Clinical trial NCT05029128: Enhancing Skeletal Adaptations to PTH and Exercise
Official title: Enhancing Skeletal Adaptation to Exercise by Attenuating the Acute Disruption of Calcium Homeostasis During Exercise
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Exercise
Bone Resorption
Bone Formation
Keywords: Acute exercise
Exercise training
Bone resorption
Bone formation
Parathyroid hormone
Calcium homeostasis
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2021-08-31
Enrollment: 18
Sex: ALL
Minimum age (years): 25
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All participants will undergo the same exercise intervention for this proof-of-concept project, 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.
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: C-terminal peptide of type 1 collagen (CTX)
timeFrame: 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.
measure: Procollagen 1 intact N-terminal propeptide (P1NP)
timeFrame: 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 outcomes:
measure: P1NP
timeFrame: 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
measure: Urinary calcium excretion (uCa)
timeFrame: Urinary Ca excretion is measured over the 4 hours of recovery after the 1st, 8th, and 16th exercise sessions
measure: Serum ionized Ca (iCa)
timeFrame: 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
measure: Serum total Ca (tCa)
timeFrame: 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
measure: Serum parathyroid hormone (PTH)
timeFrame: 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
measure: Serum phosphorus (PO4)
timeFrame: 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
measure: Hematocrit (Hct)
timeFrame: 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
measure: Hemoglobin (Hgb)
timeFrame: 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 outcomes:
measure: Maximal heart rate (HRmax)
timeFrame: HRmax is measured at baseline during a maximal treadmill test
measure: Peak aerobic power (VO2peak)
timeFrame: VO2peak is measured at baseline during a maximal treadmill test
measure: Bone mineral density (BMD)
timeFrame: BMD of the lumbar spine and proximal femur is measured at baseline
measure: Fat mass (FM)
timeFrame: FM is measured at baseline
measure: Fat-free mass (FFM)
timeFrame: FFM is measured at baseline
Locations:
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
Study officials:
affiliation: Rocky Mountain Regional VA Medical Center, Aurora, CO
name: Wendy M Kohrt, PhD
role: PRINCIPAL_INVESTIGATOR
References: