The dynamic relationships between the active and catabolic vitamin D metabolites, their ratios, and associations with PTH

Vitamin D status, assessed by serum concentration of 25(OH)D, is the prime candidate marker for many disease-association studies, but the interplay between the subsequent 1,25-dihydroxyvitamin D (1,25(OH)2D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) metabolites is unclear. In this study, we conducted an analysis from a large cohort of healthy, physically fit, young army recruits (n = 940). We found a significant, inverse relationship between serum 25(OH)D and 1,25(OH)2D:24,25(OH)2D vitamin D metabolite ratio (VMR) (r(2)Exp = 0.582, p /=35 to be the threshold value for vitamin D insufficiency, and >/=51 to be predictive of vitamin D deficiency. Our three-dimensional model provides mechanistic insight into the vitamin D-PTH endocrine system, and further substantiates the role of 24,25(OH)2D in human physiology. The model sets a new paradigm for vitamin D treatment strategy, and may help the establishment of vitamin D-adjusted PTH reference intervals. The study was approved by the UK Ministry of Defence research ethics committee (MODREC 165/Gen/10 and 692/MoDREC/15). ClinicalTrials.gov Identifier NCT02416895

Efficacy of High Dose Vitamin D Supplements for Elite Athletes.

PURPOSE: Supplementation with dietary forms of vitamin D is commonplace in clinical medicine, elite athletic cohorts and the general population, yet the response of all major vitamin D metabolites to high doses of vitamin D is poorly characterized. We aimed to identify the responses of all major vitamin D metabolites to moderate and high dose supplemental vitamin D3. METHODS: A repeated measures design was implemented in which 46 elite professional European athletes were block randomized based on their basal 25[OH]D concentration into two treatment groups. Athletes received either 35,000 or 70,000 IU.week vitamin D3 for 12 weeks and 42 athletes completed the trial. Blood samples were collected over 18 weeks to monitor the response to supplementation and withdrawal from supplementation. RESULTS: Both doses led to significant increases in serum 25[OH]D and 1,25[OH]2D3. 70,000 IU.week also resulted in a significant increase of the metabolite 24,25[OH]2D at weeks 6 and 12 that persisted following supplementation withdrawal at week 18, despite a marked decrease in 1,25[OH]2D3. Intact PTH was decreased in both groups by week 6 and remained suppressed throughout the trial. CONCLUSIONS: High dose vitamin D3 supplementation (70,000 IU.week) may be detrimental for its intended purposes due to increased 24,25[OH]2D production. Rapid withdrawal from high dose supplementation may inhibit the bioactivity of 1,25[OH]2D3 as a consequence of sustained increases in 24,25[OH]2D that persist as 25[OH]D and 1,25[OH]2D concentrations decrease. These data imply that lower doses of vitamin D3 ingested frequently may be most appropriate and gradual withdrawal from supplementation as opposed to rapid withdrawal may be favorable

Effects of reduced energy availability on bone metabolism in women and men

Background: The short-term effects of low energy availability (EA) on bone metabolism in physically active women and men are currently unknown. Purpose: We evaluated the effects of low EA on bone turnover markers (BTMs) in a cohort of women and a cohort of men, and compared effects between sexes. Methods: These studies were performed using a randomised, counterbalanced, crossover design. Eleven eumenorrheic women and eleven men completed two 5-day protocols of controlled (CON; 45 kcal·kgLBM-1.d-1) and restricted (RES; 15 kcal.kgLBM-1·d-1) EAs. Participants ran daily on a treadmill at 70% of their peak aerobic capacity (VO2 peak) resulting in an exercise energy expenditure of 15 kcal·kgLBM-1·d-1 and consumed diets providing 60 and 30 kcal·kgLBM-1·d-1. Blood was analysed for BTMs [β-carboxyl-terminal cross-linked telopeptide of type I collagen (β-CTX) and amino-terminal propeptide of type 1 procollagen (P1NP)], markers of calcium metabolism [( parathyroid hormone (PTH), albumin-adjusted calcium (ACa), magnesium (Mg) and phosphate (PO4)] and regulatory hormones [sclerostin, insulin-like growth factor 1 (IGF-1), triiodothyronine (T3), insulin, leptin, glucagon-like- peptide-2 (GLP-2)]. Results: In women,β-CTX AUC was significantly higher P=0.03) and P1NP AUC was significantly lower (P=0.01) in RES compared to CON. In men, neither β-CTX (P=0.46) n or P1NP (P=0.12) AUCs were significantly different between CON and RES. There were no significant differences between sexes for any BTM AUCs (all P values>0.05). Insulin and leptin AUCs were significantly lower following RES in women only (for both P=0.01). There were no differences in any AUCs of regulatory hormones or markers of calcium metabolism between men and women following RES (all P values>0.05). Conclusions: When comparing within groups, five days of low EA (15 kcal·kgLBM-1·d-1) decreased bone formation and increased bone resorption in women, but not in men, and no sex specific differences were detected

Bone metabolic responses to low energy availability achieved by diet or exercise in active eumenorrheic women

Purpose: We aimed to explore the effects of low energy availability (EA)[15 kcal·kg lean body mass (LBM)−1·d−1] achieved by diet or exercise on bone turnover markers in active, eumenorrheic women. Methods: By using a crossover design, ten eumenorrheic women (VO2 peak: 48.1 ± 3.3 ml·kg−1·min−1) completed all three, 3-day conditions in a randomised order: controlled EA (CON; 45 kcal·kgLBM−1·d−1), low EA through dietary energy restriction (D-RES; 15 kcal·kgLBM−1·d−1) and low EA through increasing exercise energy expenditure (E-RES; 15 kcal·kgLBM−1·d−1), during the follicular phase of three menstrual cycles. In CON, D-RES and E-RES, participants consumed diets providing 45, 15 and 45 kcal·kgLBM−1·d−1. In E-RES only, participants completed supervised running sessions (129 ± 10 min·d−1) at 70% of their VO2 peak that resulted in an exercise energy expenditure of 30 kcal·kg LBM−1·d−1. Blood samples were collected at baseline (BASE) and at the end of the 3-day period (D6) and analysed for bone turnover markers (β-CTX and P1NP), markers of calcium metabolism (PTH, albumin-adjusted Ca, Mg and PO4) and hormones (IGF-1, T3, insulin, leptin and 17β-oestradiol). Results: In D-RES, P1NP concentrations at D6 decreased by 17% (BASE: 54.8 ± 12.7 μg·L−1, D6: 45.2 ± 9.3 μg·L−1, P < 0.001, d = 0.91) and were lower than D6 concentrations in CON (D6: 52.5 ± 11.9 μg·L−1, P = 0.001). P1NP did not change significantly in E-RES (BASE: 55.3 ± 14.4 μg·L−1, D6: 50.9 ± 15.8 μg·L−1, P = 0.14). β-CTX concentrations did not change following D-RES (BASE: 0.48 ± 0.18 μg·L−1, D6: 0.55 ± 0.17 μg·L−1) or E-RES (BASE: 0.47 ± 0.24 μg·L−1, D6: 0.49 ± 0.18 μg·L−1) (condition × time interaction effect, P = 0.17). There were no significant differences in P1NP (P = 0.25) or β-CTX (P = 0.13) responses between D-RES and E-RES. Both conditions resulted in reductions in IGF-1 (−13% and − 23% from BASE in D-RES and E-RES, both P < 0.01) and leptin (−59% and − 61% from BASE in D-RES and E-RES, both P < 0.001); T3 decreased in D-RES only (−15% from BASE, P = 0.002) and PO4 concentrations decreased in E-RES only (−9%, P = 0.03). Conclusions: Low EA achieved through dietary energy restriction resulted in a significant decrease in bone formation but no change in bone resorption, whereas low EA achieved through exercise energy expenditure did not significantly influence bone metabolism. Both low EA conditions elicited significant and similar changes in hormone concentrations

Bone metabolic marker concentrations across the menstrual cycle and phases of combined oral contraceptive use

There is a need to further understand the impact of the menstrual cycle and phase of combined oral contraceptive (COC) use on the pre-analytical variability of markers of bone metabolism in order to improve standardisation procedures for clinical practice and research. The aim of this study was to assess bone metabolism marker concentrations across the menstrual cycle and phases of COC use. Carboxy-terminal cross-linking telopeptide of type I collagen (β-CTX), procollagen type 1 N propeptide (P1NP) and Bone alkaline phosphatase (Bone ALP) concentrations were assessed in eumenorrheic women (n = 14) during the early follicular, ovulatory and mid-luteal phases of the menstrual cycle and in COC (Microgynon®) (n = 14) users on day 2-3 of pill consumption (PC1), day 15-16 pill consumption (PC2) and day 3-4 of the pill free interval (PFI). β-CTX was significantly (-16%) lower at PC2 compared to PC1 (P = 0.015) in COC users and was not affected by menstrual cycle phase (P > 0.05). P1NP and Bone ALP were not significantly different across either menstrual cycle phase or phase of COC use (all P > 0.05). There was no difference in pooled bone marker concentrations between eumenorrheic women and COC users (P > 0.05). In contrast to some previous studies, this study showed that bone marker concentrations do not significantly fluctuate across the menstrual cycle. Furthermore, bone resorption markers are significantly affected by phase of COC use, although bone formation markers do not significantly vary by COC phase. Therefore, the phase of COC use should be considered in clinical practice and research when assessing markers of bone metabolism as this can impact circulating concentrations of bone metabolic markers yet is not currently considered in existing guidelines for best practice

Supplementary Energy Increases Bone Formation during Arduous Military Training

Purpose: This study aimed to investigate the effect of supplementary energy on bone formation and resorption during arduous military training in energy deficit. Methods: Thirty male soldiers completed an 8-wk military combat course (mean ± SD, age = 25 ± 3 yr, height = 1.78 ± 0.05 m, body mass = 80.9 ± 7.7 kg). Participants received either the habitual diet (control group, n = 15) or an additional 5.1 MJ·d−1 to eliminate the energy deficit (supplemented group, n = 15). Circulating markers of bone formation and resorption, and reproductive, thyroid, and metabolic status, were measured at baseline and weeks 6 and 8 of training. Results: Bone-specific alkaline phosphatase decreased in controls (−4.4 ± 1.9 μg·L−1) and increased in the supplemented group (16.0 ± 6.6 μg·L−1), between baseline and week 8 (P < 0.001). Procollagen type 1 N-terminal propeptide increased between baseline and week 6 for both groups (5.6 ± 8.1 μg·L−1, P = 0.005). Beta carboxy-terminal cross-linking telopeptide of type 1 collagen decreased between baseline and week 8 for both groups (−0.16 ± 0.20 μg·L−1, P < 0.001). Prolactin increased from baseline to week 8 for the supplemented group (148 ± 151 IU·L−1, P = 0.041). The increase in adiponectin from baseline to week 8 was higher in controls (4.3 ± 1.8 mg·L−1, P < 0.001) than that in the supplemented group (1.4 ± 1.0 mg·L−1, P < 0.001). Insulin-like growth factor binding protein-3 was lower at week 8 than baseline for controls (−461 ± 395 ng·mL−1, P < 0.001). Conclusion: The increase in bone-specific alkaline phosphatase, a marker of bone formation, with supplementation supports a role of energy in osteoblastic activity; the implications for skeletal adaptation and stress fracture risk are unclear. The mechanism is likely through protecting markers of metabolic, but not reproductive or thyroid, function

Distinct neural activity associated with focused-attention meditation and loving-kindness meditation

2012-2013 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

The effects of short-term low energy availability, achieved through diet or exercise, on cognitive function in oral contraceptive users and eumenorrheic women

To date, no research has explored the effects of low energy availability on cognitive performance using dietary and exercise regimens relevant to athletes. Twenty female participants (10 eumenorrheic, 10 oral contraceptive [OC] users) completed three 3-day conditions: 1) controlled-balanced energy availability without exercise (BAL; 45 kcal·kg lean body mass [LBM]−1·day−1); 2) diet-induced low energy availability without exercise (DIET; 15 kcal·kg LBM−1·day−1); and 3) exercise-induced low energy availability (EX; 15 kcal·kg LBM−1·day−1, including 30 kcal·kg LBM−1·day−1 treadmill running at 70% maximal oxygen uptake). A cognitive test battery was completed before and after each 3-day condition. Mental rotation test accuracy improved in the BAL condition, but there was a decline in accuracy in the EX condition (BAL, +2.5%; EX, −1.4%; P = 0.042, d = 0.85). DIET (+1.3%) was not different to BAL or EX (P > 0.05). All other measures of cognitive performance were not affected by condition (P > 0.05) and OC use did not affect cognitive responses (P > 0.05). Accuracy in the mental rotation test was impaired when low energy availability was induced through increased exercise energy expenditure. All other aspects of cognition were unaffected by 3 days of low energy availability through diet or exercise. OC use did not mediate the effect of low energy availability on cognition

Vitamin D metabolites are associated with musculoskeletal injury in young adults: a prospective cohort study

The relationship between vitamin D metabolites and lower body (pelvis and lower limb) overuse injury is unclear. In a prospective cohort study, we investigated the association between vitamin D metabolites and incidence of lower body overuse musculoskeletal and bone stress injury in young adults undergoing initial military training during all seasons. In 1637 men and 530 women (age, 22.6 ± 7.5 years; BMI, 24.0 ± 2.6 kg∙m-2 ; 94.3% white ethnicity), we measured serum 25-hydroxyvitamin D (25(OH)D) and 24,25- dihydroxyvitamin D (24,25(OH)2D) by high-performance liquid chromatography tandem mass spectrometry, and 1,25-dihydroxyvitamin D (1,25(OH)2D) by immunoassay during week 1 of training. We examined whether the relationship between 25(OH)D and 1,25(OH)2D:24,25(OH)2D ratio was associated with overuse injury. During 12 weeks training, 21.0% sustained ≥1 overuse musculoskeletal injury, and 5.6% sustained ≥1 bone stress injury. After controlling for sex, BMI, 2.4 km run time, smoking, bone injury history, and Army training course (Officer, standard, or Infantry), lower body overuse musculoskeletal injury incidence was higher for participants within the second lowest versus highest quartile of 24,25(OH)2D (OR: 1.62 [95%CI 1.13–2.32; P = 0.009]) and lowest versus highest cluster of 25(OH)D and 1,25(OH)2D:24,25(OH)2D (OR: 6.30 [95%CI 1.89–21.2; P = 0.003]). Lower body bone stress injury incidence was higher for participants within the lowest versus highest quartile of 24,25(OH)2D (OR: 4.02 [95%CI 1.82–8.87; P < 0.001]) and lowest versus highest cluster of 25(OH)D and 1,25(OH)2D:24,25(OH)2D (OR: 22.08 [95%CI 3.26–149.4; P = 0.001]), after controlling for the same covariates. Greater conversion of 25(OH)D to 24,25(OH)2D, relative to 1,25(OH)2D (i.e., low 1,25(OH)2D:24,25(OH)2D), and higher serum 24,25(OH)2D were associated with a lower incidence of lower body overuse musculoskeletal and bone stress injury. Serum 24,25(OH)2D may have a role in preventing overuse injury in young adults undertaking arduous physical training

Elevated urinary excretion of free pyridinoline in Friesian horses suggests a breed-specific increase in collagen degradation

Background: Friesian horses are known for their high inbreeding rate resulting in several genetic diseases such as hydrocephaly and dwarfism. This last decade, several studies focused on two other presumed hereditary traits in Friesian horses: megaoesophagus and aortic rupture. The pathogenesis of these diseases remains obscure but an important role of collagen has been hypothesized. The purpose of this study was to examine possible breed-related differences in collagen catabolism. Urinary specimens from Friesian (n = 17, median age 10 years old) and Warmblood horses (n = 17, median age 10 years old) were assessed for mature collagen cross-links, i.e. pyridinoline (PYD) (=hydroxylysylpyridinoline/HP) and deoxypyridinoline (DPD) (lysylpyridinoline /LP). Solid-phase extraction was performed, followed by reversed-phase ion-paired liquid chromatography prior to tandem mass spectrometry (MS/MS) detection. Results: Mean urinary concentrations of free PYD, expressed as fPYD/creatinine ratio, were significantly higher in Friesian horses compared to Warmblood horses (28.5 ± 5.2 versus 22.2 ± 9.6 nmol/mmol, p = 0.02) while mean fDPD/creatinine ratios were similar in both horse breeds (3.0 ± 0.7 versus 4.6 ± 3.7 nmol/mmol, p = 0.09). Conclusions: Since DPD is considered a specific bone degradation marker and PYD is more widely distributed in connective tissues, the significant elevation in the mean PYD/DPD ratio in Friesian versus Warmblood horses (9.6 ± 1.6 versus 5.7 ± 1.8, p < 0.0001) suggests a soft tissue origin for the increased fPYD levels. Considering that a previous study found no differences in total collagen content between Friesian and Warmblood horses for tendon and aortic tissue, this indicates a higher rate of collagen degradation. The latter might, at least in part, explain the predisposition of Friesians to connective tissue disorders