<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/NCT03040531</url>
  </required_header>
  <id_info>
    <org_study_id>45/16</org_study_id>
    <nct_id>NCT03040531</nct_id>
  </id_info>
  <brief_title>Effects of Genistein Aglycone in Glucocorticoid Induced Osteoporosis</brief_title>
  <official_title>Metabolic, Endocrine, and Central Effects of Genistein Aglycone in Glucocorticoid Induced Osteoporosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Messina</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health, Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Messina</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Prolonged glucocorticoid therapy affects bone fragility, cardiovascular health, glucidic and&#xD;
      lipidic metabolism, thyroid and brain function. Glucocorticoid-induced osteoporosis is&#xD;
      characterized by low bone turnover and fractures, which occur in 30-50% of patients.&#xD;
      Glucocorticoids affect predominantly cancellous or trabecular bone, increasing the risk of&#xD;
      vertebral fractures, which may be asymptomatic and occur early during the first months of&#xD;
      glucocorticoid treatment. Genistein exerts biological effects by several potential&#xD;
      mechanisms. Besides protective effects on bone loss, genistein reduces cardiovascular risk&#xD;
      markers, improves endothelial function and ameliorates glucose and lipid metabolism. This&#xD;
      study is aimed at demonstrating genistein efficacy in glucocorticoid-induced osteoporosis in&#xD;
      a cohort of caucasian post-menopausal women.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Glucocorticoid-induced osteoporosis (GIOP) is one of the primary side effects of&#xD;
      glucocorticoid use resulting in increased risk of fractures. Glucocorticoid therapy affects&#xD;
      bone mass, glucidic and lipidic metabolism, thyroid function and is also responsible for a&#xD;
      decline in cognitive function. In this study a natural approach will be used, a soy-derived&#xD;
      isoflavone, namely genistein. Genistein has been proven effective in preserving bone mineral&#xD;
      density in post-menopausal women, and has an high safety profile. Genistein was also able in&#xD;
      improving cardiovascular markers, as well as lipidic and glucidic metabolism markers without&#xD;
      interfering with thyroid function.&#xD;
&#xD;
      Treatment guidelines for the use of glucocorticoids have been established which advise that&#xD;
      if prednisolone is administered at 5 mg per day for three months or longer requires regular&#xD;
      monitoring of bone mineral density (BMD) and treatment to prevent osteoporosis must be&#xD;
      initiated (American college of Rheumatology). Vitamin D and calcium are also recommended for&#xD;
      the management of all patients treated with glucocorticoids. Bisphosphonates should be&#xD;
      considered for the prevention and treatment of this disorder, because they can prevent the&#xD;
      initial loss of bone mass from glucocorticoids. Alendronate, risedronate, and zoledronic acid&#xD;
      were shown to prevent and reverse the loss of BMD in glucocorticoid-induced osteoporosis with&#xD;
      greater effects than those observed with vitamin D and calcium. In fact, bisphosphonates&#xD;
      induce improvement of BMD that is 2-fold greater than that observed during vitamin D&#xD;
      treatment alone (4.6% vs. 2.0%, respectively). Anabolic therapy is also used for the&#xD;
      treatment of glucocorticoid-induced osteoporosis. Teriparatide causes a greater increase in&#xD;
      BMD than alendronate and greater reduction in the risk of vertebral fractures. Even with&#xD;
      these evidentiary clinical trials and guidelines, patient bone loss is, in general, poorly&#xD;
      managed. In glucocorticoid-induced osteoporosis, fractures also occur at higher BMDs than in&#xD;
      postmenopausal osteoporosis in untreated women. Consequently, guidelines for the treatment of&#xD;
      postmenopausal osteoporosis are not applicable to glucocorticoid-induced osteoporosis, and&#xD;
      patients should be treated at BMD T-scores of -1.0 to -1.5 standard deviations. In addition,&#xD;
      vertebral fractures may be asymptomatic and often require radiological diagnosis before&#xD;
      treatment.&#xD;
&#xD;
      During the initial phases of glucocorticoid exposure bone resorption is increased.&#xD;
      Glucocorticoids inhibit the formation of mature osteoblasts, but also activate an activate&#xD;
      apoptosis in these cell types. Osteoprotegrin (OPG) expression, a key factor involved in&#xD;
      modulating maturation of osteoclasts, is reduced also by glucocorticoids resulting in&#xD;
      increased osteoclastogenesis. Therefore, the combination of reduced osteoblast formation,&#xD;
      increased osteoclast maturation leads to accelerated bone loss while on glucocorticoid&#xD;
      therapy. Therapies are needed which modulate osteoclast as well as osteoblast activity to&#xD;
      restore a more normal balance to the bone remodeling process in glucocorticoid treated&#xD;
      patients.&#xD;
&#xD;
      A rational treatment for glucocorticoid-induced osteoporosis should combine a significant&#xD;
      anti-osteoporotic and anti-fracture activity with positive actions on the several undesirable&#xD;
      effects of this therapy including alteration in glucose and lipid metabolism, amplification&#xD;
      of the cardiovascular risk, impairment in thyroid and cognitive function.&#xD;
&#xD;
      Genistein aglycone represents an innovative therapeutic bullet to challenge the metabolic&#xD;
      derangements induced by glucocorticoids. Among the anabolic compounds tested in recent years&#xD;
      genistein aglycone seems a promising agent able to stimulate bone formation and to reduce&#xD;
      bone resorption, acting via a genomic as well as a non-genomic pathways. Genistein is an&#xD;
      isoflavone found in small quantities in certain legumes throughout the plant kingdom.&#xD;
      Genistein has both ER agonist and antagonist activity in different cell types and works in a&#xD;
      promoter specific manner in gene activation via ERs. Effects of genistein on bone metabolism&#xD;
      derived from direct and indirect actions on bone cells and can be summarized in stimulation&#xD;
      of osteoblastic bone formation and inhibition of osteoclastic bone resorption.&#xD;
&#xD;
      It has been demonstrated that genistein inhibits glucocorticoid receptor transactivation and&#xD;
      may also induce a proteosomal degradation of the glucocorticoid receptor complex via the p53&#xD;
      and ubiquitin pathways. Another mechanism might involve genistein activity as a tyrosine&#xD;
      kinase inhibitor via the limitation of the subcellular nuclear transport and the recycling of&#xD;
      the glucocorticoid receptors, inhibiting in turn the effects of glucocorticoids on bone. In a&#xD;
      rat model, we studied genistein preservative effects on methylprednisolone-induced bone loss&#xD;
      and osteonecrosis of the femoral head. In our study genistein succeeded in preventing&#xD;
      osteoporosis and osteonecrosis of the femoral head when co-administered with the&#xD;
      glucocorticoid. The isoflavone statistically maintained bone mineral density and content over&#xD;
      the methylprednisolone-treated group and showed comparable efficacy with the vehicle group.&#xD;
      Genistein co-administered with methylprednisolone also statistically maintained femoral&#xD;
      bone's resistance to rupture compared with the methylprednisolone group and preserved the&#xD;
      normal architecture of cartilage as well as both cortical and trabecular bones with a&#xD;
      well-organized matrix in femoral head.&#xD;
&#xD;
      Besides the protective effects on osteoporosis, genistein has been shown to positively&#xD;
      affects the cardiovascular system reducing predictors of cardiovascular risk, improving&#xD;
      endothelial function and ameliorating glucose and lipid metabolism. In addition genistein&#xD;
      possesses beneficial activity in the central nervous system and protects the hippocampus from&#xD;
      injury.&#xD;
&#xD;
      Regarding the effects of genistein on thyroid function that may be impaired by&#xD;
      glucocorticoids a recent clinical trial evaluated the effects of three year administration of&#xD;
      pure genistein aglycone (54 mg/day) on thyroid-related markers, in postmenopausal women.&#xD;
      Specifically, changes in thyroid hormone receptors and thyroid hormone enzymes, blood levels&#xD;
      of thyroid hormones and thyroid auto-antibodies were assessed. The results of this research&#xD;
      showed that daily consumption of genistein aglycone did not modified circulating fT4 (free&#xD;
      thyroxine), fT3 (free triiodothyronine), and TSH (thyroid-stimulating hormone) levels;&#xD;
      further, genistein aglycone administration over 3 yr did not affect the enzymes involved in&#xD;
      thyroid hormone production, the thyroid hormone auto-antibodies, and the expression of&#xD;
      thyroid hormone receptors then confirming that genistein does not appear to alter thyroid&#xD;
      function in postmenopausal women.&#xD;
&#xD;
      Taken together this clinical and pre-clinical observations lead the investigators to&#xD;
      hypothesize a role for genistein in the management of glucocorticoid-related side effects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 19, 2017</start_date>
  <completion_date type="Anticipated">December 30, 2018</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2018</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Drugs will be labelled as &quot;A&quot; and &quot;B&quot; and so will be the groups. Patients and doctors involved will not be aware of the treatment.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Bone mineral density</measure>
    <time_frame>24 months</time_frame>
    <description>BMD of lumbar spine and femoral will be measured by DEXA (dual energy x-ray absorptiometry)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Bone fracture</measure>
    <time_frame>24 months</time_frame>
    <description>Xrays of the lumbar spine (T4-L4) will be taken to evaluate the presence of fractures</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Bone quality</measure>
    <time_frame>24 months</time_frame>
    <description>pQCT (peripheral quantitative computed tomography) will be used for bone quality evaluation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Bone markers</measure>
    <time_frame>24 months</time_frame>
    <description>bone turnover markers will be evaluated on peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Cardiovascular markers</measure>
    <time_frame>24 months</time_frame>
    <description>Markers of cardiovascular risk will be evaluated on peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Glucose and lipid metabolism</measure>
    <time_frame>24 months</time_frame>
    <description>Glycaemia and blood lipids will be evaluated on peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Quality of life</measure>
    <time_frame>24 months</time_frame>
    <description>European Quality of Life Questionnaire will be administered to subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chage in skin elasticity</measure>
    <time_frame>24 months</time_frame>
    <description>skin elasticity will be tested in subjects taking glucocorticoids</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in thyroid markers</measure>
    <time_frame>24 months</time_frame>
    <description>markers of thyroid function will be evaluated on peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in inflammatory markers</measure>
    <time_frame>24 months</time_frame>
    <description>markers of inflammation will be evaluated on peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Polymorphisms of estrogen receptor</measure>
    <time_frame>24 months</time_frame>
    <description>Estrogen receptor polymorphisms will be evaluated on white blood cells</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Osteoporosis, Steroid Induced</condition>
  <arm_group>
    <arm_group_label>Genistein</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each tablet will contain 27 mg of 98% pure genistein + 500mg Calcium + 200 IU Vit. D3. Subjects will receive 2 tablets per day 6 days/week for all the duration of the study.&#xD;
Once a week subjects will receive a tablet containing only 500mg Calcium + 200 IU Vit. D3.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Alendronate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Each tablet will contain 500mg Calcium + 200 IU Vit. D3. Subjects will receive 2 tablets per day 6 days/week for all the duration of the study.&#xD;
Once a week subjects will take one tablet containing 70mg alendronate.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Genistein aglycone</intervention_name>
    <description>27mg bid in tablets</description>
    <arm_group_label>Genistein</arm_group_label>
    <other_name>fosteum</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alendronate Oral Tablet</intervention_name>
    <description>70 mg/week in tablets</description>
    <arm_group_label>Alendronate</arm_group_label>
    <other_name>Fosamax</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Calcium + vitamin D3 tablet</intervention_name>
    <description>500mg Calcium + 200 IU Vitamin D3 bid in tablets</description>
    <arm_group_label>Alendronate</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  being treated with glucocorticoids (5 mg of prednisone equivalents) for the preceding&#xD;
             3 months or less, and expect to continue the therapy for at least 12 months;&#xD;
&#xD;
          -  being post-menopausal;&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  use of other steroids or osteoporosis medications;&#xD;
&#xD;
          -  have been diagnosed with metabolic bone diseases (other than glucocorticoid&#xD;
             osteoporosis)&#xD;
&#xD;
          -  previous (1 year) or current use of HRT (hormone replacement therapy)&#xD;
&#xD;
          -  other diseases that may affect participation (i.e. mental illness)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Only female XX patients will be included, to avoid interactions with other steroid drugs.</gender_description>
    <minimum_age>54 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Francesco Squadrito, MD</last_name>
    <role>Study Director</role>
    <affiliation>University of Messina</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Francesco Squadrito, MD</last_name>
    <phone>+390902213648</phone>
    <email>fsquadrito@unime.it</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Messina</name>
      <address>
        <city>Messina</city>
        <zip>98123</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Francesco Squadrito, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospital</name>
      <address>
        <city>Messina</city>
        <zip>98125</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Francesco Squadrito, MD</last_name>
      <phone>+390902213648</phone>
      <email>fsquadrito@unime.it</email>
    </contact>
    <investigator>
      <last_name>Marco Atteritano, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Alessandra Bitto, MD/PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>January 30, 2017</study_first_submitted>
  <study_first_submitted_qc>January 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 2, 2017</study_first_posted>
  <last_update_submitted>March 1, 2017</last_update_submitted>
  <last_update_submitted_qc>March 1, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 3, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Messina</investigator_affiliation>
    <investigator_full_name>Francesco Squadrito</investigator_full_name>
    <investigator_title>Full Professor of Pharmacology</investigator_title>
  </responsible_party>
  <keyword>glucocorticoid</keyword>
  <keyword>genistein</keyword>
  <keyword>alendronate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoporosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Cholecalciferol</mesh_term>
    <mesh_term>Alendronate</mesh_term>
    <mesh_term>Genistein</mesh_term>
    <mesh_term>Calcium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03040531
org study id: 45/16
nct id: NCT03040531
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Prolonged glucocorticoid therapy affects bone fragility, cardiovascular health, glucidic and
      lipidic metabolism, thyroid and brain function. Glucocorticoid-induced osteoporosis is
      characterized by low bone turnover and fractures, which occur in 30-50% of patients.
      Glucocorticoids affect predominantly cancellous or trabecular bone, increasing the risk of
      vertebral fractures, which may be asymptomatic and occur early during the first months of
      glucocorticoid treatment. Genistein exerts biological effects by several potential
      mechanisms. Besides protective effects on bone loss, genistein reduces cardiovascular risk
      markers, improves endothelial function and ameliorates glucose and lipid metabolism. This
      study is aimed at demonstrating genistein efficacy in glucocorticoid-induced osteoporosis in
      a cohort of caucasian post-menopausal women.
Glucocorticoid-induced osteoporosis (GIOP) is one of the primary side effects of
      glucocorticoid use resulting in increased risk of fractures. Glucocorticoid therapy affects
      bone mass, glucidic and lipidic metabolism, thyroid function and is also responsible for a
      decline in cognitive function. In this study a natural approach will be used, a soy-derived
      isoflavone, namely genistein. Genistein has been proven effective in preserving bone mineral
      density in post-menopausal women, and has an high safety profile. Genistein was also able in
      improving cardiovascular markers, as well as lipidic and glucidic metabolism markers without
      interfering with thyroid function.

      Treatment guidelines for the use of glucocorticoids have been established which advise that
      if prednisolone is administered at 5 mg per day for three months or longer requires regular
      monitoring of bone mineral density (BMD) and treatment to prevent osteoporosis must be
      initiated (American college of Rheumatology). Vitamin D and calcium are also recommended for
      the management of all patients treated with glucocorticoids. Bisphosphonates should be
      considered for the prevention and treatment of this disorder, because they can prevent the
      initial loss of bone mass from glucocorticoids. Alendronate, risedronate, and zoledronic acid
      were shown to prevent and reverse the loss of BMD in glucocorticoid-induced osteoporosis with
      greater effects than those observed with vitamin D and calcium. In fact, bisphosphonates
      induce improvement of BMD that is 2-fold greater than that observed during vitamin D
      treatment alone (4.6% vs. 2.0%, respectively). Anabolic therapy is also used for the
      treatment of glucocorticoid-induced osteoporosis. Teriparatide causes a greater increase in
      BMD than alendronate and greater reduction in the risk of vertebral fractures. Even with
      these evidentiary clinical trials and guidelines, patient bone loss is, in general, poorly
      managed. In glucocorticoid-induced osteoporosis, fractures also occur at higher BMDs than in
      postmenopausal osteoporosis in untreated women. Consequently, guidelines for the treatment of
      postmenopausal osteoporosis are not applicable to glucocorticoid-induced osteoporosis, and
      patients should be treated at BMD T-scores of -1.0 to -1.5 standard deviations. In addition,
      vertebral fractures may be asymptomatic and often require radiological diagnosis before
      treatment.

      During the initial phases of glucocorticoid exposure bone resorption is increased.
      Glucocorticoids inhibit the formation of mature osteoblasts, but also activate an activate
      apoptosis in these cell types. Osteoprotegrin (OPG) expression, a key factor involved in
      modulating maturation of osteoclasts, is reduced also by glucocorticoids resulting in
      increased osteoclastogenesis. Therefore, the combination of reduced osteoblast formation,
      increased osteoclast maturation leads to accelerated bone loss while on glucocorticoid
      therapy. Therapies are needed which modulate osteoclast as well as osteoblast activity to
      restore a more normal balance to the bone remodeling process in glucocorticoid treated
      patients.

      A rational treatment for glucocorticoid-induced osteoporosis should combine a significant
      anti-osteoporotic and anti-fracture activity with positive actions on the several undesirable
      effects of this therapy including alteration in glucose and lipid metabolism, amplification
      of the cardiovascular risk, impairment in thyroid and cognitive function.

      Genistein aglycone represents an innovative therapeutic bullet to challenge the metabolic
      derangements induced by glucocorticoids. Among the anabolic compounds tested in recent years
      genistein aglycone seems a promising agent able to stimulate bone formation and to reduce
      bone resorption, acting via a genomic as well as a non-genomic pathways. Genistein is an
      isoflavone found in small quantities in certain legumes throughout the plant kingdom.
      Genistein has both ER agonist and antagonist activity in different cell types and works in a
      promoter specific manner in gene activation via ERs. Effects of genistein on bone metabolism
      derived from direct and indirect actions on bone cells and can be summarized in stimulation
      of osteoblastic bone formation and inhibition of osteoclastic bone resorption.

      It has been demonstrated that genistein inhibits glucocorticoid receptor transactivation and
      may also induce a proteosomal degradation of the glucocorticoid receptor complex via the p53
      and ubiquitin pathways. Another mechanism might involve genistein activity as a tyrosine
      kinase inhibitor via the limitation of the subcellular nuclear transport and the recycling of
      the glucocorticoid receptors, inhibiting in turn the effects of glucocorticoids on bone. In a
      rat model, we studied genistein preservative effects on methylprednisolone-induced bone loss
      and osteonecrosis of the femoral head. In our study genistein succeeded in preventing
      osteoporosis and osteonecrosis of the femoral head when co-administered with the
      glucocorticoid. The isoflavone statistically maintained bone mineral density and content over
      the methylprednisolone-treated group and showed comparable efficacy with the vehicle group.
      Genistein co-administered with methylprednisolone also statistically maintained femoral
      bone's resistance to rupture compared with the methylprednisolone group and preserved the
      normal architecture of cartilage as well as both cortical and trabecular bones with a
      well-organized matrix in femoral head.

      Besides the protective effects on osteoporosis, genistein has been shown to positively
      affects the cardiovascular system reducing predictors of cardiovascular risk, improving
      endothelial function and ameliorating glucose and lipid metabolism. In addition genistein
      possesses beneficial activity in the central nervous system and protects the hippocampus from
      injury.

      Regarding the effects of genistein on thyroid function that may be impaired by
      glucocorticoids a recent clinical trial evaluated the effects of three year administration of
      pure genistein aglycone (54 mg/day) on thyroid-related markers, in postmenopausal women.
      Specifically, changes in thyroid hormone receptors and thyroid hormone enzymes, blood levels
      of thyroid hormones and thyroid auto-antibodies were assessed. The results of this research
      showed that daily consumption of genistein aglycone did not modified circulating fT4 (free
      thyroxine), fT3 (free triiodothyronine), and TSH (thyroid-stimulating hormone) levels;
      further, genistein aglycone administration over 3 yr did not affect the enzymes involved in
      thyroid hormone production, the thyroid hormone auto-antibodies, and the expression of
      thyroid hormone receptors then confirming that genistein does not appear to alter thyroid
      function in postmenopausal women.

      Taken together this clinical and pre-clinical observations lead the investigators to
      hypothesize a role for genistein in the management of glucocorticoid-related side effects.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
masking description: Drugs will be labelled as "A" and "B" and so will be the groups. Patients and doctors involved will not be aware of the treatment.
measure: Change in Bone mineral density
time frame: 24 months
description: BMD of lumbar spine and femoral will be measured by DEXA (dual energy x-ray absorptiometry)
measure: Bone fracture
time frame: 24 months
description: Xrays of the lumbar spine (T4-L4) will be taken to evaluate the presence of fractures
measure: Change in Bone quality
time frame: 24 months
description: pQCT (peripheral quantitative computed tomography) will be used for bone quality evaluation
measure: Change in Bone markers
time frame: 24 months
description: bone turnover markers will be evaluated on peripheral blood
measure: Change in Cardiovascular markers
time frame: 24 months
description: Markers of cardiovascular risk will be evaluated on peripheral blood
measure: Change in Glucose and lipid metabolism
time frame: 24 months
description: Glycaemia and blood lipids will be evaluated on peripheral blood
measure: Change in Quality of life
time frame: 24 months
description: European Quality of Life Questionnaire will be administered to subjects
measure: Chage in skin elasticity
time frame: 24 months
description: skin elasticity will be tested in subjects taking glucocorticoids
measure: Change in thyroid markers
time frame: 24 months
description: markers of thyroid function will be evaluated on peripheral blood
measure: Change in inflammatory markers
time frame: 24 months
description: markers of inflammation will be evaluated on peripheral blood
measure: Polymorphisms of estrogen receptor
time frame: 24 months
description: Estrogen receptor polymorphisms will be evaluated on white blood cells
arm group label: Genistein
arm group type: Experimental
description: Each tablet will contain 27 mg of 98% pure genistein + 500mg Calcium + 200 IU Vit. D3. Subjects will receive 2 tablets per day 6 days/week for all the duration of the study.
Once a week subjects will receive a tablet containing only 500mg Calcium + 200 IU Vit. D3.
arm group label: Alendronate
arm group type: Active Comparator
description: Each tablet will contain 500mg Calcium + 200 IU Vit. D3. Subjects will receive 2 tablets per day 6 days/week for all the duration of the study.
Once a week subjects will take one tablet containing 70mg alendronate.
intervention type: Dietary Supplement
intervention name: Genistein aglycone
description: 27mg bid in tablets
arm group label: Genistein
other name: fosteum
intervention type: Drug
intervention name: Alendronate Oral Tablet
description: 70 mg/week in tablets
arm group label: Alendronate
other name: Fosamax
intervention type: Dietary Supplement
intervention name: Calcium + vitamin D3 tablet
description: 500mg Calcium + 200 IU Vitamin D3 bid in tablets
arm group label: Alendronate
criteria: 
gender: Female
gender based: Yes
gender description: Only female XX patients will be included, to avoid interactions with other steroid drugs.
minimum age: 54 Years
maximum age: 75 Years
healthy volunteers: No
last name: Francesco Squadrito, MD
role: Study Director
affiliation: University of Messina
last name: Francesco Squadrito, MD
phone: +390902213648
email: fsquadrito@unime.it
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: University of Messina
investigator full name: Francesco Squadrito
investigator title: Full Professor of Pharmacology
mesh term: Osteoporosis
mesh term: Vitamin D
mesh term: Cholecalciferol
mesh term: Alendronate
mesh term: Genistein
mesh term: Calcium
sharing ipd: No