Enhancing Skeletal Adaptations to PTH and Exercise (ESkAPE)

• ClinicalTrials.gov Identifier: NCT05029128
• Recruitment Status: Recruiting
• First Posted: August 31, 2021
• Last Update Posted: March 27, 2023
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

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.

Condition or disease	Intervention/treatment	Phase
Exercise; Bone Resorption; Bone Formation	Behavioral: Endurance exercise intervention	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment

Intervention 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)
• Primary Purpose: Basic Science
• Official Title: Enhancing Skeletal Adaptation to Exercise by Attenuating the Acute Disruption of Calcium Homeostasis During Exercise
• Actual Study Start Date: January 1, 2023
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: December 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Exercise; All participants engage in exercise training	Behavioral: Endurance exercise intervention; All participants engage in treadmill walking 4 days/week, 60 minutes/day, at 70-80% of HRmax for 4 weeks.

Outcome Measures

Primary Outcome Measures :

1. C-terminal peptide of type 1 collagen (CTX) [ 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. ]
   CTX is a marker of bone resorption. An increase in CTX in response to exercise is evidence of an acute catabolic response of bone.
2. Procollagen 1 intact N-terminal propeptide (P1NP) [ 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. ]
   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 :

1. P1NP [ 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 ]
   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
2. Urinary calcium excretion (uCa) [ Time Frame: Urinary Ca excretion is measured over the 4 hours of recovery after the 1st, 8th, and 16th exercise sessions ]
   Urinary tCa is used to account for Ca loss subsequent to the activation of bone resorption during exercise
3. Serum ionized Ca (iCa) [ 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 ]
   Serum iCa is measured to assess the stimulus for PTH secretion and to describe the pattern of change in iCa during and after exercise
4. Serum total Ca (tCa) [ 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 ]
   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
5. Serum parathyroid hormone (PTH) [ 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 ]
   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
6. Serum phosphorus (PO4) [ 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 ]
   Serum PO4 is measured because it is a potential stimulus for PTH secretion
7. Hematocrit (Hct) [ 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 ]
   Hct is used to adjust iCa, tCa, PTH, CTX, P1NP, and PO4 for the plasma volume contraction that occurs with exercise
8. Hemoglobin (Hgb) [ 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 ]
   Hgb is used to adjust iCa, tCa, PTH, CTX, P1NP, and PO4 for the plasma volume contraction that occurs with exercise

Other Outcome Measures:

1. Maximal heart rate (HRmax) [ Time Frame: HRmax is measured at baseline during a maximal treadmill test ]
   HRmax is used to describe the cohort and generate individual exercise prescriptions for the intervention
2. Peak aerobic power (VO2peak) [ Time Frame: VO2peak is measured at baseline during a maximal treadmill test ]
   VO2peak is used to describe the cardiorespiratory fitness of the participants
3. Bone mineral density (BMD) [ Time Frame: BMD of the lumbar spine and proximal femur is measured at baseline ]
   BMD is used to describe the bone health status of the participants
4. Fat mass (FM) [ Time Frame: FM is measured at baseline ]
   FM is used to describe the body composition of participants
5. Fat-free mass (FFM) [ Time Frame: FFM is measured at baseline ]
   FFM is used to describe the body composition of participants

Eligibility Criteria

• Ages Eligible for Study: 25 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Contacts

Contact: Sarah J Wherry, PhD; (720) 848-6475; sarah.wherry@va.gov

Contact: Wendy M Kohrt, PhD; wendy.kohrt@cuanschutz.edu

Locations

United States, Colorado

Rocky Mountain Regional VA Medical Center, Aurora, CO; Recruiting

Aurora, Colorado, United States, 80045

Contact: Todd R Furbacher, PhD 720-857-5105 todd.furbacher@va.gov

Contact: Kimberly K Owens, MPH (720) 857-5667 kimberly.owens9@va.gov

Principal Investigator: Wendy M Kohrt, PhD

Sponsors and Collaborators

VA Office of Research and Development

Investigators

• Principal Investigator: Wendy M Kohrt, PhD; Rocky Mountain Regional VA Medical Center, Aurora, CO

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT05029128
• Other Study ID Numbers: ENDB-007-20F; 1 I01 CX00284 ( Other Grant/Funding Number: VA CSR&D )
• First Posted: August 31, 2021
• Last Update Posted: March 27, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• 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.
• Access Criteria: Data will become available after publication of study results and be available at least 3 years beyond the completion of the study.

• 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

Keywords provided by VA Office of Research and Development:

Acute exercise; Exercise training; Bone resorption; Bone formation; Parathyroid hormone; Calcium homeostasis

Additional relevant MeSH terms:

Bone Resorption; Bone Diseases; Musculoskeletal Diseases