DHEA Augmentation of Musculoskeletal Adaptations to Exercise in Older Women

To determine whether the musculoskeletal adaptations to bone-loading exercise can be significantly augmented in older women (aged 60-85) with low bone mass (osteopenia; T-scores <-1.0 and >-2.5) or moderate osteoporosis (T-scores < -2.5 and >= -3.0) and by restoring serum DHEAS to young adult levels by oral DHEA replacement.

Study Overview

• Status: Recruiting
• Conditions: Osteoporosis, Postmenopausal; Low Bone Mass
• Intervention / Treatment: Other: DHEA; Behavioral: Exercise; Other: Placebo

Detailed Description

This will be the first study to measure changes in areal bone mineral density (aBMD) and fat-free mass (FFM) in response to dehydroepiandrosterone (DHEA) alone and combined with exercise in postmenopausal women. The body of evidence from carefully executed Randomized Controlled Studies (RCTs) provides support for DHEA therapy to increase aBMD and FFM in older women. Less is known about whether DHEA therapy enhances the effects of exercise on the aging musculoskeletal system when an appropriate mechanical stimulus is applied.

• Study Type: Interventional
• Enrollment (Anticipated): 225
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Anschutz Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• non-frail, as determined by short physical performance battery (SPPB) score > 9 (0-12 scale);
• 5 years or longer since menopause (defined as last menstrual period);
• willing to participate in a 36-week exercise program that will start at a moderate intensity and gradually progress to a higher intensity;
• willing to be randomized to an exercise or a no-exercise arm of the study;
• willing to take DHEA (50mg/d) or a placebo pill daily and remain blinded for up to 36 weeks;
• not performing resistance exercise training or high impact weight-bearing exercise (e.g., jogging) ≥ 2 days per week in the past 6 months;
• ambulatory without assistive devices;
• serum DHEAS < 140 μg/dL (3.8 μmol/L);
• low bone mass or moderate osteoporosis defined as lumbar spine or proximal hip aBMD t-scores < -1.0 and > = -3.0;
• refusal of standard osteoporosis treatment in women with moderate osteoporosis (BMD t-scores >=-3.0 and =< 2.5).
• evidence of a negative (no findings suspicious for breast cancer) mammogram within the past 12 months;
• planning to reside in the Denver area for the duration of the study
• normal cognitive function, as determined by a Mini-Cog score > = 4

Exclusion Criteria:

• history of hospitalization for Corona Virus Disease-19 (COVID-19)
• does not meet Centers for Disease Control and Prevention (CDC) recommendations for home isolation because has had a positive severe acute respiratory syndrome corona virus-2 (SARS-COV-2) test less than 10 days before study entry; or has had fever within the past 3 days and respiratory symptoms have not improved; or symptoms first appeared less than 10 days before study entry
• uncontrolled hypertension defined as resting systolic blood pressure (sBP) >150 mmHg or diastolic blood pressure (dBP) >90 mmHg; participants who do not meet these criteria at first screening will be re-evaluated, including follow-up evaluation by their Primary Care Physician (PCP) with initiation or adjustment of anti-hypertensive medications;
• diagnosed ischemic heart disease or indicators of unstable ischemic heart disease (e.g., angina, ST segment depression) or arrhythmias at rest or during the Gated Exercise Test (GXT) without negative follow-up evaluation will be cause for exclusion; follow-up evaluation must include diagnostic testing (e.g., thallium stress test) with interpretation by a cardiologist;
• diagnosis of heart failure, clinically significant aortic stenosis, uncontrolled angina, or uncontrolled arrhythmia.
• pulmonary disease requiring use of oral steroids within the previous 6 months or the use of supplemental oxygen ≥ 4 liters with physical exertion
• orthopedic problems (e.g., severe osteoarthritis, rheumatoid arthritis) that greatly limit the ability to perform moderate to high intensity resistance exercise (e.g., unable to be properly positioned in exercise equipment or to have severely restricted range of motion even after modifications have been made)
• hip fracture, hip or knee replacement, or spinal surgery in the past 6 months;
• undergoing physical therapy involving the lower extremities;
• hematocrit (HCT) > 54%;
• thyroid dysfunction, defined as an ultrasensitive thyroid stimulating hormone (TSH) < 0.4 or > 10.0 microunits/mL;, without signs or symptoms of clinical hypo- or hyperthyroidism. Volunteers with abnormal TSH values will be re-considered for participation in the study after follow-up evaluation by their PCP with initiation or adjustment of thyroid hormone replacement;
• acute liver disease indicated by liver function tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase) ≥ 1.5 times the upper limits of normal;
• estimated glomerular filtration rate (eGFR) < 45, using the Modification of Diet in Renal Disease (MDRD) equation (Levey et al, Annals Inter Med, 1999; Munter et al, Clin J Am Soc Nephrology, 2009);
• poorly controlled diabetes mellitus based on HbA1c > 8.5%, or use of insulin;
• fasted serum triglycerides > 400 mg/dL;
• serum 25-hydroxy vitamin D <20 ng/mL; volunteers will be re-considered for participation in the study after follow-up evaluation by their PCP with initiation or adjustment of vitamin D supplementation per the study's vitamin D repletion protocol.
• use of DHEA supplementation or sex hormones in the past 6 months. Use of prescription low dose vaginal estrogen creams (Premarin or Estrace) 3 days per week will not be exclusionary.
• use in the past 6 months of any medications known to alter bone metabolism (e.g., oral glucocorticoids, bone anti-resorptive agents);
• documented history of cognitive impairment or dementia, or Mini-Cog < 4;
• current smoker;
• personal history of breast, ovarian, metastatic endometrial, or cervical cancer;
• any cancer requiring treatment in the past 3 years except non-melanoma skin cancers;
• un-diagnosed vaginal bleeding;
• women who, in the judgment of the study physician, appear incapable of safely participating in the exercise (e.g., neuromuscular/musculoskeletal impairment)
• use of insulin;
• lumbar spine, total hip, or femoral neck aBMD t-scores < -3.0;
• secondary osteoporosis

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Exercise and DHEA; 1 study pill containing 50 mg of DHEA daily for 36 weeks and supervised bone-loading exercise on 3 days per week for 36 weeks.	Other: DHEA; Participants will take 1 study pill (50 mg DHEA) daily for 36 weeks.; Other Names: DHEA therapy; Behavioral: Exercise; bone-loading exercise on 3 days per week for 38 weeks; Other Names: bone-loading exercise
Active Comparator: Exercise and Placebo; 1 study pill containing placebo daily for 36 weeks and supervised bone-loading exercise on 3 days per week for 36 weeks.	Behavioral: Exercise; bone-loading exercise on 3 days per week for 38 weeks; Other Names: bone-loading exercise; Other: Placebo; Participants will take placebo daily for 36 weeks.
Active Comparator: DHEA only; 1 study pill containing 50 mg of DHEA daily for 36 weeks	Other: DHEA; Participants will take 1 study pill (50 mg DHEA) daily for 36 weeks.; Other Names: DHEA therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in lumbar spine aBMD	mean change from baseline in lumbar spine aBMD	Baseline and 36 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total hip aBMD	mean change from baseline in total hip aBMD	36 Weeks
Change in regional hip aBMD	mean change from baseline in regional hip aBMD	Baseline and 36 Weeks
Change in Vertebral (L1-2) total volumetric bone mineral density (vBMD)	mean change from baseline in vertebral total volumetric BMD	Baseline and 36 Weeks
Change in Vertebral (L1-2) cortical vBMD	mean change from baseline in vertebral cortical volumetric BMD	Baseline and 36 Weeks
Change in Vertebral (L1-2) trabecular vBMD	mean change from baseline in vertebral trabecular volumetric BMD	Baseline and 36 Weeks
Change in Femoral total vBMD	mean change from baseline in femoral total volumetric BMD	Baseline and 36 Weeks
Change in Femoral cortical vBMD	mean change from baseline in femoral cortical volumetric BMD	Baseline and 36 Weeks
Change in Femoral trabecular vBMD	mean change from baseline in femoral trabecular volumetric BMD	Baseline and 36 Weeks
Change in Vertebral (L1-2) strength, stance model	mean change from baseline in the estimated strength of L1-2 vertebrae in a stance model	Baseline and 36 Weeks
Change in Vertebral (L1-2) strength, fall model	mean change from baseline in the estimated strength of L1-2 vertebrae in a fall model	Baseline and 36 Weeks
Change in Proximal femur strength, stance model	mean change from baseline in the estimated strength of the proximal femur in a stance model	Baseline and 36 Weeks
Change in Proximal femur strength, fall model	mean change from baseline in the estimated strength of the proximal femur in a fall model	Baseline and 36 Weeks
Change in Total body fat-free mass	mean change from baseline in total body fat-free mass	Baseline and 36 Weeks

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute on Aging (NIA)

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2018
• Primary Completion (Anticipated): April 1, 2024
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: July 20, 2017
• First Submitted That Met QC Criteria: July 20, 2017
• First Posted (Actual): July 24, 2017

Study Record Updates

• Last Update Posted (Actual): March 14, 2023
• Last Update Submitted That Met QC Criteria: March 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: exercise; postmenopause; dehydroepiandrosterone (DHEA); sex hormones; areal bone mineral density
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Osteoporosis, Postmenopausal; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Dehydroepiandrosterone
• Other Study ID Numbers: 16-2427; R01AG053489 (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: No
• Studies a U.S. FDA-regulated device product: No