Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism

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.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes Mellitus; Hypogonadism
• Intervention / Treatment: Drug: Testosterone gel 1.62%; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 166
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Reina C Villareal, MD; Phone Number: 27534 (713) 791-1414; Email: Reina.Villareal@va.gov
• Study Contact Backup: Name: Paula A Kinsel, MHA MBA; Phone Number: (713) 794-7939; Email: Paula.Kinsel@va.gov

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030-4211
      • Recruiting
      • Michael E. DeBakey VA Medical Center, Houston, TX
      • Contact: Reina C Villareal, MD; Phone Number: 27534 713-791-1414; Email: Reina.Villareal@va.gov
      • Principal Investigator: Reina C. Villareal, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 33 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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%.	5 years
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.	5 years

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Reina C. Villareal, MD, Michael E. DeBakey VA Medical Center, Houston, TX

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: March 21, 2019
• First Submitted That Met QC Criteria: March 21, 2019
• First Posted (Actual): March 25, 2019

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: hypogonadism; bone quality; diabetes mellitus; testosterone
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Gonadal Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypogonadism; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Androgens; Testosterone
• Other Study ID Numbers: ENDB-009-18F; 1I01CX001665-01A2 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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