Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Endocrine, Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 40 - 65 |
| Updated: | 4/6/2019 |
| Start Date: | July 1, 2019 |
| End Date: | June 30, 2025 |
| Contact: | Reina C Villareal, MD |
| Email: | Reina.Villareal@va.gov |
| Phone: | (713) 791-1414 |
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.
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.
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.
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.
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
We found this trial at
1
site
Houston, Texas 77030
Principal Investigator: Reina C. Villareal, MD
Phone: 713-794-8623
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