<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/NCT03812367</url>
  </required_header>
  <id_info>
    <org_study_id>1030286</org_study_id>
    <nct_id>NCT03812367</nct_id>
  </id_info>
  <brief_title>Activity of Pre-Osteoclasts and Osteoclasts Over Time in Postmenopausal Women Treated With Denosumab or Zoledronic Acid</brief_title>
  <official_title>Prospective Study to Assess Changes in the Number and Activity of Pre-Osteoclasts and Osteoclasts Over Time in Postmenopausal Women Treated With Denosumab or Zoledronic Acid</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, Davis</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, Davis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates how patients treated with denosumab or zoledronic acid for osteoporosis&#xD;
      may change the number of peripheral osteoclast precursors and osteoclast activity, and how&#xD;
      that may be associated with changes in bone mass.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Postmenopausal osteoporosis is the leading cause of low trauma fractures. At the time of&#xD;
      menopause there is an uncoupling of bone turnover, with osteoclast mediated bone resorption&#xD;
      increased more than bone formation, resulting in both loss of bone mass and architecture such&#xD;
      that bone fractures with very little force.&#xD;
&#xD;
      Bisphosphonates are commonly used to treat postmenopausal osteoporosis, although the&#xD;
      mechanisms of their action on bone are not completely understood. Gossiel and colleagues&#xD;
      recently examined the effects of ibandronate, alendronate and risedronate on osteoclast&#xD;
      precursor cells in a study of women (n=62) with postmenopausal osteoporosis. Fasting serum&#xD;
      was collected at baseline and after 1 and 48 weeks of bisphosphonate treatment.&#xD;
      Fluorescent-activated cell sorting (FACS)-Calibur was used to extract peripheral blood&#xD;
      mononuclear cells (PBMC), and cells were stained for receptors of macrophage colony&#xD;
      stimulating factor (M-CSFR) and tumor necrosis factor 2 (TNFR2), as well as adhesion&#xD;
      molecules (CD11b and CD14). These cell surface antigens are important for osteoclast&#xD;
      differentiation and activity. Osteoclast precursor cells were identified using flow cytometry&#xD;
      to find cells that were dual positive (CD14+/M-CSFR+, CD14+/CD11b+, CD14+/TNFR2+). Results&#xD;
      showed a significant (p&lt;0.01) reduction in in expression of M-CSFR (53% decrease) and CD11b&#xD;
      (49% decrease) after 48 weeks of treatment, suggesting that the action of bisphosphonates on&#xD;
      mature osteoclasts may be mediated by reduction of osteoclast precursor cells.&#xD;
&#xD;
      Treatment with denosumab (a monoclonal antibody that blocks the ability of receptor activator&#xD;
      of NFκB ligand [RANKL] to bind to its receptor RANK on the osteoclast surface and inhibits&#xD;
      the maturation and activity of osteoclasts) has been found to increase bone mineral density&#xD;
      (BMD) at the lumbar spine and hip in both postmenopausal women and elderly men with&#xD;
      osteopenia. However, after denosumab is discontinued there can be a rapid loss of BMD and an&#xD;
      increased incidence of vertebral fractures. Current data suggests that the incidence of&#xD;
      vertebral fracrure increases to levels similar to placebo after denosumab discontinuation,&#xD;
      and only the incidence of multiple vertebral fracture is higher after denosumab&#xD;
      discontinuation compared with placebo discontinuation, though further research is needed. The&#xD;
      increase in the observed bone loss may be from increased osteoclast maturation and activity,&#xD;
      or an change in the number circulating monocytes (the precursors of osteoclasts) during the&#xD;
      denosumab treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    The Investigator decided not to pursue this study.&#xD;
  </why_stopped>
  <start_date type="Actual">January 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">June 1, 2021</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>Percent change in osteoclast circulation</measure>
    <time_frame>1 month, 6 months, 12 months</time_frame>
    <description>Percent change (%Δ) from baseline in number of circulating osteoclast precursor cells by FACS analysis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent change in osteoclast maturation and activity</measure>
    <time_frame>1 month, 6 months, 12 months</time_frame>
    <description>Percent change (%Δ) in osteoclast maturation and activity, as assessed by resorption on dentin slides and expression of genes critical for osteoclast differentiation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent change in number of TRAP cells</measure>
    <time_frame>1 month, 6 months, 12 months</time_frame>
    <description>Percent change (%Δ) from baseline in the number of tartrate-resistant acid phosphatase (TRAP)+cells with 3 or mor nuclei by in vitro maturation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent change in bone mass density</measure>
    <time_frame>1 month, 6 months, 12 months</time_frame>
    <description>Percent change (%Δ) from baseline in BMD at the total hip and lumbar spine</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent change in bone turnover markers</measure>
    <time_frame>1 month, 6 months, 12 months</time_frame>
    <description>Percent change (% Δ) from baseline in bone turnover markers C-telopeptide of type 1 collagen (CTX) and procollagen type 1 propeptide (P1NP)</description>
  </primary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Actual">0</enrollment>
  <condition>Osteoporosis, Postmenopausal</condition>
  <arm_group>
    <arm_group_label>Group 1</arm_group_label>
    <description>The denosumab naïve group</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2</arm_group_label>
    <description>The zoledronic acid naïve group</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 3</arm_group_label>
    <description>The chronic denosumab (&gt; 1 year with at least 3 biannual injections)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 4</arm_group_label>
    <description>The chronic zoledronic acid (≥2 years with at least 2 annual injections)</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood specimens&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Women aged &gt; 50 with diagnosis of osteoporosis.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Women at least 50 years of age who are postmenopausal. Postmenopausal is defined as&#xD;
             being amenorrheic for at a period of at least 12 months.&#xD;
&#xD;
          2. Diagnosis of osteoporosis by T score of &lt; -2.5 at either lumbar spine or the&#xD;
             hip/femoral neck, or osteopenia that qualifies for treatment by FRAX calculation&#xD;
             (10-year risk of hip fracture &gt; 3% and/or major osteoporotic fracture of &gt; 20%).&#xD;
&#xD;
        3a. Subjects who have had chronic treatment of denosumab (as defined as &gt; 1 year [at least&#xD;
        3 6-monthly injections]) or zoledronic acid (defined as ≥ 2 years [at least 2 annual&#xD;
        injections]) . Note: At the time of treatment initiation, subjects must have met criteria&#xD;
        for on-label use (e.g. criterion 2 above).&#xD;
&#xD;
        OR 3b. Subjects who are naïve to treatment with denosumab and/or zoledronic acid.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Renal insufficiency, with glomerular filtration rate (GFR) &lt; 35 ml/min.&#xD;
&#xD;
          2. Hypocalcemia within 6 months of study initiation.&#xD;
&#xD;
          3. Known hypersensitivity to denosumab or zoledronic acid.&#xD;
&#xD;
          4. Medications that could alter bone turnover including prednisone, anti-rheumatic&#xD;
             medications, anti-metabolites (Cytoxan). Subjects who have been on stable doses of&#xD;
             thyroid replacement or diabetes medications for more than 3 months are eligible.&#xD;
&#xD;
          5. Evidence of untreated oral cavities or oral infections. Preventative dental exams&#xD;
             should be performed before starting denosumab or zoledronic acid. Subjects must avoid&#xD;
             invasive dental procedures during treatment with denosumab or zoledronic acid.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nancy Lane, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, Davis</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UC Davis Health, Center for Musculoskeletal Health</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>January 18, 2019</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <last_update_submitted>June 12, 2019</last_update_submitted>
  <last_update_submitted_qc>June 12, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 14, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoporosis</mesh_term>
    <mesh_term>Osteoporosis, Postmenopausal</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03812367
org study id: 1030286
nct id: NCT03812367
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study evaluates how patients treated with denosumab or zoledronic acid for osteoporosis
      may change the number of peripheral osteoclast precursors and osteoclast activity, and how
      that may be associated with changes in bone mass.
Postmenopausal osteoporosis is the leading cause of low trauma fractures. At the time of
      menopause there is an uncoupling of bone turnover, with osteoclast mediated bone resorption
      increased more than bone formation, resulting in both loss of bone mass and architecture such
      that bone fractures with very little force.

      Bisphosphonates are commonly used to treat postmenopausal osteoporosis, although the
      mechanisms of their action on bone are not completely understood. Gossiel and colleagues
      recently examined the effects of ibandronate, alendronate and risedronate on osteoclast
      precursor cells in a study of women (n=62) with postmenopausal osteoporosis. Fasting serum
      was collected at baseline and after 1 and 48 weeks of bisphosphonate treatment.
      Fluorescent-activated cell sorting (FACS)-Calibur was used to extract peripheral blood
      mononuclear cells (PBMC), and cells were stained for receptors of macrophage colony
      stimulating factor (M-CSFR) and tumor necrosis factor 2 (TNFR2), as well as adhesion
      molecules (CD11b and CD14). These cell surface antigens are important for osteoclast
      differentiation and activity. Osteoclast precursor cells were identified using flow cytometry
      to find cells that were dual positive (CD14+/M-CSFR+, CD14+/CD11b+, CD14+/TNFR2+). Results
      showed a significant (p<0.01) reduction in in expression of M-CSFR (53% decrease) and CD11b
      (49% decrease) after 48 weeks of treatment, suggesting that the action of bisphosphonates on
      mature osteoclasts may be mediated by reduction of osteoclast precursor cells.

      Treatment with denosumab (a monoclonal antibody that blocks the ability of receptor activator
      of NFκB ligand [RANKL] to bind to its receptor RANK on the osteoclast surface and inhibits
      the maturation and activity of osteoclasts) has been found to increase bone mineral density
      (BMD) at the lumbar spine and hip in both postmenopausal women and elderly men with
      osteopenia. However, after denosumab is discontinued there can be a rapid loss of BMD and an
      increased incidence of vertebral fractures. Current data suggests that the incidence of
      vertebral fracrure increases to levels similar to placebo after denosumab discontinuation,
      and only the incidence of multiple vertebral fracture is higher after denosumab
      discontinuation compared with placebo discontinuation, though further research is needed. The
      increase in the observed bone loss may be from increased osteoclast maturation and activity,
      or an change in the number circulating monocytes (the precursors of osteoclasts) during the
      denosumab treatment.
observational model: Case-Control
time perspective: Prospective
measure: Percent change in osteoclast circulation
time frame: 1 month, 6 months, 12 months
description: Percent change (%Δ) from baseline in number of circulating osteoclast precursor cells by FACS analysis
measure: Percent change in osteoclast maturation and activity
time frame: 1 month, 6 months, 12 months
description: Percent change (%Δ) in osteoclast maturation and activity, as assessed by resorption on dentin slides and expression of genes critical for osteoclast differentiation
measure: Percent change in number of TRAP cells
time frame: 1 month, 6 months, 12 months
description: Percent change (%Δ) from baseline in the number of tartrate-resistant acid phosphatase (TRAP)+cells with 3 or mor nuclei by in vitro maturation
measure: Percent change in bone mass density
time frame: 1 month, 6 months, 12 months
description: Percent change (%Δ) from baseline in BMD at the total hip and lumbar spine
measure: Percent change in bone turnover markers
time frame: 1 month, 6 months, 12 months
description: Percent change (% Δ) from baseline in bone turnover markers C-telopeptide of type 1 collagen (CTX) and procollagen type 1 propeptide (P1NP)
arm group label: Group 1
description: The denosumab naïve group
arm group label: Group 2
description: The zoledronic acid naïve group
arm group label: Group 3
description: The chronic denosumab (> 1 year with at least 3 biannual injections)
arm group label: Group 4
description: The chronic zoledronic acid (≥2 years with at least 2 annual injections)
Blood specimens
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 50 Years
maximum age: N/A
healthy volunteers: No
last name: Nancy Lane, MD
role: Principal Investigator
affiliation: University of California, Davis
facility: 
country: United States
responsible party type: Sponsor
mesh term: Osteoporosis
mesh term: Osteoporosis, Postmenopausal
sharing ipd: Undecided