Enhancing Skeletal Adaptations to PTH and Exercise (ESkAPE)

Enhancing Skeletal Adaptation to Exercise by Attenuating the Acute Disruption of Calcium Homeostasis During Exercise

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.

Study Overview

• Status: Completed
• Conditions: Exercise; Bone Resorption; Bone Formation
• Intervention / Treatment: Behavioral: Endurance exercise intervention

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 Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045-7211
      • Rocky Mountain Regional VA Medical Center, Aurora, CO

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 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.	The primary outcome for Aim 1 is the change in CTX from immediately before exercise to 60 minutes after exercise during the 1st, 8th, and 16th exercise bout. Results are for each exercise bout and for the average of all the bouts combined.
Change in 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.	The primary outcome for Aim 2 is the change in the pre-exercise P1NP (15 minutes before exercise) between the 1st and the 16th exercise bout (comparison of 2 time points).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in P1NP During Exercise	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	Change in serum P1NP is measured from before to immediately after the 60 minutes of exercise during the 1st, 8th, and 16th exercise bout. The average change across all exercise bouts is also included.
Urinary Calcium Excretion (uCa)	Urinary tCa is used to account for Ca loss subsequent to the activation of bone resorption during exercise	Urinary Ca excretion is measured over the 4 hours of recovery after exercise. Results are presented for the 1st, 8th, and 16th exercise bout individually and for the average excretion across all 3 collections.
Change in 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 iCa is measured before and 15 minutes after the 60 minutes of exercise during the 1st, 8th, and 16th exercise bout. Average change across all three exercise collection bouts is also provided.
Change in 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	Change in serum tCa is measured before and 15 minutes after the 60 minute exercise bout during the 1st, 8th, and 16th exercise bouts. Average change across all 3 collection bouts is also included.
Change in 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 PTH is measured before and 15 minutes after the 60 minute exercise bout. Results are presented for the 1st, 8th, and 16th exercise bouts individually and for the average change across all 3 collection bouts.
Change in Serum Phosphorus (PO4)	Serum PO4 is measured because it is a potential stimulus for PTH secretion	Serum PO4 is measured before and 15 minutes after the end of the 60 minute exercise bout at the 1st, 8th, and 16th exercise bout. Overall change across all 3 visits is also reported.
Change in Hematocrit (Hct)	Hct is used to adjust iCa, tCa, PTH, CTX, P1NP, and PO4 for the plasma volume contraction that occurs with exercise	Hct is measured before and 15 minutes after the 60 minutes of exercise to correct for plasma volume shifts at the 1st, 8th, and 16th exercise bout. Average change across all 3 exercise bouts is also provided.
Change in Hemoglobin (Hgb)	Hgb is used to adjust iCa, tCa, PTH, CTX, P1NP, and PO4 for the plasma volume contraction that occurs with exercise	Hgb is measured before and 15 minutes after 60 minutes of exercise to correct for plasma volume shifts. Results are presented for the 1st, 8th, and 16th exercise bouts individually and the average across all 3 exercise collection bouts.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal Heart Rate (HRmax)	HRmax is used to describe the cohort and generate individual exercise prescriptions for the intervention	HRmax is measured at only at baseline during the screening maximal treadmill test
Peak Aerobic Power (VO2peak)	VO2peak is used to describe the cardiorespiratory fitness of the participants	VO2peak is only measured at baseline during the screening maximal treadmill test as a demographic outcome.
Bone Mineral Density (BMD)	BMD is used to describe the bone health status of the participants	BMD of the total hip is measured at baseline
Fat Mass (FM)	FM is used to describe the body composition of participants	FM is measured at baseline
Fat-free Mass (FFM)	FFM is used to describe the body composition of participants	FFM is measured at baseline

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Wendy M Kohrt, PhD, Rocky Mountain Regional VA Medical Center, Aurora, CO

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Actual): April 1, 2025
• Study Completion (Actual): December 1, 2025

Study Registration Dates

• First Submitted: August 12, 2021
• First Submitted That Met QC Criteria: August 25, 2021
• First Posted (Actual): August 31, 2021

Study Record Updates

• Last Update Posted (Actual): April 6, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Exercise training; Acute exercise; Parathyroid hormone; Bone formation; Bone resorption; Calcium homeostasis
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Behavior; Bone Resorption; Motor Activity
• Other Study ID Numbers: ENDB-007-20F; 1 I01 CX00284 (Other Grant/Funding Number: VA CSR&D)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.

Drug and device information, study documents

• 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