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Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03887936
Recruitment Status : Recruiting
First Posted : March 25, 2019
Last Update Posted : March 4, 2020
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Hypogonadism Drug: Testosterone gel 1.62% Drug: Placebo Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 166 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: No other parties will be masked.
Primary Purpose: Treatment
Official Title: Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism
Actual Study Start Date : October 1, 2019
Estimated Primary Completion Date : September 30, 2024
Estimated Study Completion Date : September 30, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Testosterone arm
Testosterone gel 1.62%
Drug: Testosterone gel 1.62%
Testosterone gel 1.62%, apply 2 pumps to upper arm and shoulder.
Other Name: Androgel

Placebo Comparator: Placebo arm
Matching placebo will be prepared by the Michael DeBakey VA Medical Center Pharmacy.
Drug: Placebo
Matching placebo gel, apply 2 pumps to upper arm and shoulder




Primary Outcome Measures :
  1. Finite element analysis of bone to measure bone strength [ Time Frame: 5 years ]
    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 :
  1. Markers of bone turnover to measure bone metabolism [ Time Frame: 5 years ]
    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%.

  2. Osteoblast and osteoclast progenitor cells which are cells found in bone [ Time Frame: 5 years ]
    Osteoblast and osteoclast progenitor cells will be harvested from the serum at baseline, 6 and 12 months.



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male veterans only
  • 40 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 <9.5 %
    • a fasting blood sugar of 180 mg/dl
    • body mass index (BMI) <35 kg/m2
    • with DM of 10 years duration 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03887936


Contacts
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Contact: Reina C Villareal, MD (713) 791-1414 ext 27534 Reina.Villareal@va.gov
Contact: Paula A Kinsel (713) 794-7939 Paula.Kinsel@va.gov

Locations
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United States, Texas
Michael E. DeBakey VA Medical Center, Houston, TX Recruiting
Houston, Texas, United States, 77030
Contact: Reina C Villareal, MD    713-791-1414 ext 27534    Reina.Villareal@va.gov   
Principal Investigator: Reina C. Villareal, MD         
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Reina C. Villareal, MD Michael E. DeBakey VA Medical Center, Houston, TX
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT03887936    
Other Study ID Numbers: ENDB-009-18F
1I01CX001665-01A2 ( U.S. NIH Grant/Contract )
First Posted: March 25, 2019    Key Record Dates
Last Update Posted: March 4, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by VA Office of Research and Development:
diabetes mellitus
hypogonadism
testosterone
bone quality
Additional relevant MeSH terms:
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Diabetes Mellitus
Hypogonadism
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Gonadal Disorders
Testosterone
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs