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Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism

Primary Purpose

Type 2 Diabetes Mellitus, Hypogonadism

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Testosterone gel 1.62%
Placebo
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus focused on measuring diabetes mellitus, hypogonadism, testosterone, bone quality

Eligibility Criteria

35 Years - 65 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Male veterans only
  • 35 to 65 years old
  • With an average fasting morning T level from 2 measurements of <300 ng/dl taken at least a day apart

    • symptoms of hypogonadism as assessed using the androgen deficiency in aging male (ADAM) questionnaire
  • Participants should have

    • T2D
    • an A1C of <10.5 %
    • a fasting blood sugar of 180 mg/dl
    • body mass index (BMI) <35 kg/m2
    • with DM of 15 years duration or less to target men who have relatively less complications from long-term DM

Exclusion Criteria:

  • history of prostate or breast cancer
  • history of testicular disease
  • untreated severe sleep apnea
  • ongoing illness that could prevent the subject from completing the study
  • a hematocrit of >50%
  • prostate-related findings as:

    • a palpable prostate nodule on digital rectal exam (DRE)
  • serum PSA of 4.0 ng/ml
  • International Prostate Symptom Score (IPSS) >19 (severe)
  • on androgen therapy or selective androgen receptor modulators
  • on medications that affect bone metabolism such as:

    • estrogen
    • selective estrogen receptor modulator as:

      • raloxifene
      • aromatase inhibitors
      • GnRH analogs
      • glucocorticoids with prednisone equivalent of least 5 mg daily for 1 month
      • anabolic steroids
      • phenobarbital and Dilantin
  • use of bisphosphonates within two years of study entry, i.e.:

    • risedronate
    • alendronate
    • zoledronic acid
    • pamidronate
  • diseases that interfere with bone metabolism, as:

    • hyperparathyroidism
    • untreated hyperthyroidism
    • osteomalacia
    • chronic liver disease
    • renal failure
    • hypercortisolism
    • malabsorption
    • immobilization
  • current alcohol use of > 3 drinks/day
  • those with a history of:

    • deep vein thrombosis
    • pulmonary embolism
    • stroke or recent diagnosis of coronary artery disease
  • because of the potential of being randomized to placebo, subjects with osteoporosis or a BMD T-score by DXA of -2.5 in the lumbar spine, total femur or femoral neck and those with a history of fragility fractures

    • spine
    • hip
    • wrist

Sites / Locations

  • Michael E. DeBakey VA Medical Center, Houston, TXRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Testosterone arm

Placebo arm

Arm Description

Testosterone gel 1.62%

Matching placebo will be prepared by the Michael DeBakey VA Medical Center Pharmacy.

Outcomes

Primary Outcome Measures

Finite element analysis of bone to measure bone strength
The FEA (or FEA) is a surrogate measure of strength using computational biomechanical principles and integrate bone morphology and bone mass to calculate bone strength under various loading conditions normally seen in daily living activities. In addition, the ratio of load to strength can be calculated by using patient information (i.e. weight and height) and FEA derived bone strength to mechanistically simulate bone failure and thus, whether fracture is likely during a given activity. Using high-resolution peripheral quantitative computer tomography we will compute for FEA, using finite element analysis software with images generated using Image Processing Language to estimate the biomechanical properties of the bone. Each bone voxel will be converted to hexahedral finite elements with linear-elastic and isotropic material behavior. The FEA model will be subject to uniaxial compression and stiffness and failure load will be estimated. FEA will be assessed at months 0, 6 and 12.

Secondary Outcome Measures

Markers of bone turnover to measure bone metabolism
Two markers of bone resorption, serum C-telopeptide (CTX) and tartrate-resistant acid phosphatase 5b (TRAP5b) and 2 markers of bone formation osteocalcin (OCN) and N-terminal propeptide of type 1 collagen (P1NP) will be evaluated. These markers will be obtained at months 0, 6, and 12. Enzyme-linked immunosorbent assay will be used to measure serum CTX (serum crosslaps, Osteometer, Hawthorne, CA), tartrate-resistant acid phosphatase 5b (TRAP5b) (EIA) (Microvue Bonehealth, Quidel Corporation, Biosource); and serum osteocalcin (ALPCO, Salem, NH). Serum P1NP will be measured by competitive radioimmunoassay (UniqTM P1NP RIA, Immunodiagnostic Systems, Scottsdale, AZ). Coefficients of variations for these assays are <10%.
Osteoblast and osteoclast progenitor cells which are cells found in bone
Osteoblast and osteoclast progenitor cells will be harvested from the serum at baseline, 6 and 12 months.

Full Information

First Posted
March 21, 2019
Last Updated
October 19, 2023
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT03887936
Brief Title
Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism
Official Title
Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2019 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
September 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Low testosterone and diabetes mellitus are each associated with increased risk for fractures. Men with diabetes mellitus are commonly found to have low testosterone as well. Testosterone has been shown to improve the bone health of patients with low testosterone but has not been tested in patients who also have diabetes mellitus in addition to low testosterone. To date, there is no treatment that is specifically recommended for bone disease among patients with diabetes. This study will evaluate the effect of testosterone on the bone health of male Veterans who have both diabetes and low testosterone, both of which are highly prevalent in this subset of the population.
Detailed Description
An existing mutual influence between testosterone (T) and glucose metabolism has been suggested by studies showing that men with low T have impaired glucose tolerance, while a significant number of men with type 2 diabetes mellitus (T2D) and obesity have low T. Thus, it is not surprising that as much as 64% of men with T2D were found to have low T. Hypogonadism and diabetes mellitus (DM) each is associated with increased risk for fractures. While hypogonadism is associated with increased bone turnover and bone loss. DM is associated with low bone turnover and normal or high bone mineral density (BMD) but paradoxically a high risk for fractures. The preliminary data showed that compared to non-diabetic hypogonadal men, men with both conditions have suppressed bone turnover, higher volumetric BMD (vBMD) and smaller bone size. As the effect of T on the male skeleton is mainly mediated by its conversion to estradiol (E2) by the enzyme aromatase, the possibility of further suppression of bone turnover with T therapy in these patients would be a concern. However, the investigators' initial data also showed that T therapy in men with both conditions resulted in increased in markers of bone turnover and bone size compared to the decrease in bone turnover and decrease in bone size in men with hypogonadism only, suggesting activation in bone remodeling and improvement in bone geometry in the former. Furthermore, the investigators also found a trend for increase in bone strength (by finite element analysis or FEA) in the limited number of men with both low T and T2D randomized to T compared to placebo. These findings only suggest but do not prove with certainty that T therapy would be beneficial to men with both low T and T2D. The central hypothesis of this study is that T therapy will result in improvement in bone quality in patients who have both hypogonadism and T2D. Thus, the specific aims of this proposal are: 1) to determine the effect of T therapy on bone strength as assessed by finite element analysis ( FEA) using high-resolution peripheral quantitative computer tomography (HR-pQCT), 2) to determine the effect of T therapy on markers of bone turnover, and 3) an exploratory aim, to evaluate the mechanism for improvement in bone quality from T therapy. The investigators hypothesize that because T stimulates osteoblastic proliferation and differentiation, the ensuing increase in osteoblast number will lead to an enhanced cross-talk between osteoblast and osteoclast resulting in activation of bone remodeling and replacement of old with new bone, hence, improvement in bone quality. In this study the investigators will enroll 166 men with T2D and hypogonadism and randomize them to either testosterone gel 1.62% or placebo for 12 months. The following main outcomes will be evaluated: aim# 1) change in the primary endpoint which is FEA, by HRpQCT, #2) changes in C-telopeptide (CTX) a marker of bone resorption, and aim #3) changes in circulating osteoblast progenitor (COP). The investigators anticipate an increase in FEA at the tibia and radius suggesting improvement in bone strength, increase CTX and increase in circulating osteoblast progenitors. The investigators further anticipate an increase in other markers of bone turnover (both bone formation and resorption) and osteoclast precursors in men with hypogonadism and T2D randomized to T compared to placebo. Given the suppressed bone turnover at baseline in men with low T and T2D, the investigators hypothesize that the beneficial effect of T is its effect in activating bone remodeling ultimately resulting in improvement in bone quality. Results from this study will provide information on the utility of T not only in improving quality of life but also in improving bone quality in hypogonadal men with T2D. Given the relationship between glucose metabolism and testosterone production, and the increasing number of male patients diagnosed with both hypogonadism and T2D, this study will benefit not only the significant number of male Veterans who have both conditions but also men in general.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus, Hypogonadism
Keywords
diabetes mellitus, hypogonadism, testosterone, bone quality

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Double-blind randomized placebo-controlled study comparing the effect of testosterone therapy in men with both type 2 diabetes mellitus and hypogonadism on bone quality, bone turnover markers and circulating osteoblast and osteoclast progenitors.
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
No other parties will be masked.
Allocation
Randomized
Enrollment
166 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Testosterone arm
Arm Type
Experimental
Arm Description
Testosterone gel 1.62%
Arm Title
Placebo arm
Arm Type
Placebo Comparator
Arm Description
Matching placebo will be prepared by the Michael DeBakey VA Medical Center Pharmacy.
Intervention Type
Drug
Intervention Name(s)
Testosterone gel 1.62%
Other Intervention Name(s)
Androgel
Intervention Description
Testosterone gel 1.62%, apply 2 pumps to upper arm and shoulder.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo gel, apply 2 pumps to upper arm and shoulder
Primary Outcome Measure Information:
Title
Finite element analysis of bone to measure bone strength
Description
The FEA (or FEA) is a surrogate measure of strength using computational biomechanical principles and integrate bone morphology and bone mass to calculate bone strength under various loading conditions normally seen in daily living activities. In addition, the ratio of load to strength can be calculated by using patient information (i.e. weight and height) and FEA derived bone strength to mechanistically simulate bone failure and thus, whether fracture is likely during a given activity. Using high-resolution peripheral quantitative computer tomography we will compute for FEA, using finite element analysis software with images generated using Image Processing Language to estimate the biomechanical properties of the bone. Each bone voxel will be converted to hexahedral finite elements with linear-elastic and isotropic material behavior. The FEA model will be subject to uniaxial compression and stiffness and failure load will be estimated. FEA will be assessed at months 0, 6 and 12.
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Markers of bone turnover to measure bone metabolism
Description
Two markers of bone resorption, serum C-telopeptide (CTX) and tartrate-resistant acid phosphatase 5b (TRAP5b) and 2 markers of bone formation osteocalcin (OCN) and N-terminal propeptide of type 1 collagen (P1NP) will be evaluated. These markers will be obtained at months 0, 6, and 12. Enzyme-linked immunosorbent assay will be used to measure serum CTX (serum crosslaps, Osteometer, Hawthorne, CA), tartrate-resistant acid phosphatase 5b (TRAP5b) (EIA) (Microvue Bonehealth, Quidel Corporation, Biosource); and serum osteocalcin (ALPCO, Salem, NH). Serum P1NP will be measured by competitive radioimmunoassay (UniqTM P1NP RIA, Immunodiagnostic Systems, Scottsdale, AZ). Coefficients of variations for these assays are <10%.
Time Frame
5 years
Title
Osteoblast and osteoclast progenitor cells which are cells found in bone
Description
Osteoblast and osteoclast progenitor cells will be harvested from the serum at baseline, 6 and 12 months.
Time Frame
5 years

10. Eligibility

Sex
Male
Gender Based
Yes
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male veterans only 35 to 65 years old With an average fasting morning T level from 2 measurements of <300 ng/dl taken at least a day apart symptoms of hypogonadism as assessed using the androgen deficiency in aging male (ADAM) questionnaire Participants should have T2D an A1C of <10.5 % a fasting blood sugar of 180 mg/dl body mass index (BMI) <35 kg/m2 with DM of 15 years duration or less to target men who have relatively less complications from long-term DM Exclusion Criteria: history of prostate or breast cancer history of testicular disease untreated severe sleep apnea ongoing illness that could prevent the subject from completing the study a hematocrit of >50% prostate-related findings as: a palpable prostate nodule on digital rectal exam (DRE) serum PSA of 4.0 ng/ml International Prostate Symptom Score (IPSS) >19 (severe) on androgen therapy or selective androgen receptor modulators on medications that affect bone metabolism such as: estrogen selective estrogen receptor modulator as: raloxifene aromatase inhibitors GnRH analogs glucocorticoids with prednisone equivalent of least 5 mg daily for 1 month anabolic steroids phenobarbital and Dilantin use of bisphosphonates within two years of study entry, i.e.: risedronate alendronate zoledronic acid pamidronate diseases that interfere with bone metabolism, as: hyperparathyroidism untreated hyperthyroidism osteomalacia chronic liver disease renal failure hypercortisolism malabsorption immobilization current alcohol use of > 3 drinks/day those with a history of: deep vein thrombosis pulmonary embolism stroke or recent diagnosis of coronary artery disease because of the potential of being randomized to placebo, subjects with osteoporosis or a BMD T-score by DXA of -2.5 in the lumbar spine, total femur or femoral neck and those with a history of fragility fractures spine hip wrist
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Reina C Villareal, MD
Phone
(713) 791-1414
Ext
27534
Email
Reina.Villareal@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Paula A Kinsel, MHA MBA
Phone
(713) 794-7939
Email
Paula.Kinsel@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Reina C. Villareal, MD
Organizational Affiliation
Michael E. DeBakey VA Medical Center, Houston, TX
Official's Role
Principal Investigator
Facility Information:
Facility Name
Michael E. DeBakey VA Medical Center, Houston, TX
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-4211
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Reina C Villareal, MD
Phone
713-791-1414
Ext
27534
Email
Reina.Villareal@va.gov
First Name & Middle Initial & Last Name & Degree
Reina C. Villareal, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33718653
Citation
Russo V, Colleluori G, Chen R, Mediwala S, Qualls C, Liebschner M, Villareal DT, Armamento-Villareal R. Testosterone therapy and bone quality in men with diabetes and hypogonadism: Study design and protocol. Contemp Clin Trials Commun. 2021 Jan 20;21:100723. doi: 10.1016/j.conctc.2021.100723. eCollection 2021 Mar.
Results Reference
background
PubMed Identifier
33537005
Citation
Russo V, Chen R, Armamento-Villareal R. Hypogonadism, Type-2 Diabetes Mellitus, and Bone Health: A Narrative Review. Front Endocrinol (Lausanne). 2021 Jan 18;11:607240. doi: 10.3389/fendo.2020.607240. eCollection 2020.
Results Reference
background
PubMed Identifier
35898448
Citation
Deepika F, Ballato E, Colleluori G, Aguirre L, Chen R, Qualls C, Villareal DT, Armamento-Villareal R. Baseline Testosterone Predicts Body Composition and Metabolic Response to Testosterone Therapy. Front Endocrinol (Lausanne). 2022 Jul 11;13:915309. doi: 10.3389/fendo.2022.915309. eCollection 2022.
Results Reference
background
PubMed Identifier
37576965
Citation
Bathina S, Armamento-Villareal R. The complex pathophysiology of bone fragility in obesity and type 2 diabetes mellitus: therapeutic targets to promote osteogenesis. Front Endocrinol (Lausanne). 2023 Jul 20;14:1168687. doi: 10.3389/fendo.2023.1168687. eCollection 2023.
Results Reference
background
PubMed Identifier
36831180
Citation
Deepika F, Bathina S, Armamento-Villareal R. Novel Adipokines and Their Role in Bone Metabolism: A Narrative Review. Biomedicines. 2023 Feb 20;11(2):644. doi: 10.3390/biomedicines11020644.
Results Reference
background
PubMed Identifier
35665818
Citation
Ballato E, Deepika FNU, Russo V, Fleires-Gutierrez A, Colleluori G, Fuenmayor V, Chen R, Villareal DT, Qualls C, Armamento-Villareal R. One-Year Mean A1c of > 7% is Associated with Poor Bone Microarchitecture and Strength in Men with Type 2 Diabetes Mellitus. Calcif Tissue Int. 2022 Sep;111(3):267-278. doi: 10.1007/s00223-022-00993-x. Epub 2022 Jun 4.
Results Reference
result

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Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism

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