tolerance test and the intravenous glucose tolerance test, in order to detect differences in bone marker status.
measure: The formative bone marker S-P1NP
time frame: Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).
description: This outcome will be measured for both the oral glucose tolerance test and the intravenous glucose tolerance test, in order to detect differences in bone marker status.
measure: S-NTX
time frame: Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).
description: Same as for primary outcome.
measure: S-OC
time frame: Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).
description: Same as for primary outcome.
measure: RANKL.
time frame: Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).
description: Same as for primary outcomes.
measure: Inflammatory markers.
time frame: Change from baseline (at 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours).
description: Same as for primary outcomes.
arm group label: Healthy males
arm group type: Experimental
description: Oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT).
intervention type: Other
intervention name: Oral Glucose Tolerance Test (OGTT)
description: At baseline participants are asked to drink a glucose solution consisting of 75 grams of glucose dissolved in 250 ml of water. Meanwhile and 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours later, blood is collected from an intravenous access, in order to asses primary and secondary outcomes.
arm group label: Healthy males
intervention type: Other
intervention name: Intravenous Glucose Tolerance Test (IVGTT)
description: In this intervention, the participant needs to have two intravenous accesses. In one we infuse an adjustable 20% glucose solution, and try to mimic the glucose profile found in the oral glucose tolerance test. In order to do this, blood glucose is measured every 5 minutes. At baseline and 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours later, blood is collected from another intravenous access, in order to asses primary and secondary outcomes.
arm group label: Healthy males
criteria: 
gender: Male
minimum age: 20 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Denmark
responsible party type: Sponsor