search
Back to results

Enhancing Skeletal Adaptations to PTH and Exercise (ESkAPE)

Primary Purpose

Exercise, Bone Resorption, Bone Formation

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Endurance exercise intervention
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Exercise focused on measuring Acute exercise, Exercise training, Bone resorption, Bone formation, Parathyroid hormone, Calcium homeostasis

Eligibility Criteria

25 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Female and male Veterans aged 25 to 45 y and 55 to 75 y will be enrolled. Eligible volunteers will be normally active (e.g., recreational cycling or walking) but will not participate in regular moderate-to-vigorous exercise. Women will be premenopausal with regular menstrual cycles or postmenopausal, defined as absence of menses for at least 12 mo or, in those who underwent a hysterectomy, a serum follicle stimulating hormone (FSH) >30 mIU/mL.

Exclusion Criteria:

  • Initiation or change in dose in the past 6 months of medications that affect bone metabolism

    • e.g., osteoporosis medications, thiazide/loop diuretics, systemic glucocorticoids
  • BMD T-score <-2.5 at the total hip, femoral neck, or lumbar spine
  • Impaired renal function, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2
  • Abnormal alkaline phosphatase
  • Untreated thyroid dysfunction, defined as an ultrasensitive thyroid stimulating hormone (TSH) <0.5 or >5.0 mU/L
  • Serum Ca <8.5 or >10.3 mg/dL
  • Serum 25(OH)D <20 ng/mL
  • Uncontrolled hypertension (resting systolic blood pressure (BP) >150 mmHg or diastolic BP >90 mmHg)
  • Type 1 diabetes
  • Type 2 diabetes if on insulin or sulfonylurea therapy
  • hemoglobin A1c >7%
  • Cardiovascular disease; defined as subjective or objective indicators of ischemic heart disease (e.g., angina, ST segment depression) or serious arrhythmias at rest or during the graded exercise test (GXT)

    • volunteers who have a positive GXT can be re-considered after follow-up evaluation by a cardiologist
  • Anemia (hemoglobin <12.1 g/dL for women, <14.3 g/dL for men)
  • Fracture in the past 6 months
  • Body mass index >39 kg/m2

    • In the event of abnormal eGFR, alkaline phosphatase, TSH, BP, 25(OH)D, or hemoglobin values, volunteers can be reassessed, including after appropriate follow-up evaluation and treatment by their health care provider

Sites / Locations

  • Rocky Mountain Regional VA Medical Center, Aurora, CORecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Exercise

Arm Description

All participants engage in exercise training

Outcomes

Primary Outcome Measures

C-terminal peptide of type 1 collagen (CTX)
CTX is a marker of bone resorption. An increase in CTX in response to exercise is evidence of an acute catabolic response of bone.
Procollagen 1 intact N-terminal propeptide (P1NP)
P1NP is a marker of bone formation. An increase in P1NP from before to after an exercise intervention is evidence of an anabolic response of bone.

Secondary Outcome Measures

P1NP
Serum P1NP is measured to determine if there is an acute anabolic response of bone to exercise and whether it changes in response to exercise training
Urinary calcium excretion (uCa)
Urinary tCa is used to account for Ca loss subsequent to the activation of bone resorption during exercise
Serum ionized Ca (iCa)
Serum iCa is measured to assess the stimulus for PTH secretion and to describe the pattern of change in iCa during and after exercise
Serum total Ca (tCa)
Serum tCa is measured to help interpret changes in iCa (e.g., changes in Ca binding) and to describe the pattern of change in tCa during and after exercise
Serum parathyroid hormone (PTH)
Serum PTH is measured to assess the stimulus for the activation of bone resorption and to describe the pattern of change in PTH during and after exercise
Serum phosphorus (PO4)
Serum PO4 is measured because it is a potential stimulus for PTH secretion
Hematocrit (Hct)
Hct is used to adjust iCa, tCa, PTH, CTX, P1NP, and PO4 for the plasma volume contraction that occurs with exercise
Hemoglobin (Hgb)
Hgb is used to adjust iCa, tCa, PTH, CTX, P1NP, and PO4 for the plasma volume contraction that occurs with exercise

Full Information

First Posted
August 12, 2021
Last Updated
March 24, 2023
Sponsor
VA Office of Research and Development
search

1. Study Identification

Unique Protocol Identification Number
NCT05029128
Brief Title
Enhancing Skeletal Adaptations to PTH and Exercise
Acronym
ESkAPE
Official Title
Enhancing Skeletal Adaptation to Exercise by Attenuating the Acute Disruption of Calcium Homeostasis During Exercise
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 1, 2023 (Actual)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Exercise is essential for building and maintaining bone mass and strength, but current exercise recommendations for how to achieve this lack detail on the optimal exercise prescription. Recent studies found that blood calcium level decreases during exercise, and that calcium is mobilized from bone to slow the decline. If this occurs repeatedly during exercise training, it could diminish the potential benefits of exercise to improve bone health. The proposed study will determine whether further research on pre-exercise supplemental calcium to minimize the decline in blood calcium level during exercise is warranted. This research is important for Veterans because they are at increased risk of hip fracture when compared with non-Veterans. Further, because osteoporosis in men is under-recognized and under-treated, providing male (and female) Veterans with more specific exercise and nutrition guidelines has the potential to enhance bone health, reduce fracture risk, and improve quality of life.
Detailed Description
Exercise is essential for building and maintaining bone mass and strength, but recent work has raised the possibility that current exercise recommendations for bone health may not be appropriate. There is strong evidence that a single bout of vigorous exercise has an acute catabolic effect in bone (i.e., increased resorption) that lasts several hours. This is mediated by a decrease in serum calcium (Ca) during exercise, which stimulates parathyroid hormone (PTH) secretion. PTH then activates bone resorption to mobilize Ca from bone, presumably to prevent the decrease in serum Ca from progressing to a harmful level. This cascade of events can be markedly attenuated by minimizing the decline in serum Ca during exercise via either intravenous or oral Ca administration. The timing of Ca supplementation relative to exercise is likely important, because it must be available for gut absorption during exercise. Interestingly, repeated pharmacologic stimulation of the PTH receptor with PTH analogs (teriparatide, abaloparatide) has anabolic effects on bone, suggesting that repeated exercise-induced increases in PTH could have a chronic anabolic skeletal effect, in addition to the acute catabolic effect, which may be apparent only after repeated exercise sessions. If this is the case, suppressing the PTH response with pre-exercise Ca supplementation may not be appropriate. In this context, this proof-of-concept study will include a short exercise intervention consisting of treadmill exercise at 70% to 80% of maximal heart rate, 60 minutes per day, 4 days per week, for 4 weeks. Serum markers of bone formation and resorption will be measured before, during, and for 24 hours after the 1st, 8th, and 16th exercise sessions to address two questions: 1) Does the acute catabolic response of bone to a single bout of exercise continue to occur with repeated exercise sessions (i.e., exercise training)? 2) Does exercise training also generate an anabolic PTH-mediated bone response, similar to the anabolic response to PTH analog therapy? If the answers to questions 1 and 2 are YES (persistent catabolic signal) and NO (lack of anabolic signal), this will support the need for the randomized controlled trial (RCT), which will evaluate whether taking Ca before exercise to attenuate the acute catabolic response improves skeletal adaptations to exercise training. The overarching goal is to improve the currently imprecise recommendations for exercise to improve and maintain bone health. This research is of high relevance to Veterans, who are at increased risk of hip fracture when compared with non-Veterans. Further, because osteoporosis in men is under-recognized, under-diagnosed, and under-treated, providing male Veterans with an effective non-pharmacologic therapeutic option to reduce fracture risk may help close this treatment gap. The potential impact of this research also extends beyond Veterans. It could lead to reduced risk of exercise-related bone injury (i.e., stress fractures) in active duty military personnel and athletes and to improved bone health in the general population.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Exercise, Bone Resorption, Bone Formation
Keywords
Acute exercise, Exercise training, Bone resorption, Bone formation, Parathyroid hormone, Calcium homeostasis

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
All participants will undergo the same exercise intervention, so there is no randomization. The exercise will be treadmill walking at 70-80% of HRmax for 60 min/d, 4 d/wk, for 4 wk. The mode and intensity of exercise were selected because high-intensity weight-bearing exercise is recommended for bone health, and walking is the most common weight-bearing activity. Although "high-intensity" exercise for bone health refers to the intensity of bone-loading forces, %HRmax is a good proxy because peak bone-loading forces increase as walking or running speed increases. Exercise sessions will be supervised by the research team. This exercise prescription was used in the studies of young and older adults that provided the scientific premise for the current study and resulted in robust PTH and CTX responses.
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Exercise
Arm Type
Other
Arm Description
All participants engage in exercise training
Intervention Type
Behavioral
Intervention Name(s)
Endurance exercise intervention
Intervention Description
All participants engage in treadmill walking 4 days/week, 60 minutes/day, at 70-80% of HRmax for 4 weeks.
Primary Outcome Measure Information:
Title
C-terminal peptide of type 1 collagen (CTX)
Description
CTX is a marker of bone resorption. An increase in CTX in response to exercise is evidence of an acute catabolic response of bone.
Time Frame
The primary outcome for Aim 1 is the change in CTX (dCTX) from before exercise to the peak during 4 hours of recovery measured during the 1st, 8th, and 16th exercise sessions.
Title
Procollagen 1 intact N-terminal propeptide (P1NP)
Description
P1NP is a marker of bone formation. An increase in P1NP from before to after an exercise intervention is evidence of an anabolic response of bone.
Time Frame
The primary outcome for Aim 2 is the change in the pre-exercise P1NP (15 minutes before the start of exercise) from the 1st to the 16th exercise session.
Secondary Outcome Measure Information:
Title
P1NP
Description
Serum P1NP is measured to determine if there is an acute anabolic response of bone to exercise and whether it changes in response to exercise training
Time Frame
Serum P1NP is measured before (-15, 0 minutes), during (15, 30, 45, 60 minutes), and after (15, 30, 60, 120, 180, 240 minutes, 24 hours) the 1st, 8th, and 16th exercise sessions
Title
Urinary calcium excretion (uCa)
Description
Urinary tCa is used to account for Ca loss subsequent to the activation of bone resorption during exercise
Time Frame
Urinary Ca excretion is measured over the 4 hours of recovery after the 1st, 8th, and 16th exercise sessions
Title
Serum ionized Ca (iCa)
Description
Serum iCa is measured to assess the stimulus for PTH secretion and to describe the pattern of change in iCa during and after exercise
Time Frame
Serum iCa is measured before (-15, 0 minutes), during (15, 30, 45, 60 minutes), and after (15, 30, 60, 120, 180, 240 minutes, 24 hours) the 1st, 8th, and 16th exercise sessions
Title
Serum total Ca (tCa)
Description
Serum tCa is measured to help interpret changes in iCa (e.g., changes in Ca binding) and to describe the pattern of change in tCa during and after exercise
Time Frame
Serum tCa is measured before (-15, 0 minutes), during (15, 30, 45, 60 minutes), and after (15, 30, 60, 120, 180, 240 minutes, 24 hours) the 1st, 8th, and 16th exercise sessions
Title
Serum parathyroid hormone (PTH)
Description
Serum PTH is measured to assess the stimulus for the activation of bone resorption and to describe the pattern of change in PTH during and after exercise
Time Frame
Serum PTH is measured before (-15, 0 minutes), during (15, 30, 45, 60 minutes), and after (15, 30, 60, 120, 180, 240 minutes, 24 hours) the 1st, 8th, and 16th exercise sessions
Title
Serum phosphorus (PO4)
Description
Serum PO4 is measured because it is a potential stimulus for PTH secretion
Time Frame
Serum PO4 is measured before (-15, 0 minutes), during (15, 30, 45, 60 minutes), and after (15, 30, 60, 120, 180, 240 minutes, 24 hours) the 1st, 8th, and 16th exercise sessions
Title
Hematocrit (Hct)
Description
Hct is used to adjust iCa, tCa, PTH, CTX, P1NP, and PO4 for the plasma volume contraction that occurs with exercise
Time Frame
Hct is measured before (-15, 0 minutes), during (15, 30, 45, 60 minutes), and after (15, 30, 60, 120, 180, 240 minutes, 24 hours) the 1st, 8th, and 16th exercise sessions
Title
Hemoglobin (Hgb)
Description
Hgb is used to adjust iCa, tCa, PTH, CTX, P1NP, and PO4 for the plasma volume contraction that occurs with exercise
Time Frame
Hgb is measured before (-15, 0 minutes), during (15, 30, 45, 60 minutes), and after (15, 30, 60, 120, 180, 240 minutes, 24 hours) the 1st, 8th, and 16th exercise sessions
Other Pre-specified Outcome Measures:
Title
Maximal heart rate (HRmax)
Description
HRmax is used to describe the cohort and generate individual exercise prescriptions for the intervention
Time Frame
HRmax is measured at baseline during a maximal treadmill test
Title
Peak aerobic power (VO2peak)
Description
VO2peak is used to describe the cardiorespiratory fitness of the participants
Time Frame
VO2peak is measured at baseline during a maximal treadmill test
Title
Bone mineral density (BMD)
Description
BMD is used to describe the bone health status of the participants
Time Frame
BMD of the lumbar spine and proximal femur is measured at baseline
Title
Fat mass (FM)
Description
FM is used to describe the body composition of participants
Time Frame
FM is measured at baseline
Title
Fat-free mass (FFM)
Description
FFM is used to describe the body composition of participants
Time Frame
FFM is measured at baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Female and male Veterans aged 25 to 45 y and 55 to 75 y will be enrolled. Eligible volunteers will be normally active (e.g., recreational cycling or walking) but will not participate in regular moderate-to-vigorous exercise. Women will be premenopausal with regular menstrual cycles or postmenopausal, defined as absence of menses for at least 12 mo or, in those who underwent a hysterectomy, a serum follicle stimulating hormone (FSH) >30 mIU/mL. Exclusion Criteria: Initiation or change in dose in the past 6 months of medications that affect bone metabolism e.g., osteoporosis medications, thiazide/loop diuretics, systemic glucocorticoids BMD T-score <-2.5 at the total hip, femoral neck, or lumbar spine Impaired renal function, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 Abnormal alkaline phosphatase Untreated thyroid dysfunction, defined as an ultrasensitive thyroid stimulating hormone (TSH) <0.5 or >5.0 mU/L Serum Ca <8.5 or >10.3 mg/dL Serum 25(OH)D <20 ng/mL Uncontrolled hypertension (resting systolic blood pressure (BP) >150 mmHg or diastolic BP >90 mmHg) Type 1 diabetes Type 2 diabetes if on insulin or sulfonylurea therapy hemoglobin A1c >7% Cardiovascular disease; defined as subjective or objective indicators of ischemic heart disease (e.g., angina, ST segment depression) or serious arrhythmias at rest or during the graded exercise test (GXT) volunteers who have a positive GXT can be re-considered after follow-up evaluation by a cardiologist Anemia (hemoglobin <12.1 g/dL for women, <14.3 g/dL for men) Fracture in the past 6 months Body mass index >39 kg/m2 In the event of abnormal eGFR, alkaline phosphatase, TSH, BP, 25(OH)D, or hemoglobin values, volunteers can be reassessed, including after appropriate follow-up evaluation and treatment by their health care provider
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sarah J Wherry, PhD
Phone
(720) 848-6475
Email
sarah.wherry@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Wendy M Kohrt, PhD
Email
wendy.kohrt@cuanschutz.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wendy M Kohrt, PhD
Organizational Affiliation
Rocky Mountain Regional VA Medical Center, Aurora, CO
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rocky Mountain Regional VA Medical Center, Aurora, CO
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Todd R Furbacher, PhD
Phone
720-857-5105
Email
todd.furbacher@va.gov
First Name & Middle Initial & Last Name & Degree
Kimberly K Owens, MPH
Phone
(720) 857-5667
Email
kimberly.owens9@va.gov
First Name & Middle Initial & Last Name & Degree
Wendy M Kohrt, PhD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Because some journals now require authors to provide access to data, de-identified, anonymized data sets (individual- and group-level data) will be created after study results are published, and made available upon requests for general research purposes, based on availability of resources. To the extent possible, care will be taken to ensure that individual-level data are at very low risk of re-identification and there will be no links to personally identifiable information.
IPD Sharing Time Frame
There is no formal plan to share these documents, although requests will be considered. Information related to the protocol and statistical analysis plan will be in the public domain when study results are published.
IPD Sharing Access Criteria
Data will become available after publication of study results and be available at least 3 years beyond the completion of the study.

Learn more about this trial

Enhancing Skeletal Adaptations to PTH and Exercise

We'll reach out to this number within 24 hrs