Clinical trial NCT03887936: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Hypogonadism
Keywords: diabetes mellitus
hypogonadism
testosterone
bone quality
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2019-03-25
Enrollment: 92
Sex: MALE
Minimum age (years): 35
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* Male veterans only
* 35 to 70 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 \<11.5 %
  * a fasting blood sugar of 180 mg/dl
  * body mass index (BMI) \<40 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 with estimated glomerular filtration rate of \<45 ml/min
  * hypercortisolism
  * malabsorption
  * immobilization
* current alcohol use of \> 3 drinks/day
* those with a history of:

  * deep vein thrombosis
  * pulmonary embolism
  * recent stroke or recent diagnosis of coronary artery disease of \< 6 months
* 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

Primary outcomes:
measure: Finite element analysis of bone to measure bone strength
timeFrame: 5 years
Secondary outcomes:
measure: Markers of bone turnover to measure bone metabolism
timeFrame: 5 years
measure: Osteoblast and osteoclast progenitor cells which are cells found in bone
timeFrame: 5 years
Other outcomes:
Locations:
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
Study officials:
affiliation: Michael E. DeBakey VA Medical Center, Houston, TX
name: Reina C. Villareal, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.