The Effect of Calcium Intake and Low Energy Availability on Calcium and Bone Metabolism During Load Carriage in Women

Overview

This randomised trial will investigate the effect of low energy availability (energy intake minus exercise energy expenditure), and calcium supplementation during low energy availability, on bone and calcium metabolism in women during acute load carriage exercise. This study will test the following hypotheses: i) low energy availability will result in an uncoupling of bone turnover and a negative calcium balance during load carriage; ii) calcium supplementation during low energy availability will attenuate the increase in bone resorption and negative calcium balance.

Full Title of Study: “The Effect of Calcium Intake and Low Energy Availability on Calcium and Bone Metabolism During Load Carriage in Women: a Randomised Controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: June 2022

Detailed Description

Military field exercises are characterised by high exercising energy expenditures, restricted dietary intake and prolonged periods of load carriage. These exercise and nutritional challenges can result in impaired bone turnover, a negative calcium balance and an increased risk of stress fracture. Women have increased sensitivity to metabolic and endocrine disturbances associated with energy deficit, and have a higher incidence of stress fracture during military training compared with men. This randomised trial will investigate the effect of low energy availability (energy intake minus exercise energy expenditure), and calcium supplementation during low energy availability, on bone and calcium metabolism in women during acute load carriage exercise. This randomised controlled trial will randomise women into three groups, stratified by aerobic fitness, body mass index and contraception. Each participant will complete two 6-day experimental testing sessions before (baseline) and after (follow-up) 2 weeks of an experimental diet: Group 1) adequate energy (45 kcal∙kg fat free mass [FFM]∙d-1) / adequate calcium (1500 mg∙d-1); Group 2) low energy availability (15 kcal∙kg FFM∙d-1) / adequate calcium (1500 mg∙d-1), and; Group 3) low energy availability (15 kcal∙kg FFM∙d-1) / low calcium (250 mg∙d-1). Each 6-day trial will involve three bouts of load carriage (9.7 km in 90 minutes carrying 20 kg), separated by 24 to 48 hours recovery whilst remaining on the experimental diet. During each experimental trial blood and urine will be sampled for markers of bone and calcium metabolism, and endocrine function. Following the completion of the second, 6-day experimental trial, participants will return to their habitual diet for 2 weeks and then provide a recovery blood and urine sample. Primary Outcome: The absolute change in urinary calcium balance (Ca44:Ca42) from Experimental Testing 1 to 2 will be compared between groups (Group 1 vs Group 2 and Group 2 vs Group 3) using one-way ANCOVAs with calcium balance (either as a ratio, or both the numerator and denominator) in Experimental Testing 1 and baseline body mass as the covariates, or a linear mixed model with the restricted maximum likelihood estimation to allow incorporation of incomplete data. Secondary Outcomes: Absolute change for AUC for circulating measures of bone turnover and calcium metabolism during load carriage from Experimental Testing 1 to 2 will be compared between groups using one-way ANCOVAs (Group 1 vs Group 2 and Group 2 vs Group 3) with AUC in Experimental Testing 1 as the covariate, or a linear mixed model with the restricted maximum likelihood estimation to allow incorporation of incomplete data. Absolute change for fasting circulating measures of bone turnover, calcium metabolism and endocrine function from Experimental Testing 1 to 2 will be compared between groups (Group 1 vs Group 2 and Group 2 vs Group 3) using one-way ANCOVAs with baseline measures in Experimental Testing 1 as the covariate, or a linear mixed model with the restricted maximum likelihood estimation to allow incorporation of incomplete data. A mixed-design 3 × 3 (Group [Group 1 vs Group 2 vs Group 3] × time [Experimental Testing 1 vs Experimental Testing 2 vs Recovery]) ANOVA will be used to examine changes in body mass, lean mass, fat mass and aBMD.

Interventions

  • Dietary Supplement: Calcium
    • Daily calcium food supplement.
  • Dietary Supplement: Low Energy Availability
    • Restriction of dietary energy intake.

Arms, Groups and Cohorts

  • Active Comparator: Adequate energy and adequate calcium
    • All dietary food and water will be provided for 19 days. The energy content of the diet will be prescribed, according to exercise levels, to elicit an energy availability of 45 kcal per kg of fat free mass per day. Foods high in calcium will be removed and participants will be provided with a calcium and vitamin D food supplement (two daily 500 mg calcium and 400 IU vitamin D3 supplements) (total calcium intake 1500 mg per day and 800 IU vitamin D3 per day).
  • Experimental: Low energy and adequate calcium
    • All dietary food and water will be provided for 19 days. The energy content of the diet will be prescribed, according to exercise levels, to elicit an energy availability of 45 kcal per kg of fat free mass per day for the first 7 days and 15 kcal per kg of fat free mass per day thereafter. Foods high in calcium will be removed and participants will be provided with a calcium and vitamin D food supplement (two daily 500 mg calcium and 400 IU vitamin D supplements) (total intake 1500 mg calcium per day and 800 IU vitamin D3 per day).
  • Active Comparator: Low energy and low calcium
    • All dietary food and water will be provided for 19 days. The energy content of the diet will be prescribed, according to exercise levels, to elicit an energy availability of 45 kcal per kg of fat free mass per day for the first 7 days and 15 kcal per kg of fat free mass per day thereafter. Foods high in calcium will be removed and participants will be provided with a vitamin D food supplement (two daily 400 IU vitamin D supplements) (total intake <500 mg calcium per day and 800 IU vitamin D3 per day).

Clinical Trial Outcome Measures

Primary Measures

  • Change in calcium balance.
    • Time Frame: Before and immediately after the two week dietary intervention.
    • The ratio of the calcium isotopes Ca44:Ca42 in total 24 hour urine measured across three days (day 1, day 3 and day 5 of each 6-day experimental trial). Calcium balance will be taken as the average of the three days.

Secondary Measures

  • Circulating calcium isotopes at rest.
    • Time Frame: Before and immediately after the two week dietary intervention.
    • The ratio of the calcium isotopes Ca44 and Ca42 (Ca44:Ca42) in blood at fasted rest on day 1 and day 6 of each 6-day experimental trial.
  • Circulating calcium isotopes during load carriage.
    • Time Frame: Immediately after the two week dietary intervention.
    • The ratio of the calcium isotopes Ca44 and Ca42 (Ca44:Ca42) in blood pre- and post- exercise on day 1 of load carriage at follow-up only.
  • Bone turnover at rest.
    • Time Frame: Before and immediately after the two week dietary intervention.
    • Fasted circulating concentration of procollagen type 1 N-terminal propeptide (P1NP), bone specific alkaline phosphate (bone ALP), beta carboxy-terminal cross-linking telopeptide of type 1 collagen (βCTX), sclerostin, osteocalcin, albumin-adjusted calcium, ionized calcium, and phosphate on day 1 and day 6 of each 6-day experimental trial.
  • Bone turnover during load carriage.
    • Time Frame: Before and immediately after the two week dietary intervention.
    • Circulating concentration of procollagen type 1 N-terminal propeptide (P1NP), beta carboxy-terminal cross-linking telopeptide of type 1 collagen (βCTX), osteocalcin and sclerostin, taken at 0, 15, 30, 45, 60, 75 and 90 minutes during, and 15, 30, 60 and 90 minutes following, load carriage exercise on day 1 of each 6-day experimental trial.
  • Calcium metabolism during load carriage.
    • Time Frame: Before and immediately after the two week dietary intervention.
    • Circulating concentration of ionized calcium, phosphate, and intact parathyroid hormone at 0, 15, 30, 45, 60, 75, 90 minutes during, and 15, 30 60, 90 minutes following load carriage exercise on day 1 of each 6-day experimental trial.
  • Circulating concentrations of reproductive hormones.
    • Time Frame: Before, immediately after, and two weeks after the two week dietary intervention.
    • Fasted circulating concentrations of luteinising hormone, follicle stimulating hormone, oestradiol, testosterone, and sex hormone binding globulin on day 1 of each 6-day experimental trial.
  • Circulating concentrations of metabolic hormones.
    • Time Frame: Before, immediately after, and two weeks after the two week dietary intervention.
    • Fasted circulating concentrations of cortisol, insulin-like growth factor I, IGF binding protein 1 and 3, 3,3,5 triiodothyronine, thyroxine, thyroid stimulating hormone, and leptin on day 1 of each 6-day experimental trial.
  • Dermal calcium loss.
    • Time Frame: Before and immediately after the two week dietary intervention.
    • Concentrations of total calcium and the ratio of the calcium isotopes Ca44 and Ca42 (Ca44:Ca42) in sweat during load carriage exercise on day 1 of each experimental trial.

Participating in This Clinical Trial

Inclusion Criteria

1. Female sex; 2. Aged 18 to 36 years old; 3. Maximal rate of oxygen uptake of ≥ 35 ml∙kg-1∙min-1; 4. Currently either taking no hormonal contraceptives or the combined oral contraceptive pill; 5. Weight stable (no change in self-reported body mass ≥ 5% over the previous 3 months); 6. BMI between 18 and 30 kg∙m2; 7. Not pregnant. Exclusion Criteria:

1. Evidence of disordered eating (≥ 20 on the EAT-26); 2. Habitual energy intake of < 35 kcal∙kg FFM∙d-1; 3. Self-reported change in body mass of ≥ 5% over the previous 3 months; 4. Vitamin D deficient (total 25(OH)D < 30 nmol∙L-1); 5. Maximal rate of oxygen uptake of < 35 ml∙kg-1∙min-1; 6. Total body BMD T-score of < -1; 7. Evidence of menstrual disturbance (oligomenorrhoea: < 9 menstrual cycles in previous 12 months or amenorrhoea: ≤ 3 menstrual cycles in the previous 12 months); 8. Pregnant; 9. Current smoker, or stopped smoking within the last three months; 10. Taking any medications known to affect bone or calcium metabolism (e.g. treatment for thyroid disorders); 11. Self-declared history of heart, liver or kidney disease, diabetes or thyroid disorder; 12. Self-reported stress fracture or any other bone injuries in the previous 12 months; 13. Anaemia (haemoglobin <12 g∙/dL-1).

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: 36 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Army Health Branch, British Army
  • Collaborator
    • University of East Anglia
  • Provider of Information About this Clinical Study
    • Principal Investigator: Dr. Thomas O’Leary, Higher Scientific Officer – Army Health Branch, British Army
  • Overall Contact(s)
    • Thomas J O’Leary, PhD, +441264886795, thomas.oleary100@mod.gov.uk

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