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

Parathyroid hormone secretion is controlled by both ionised calcium and phosphate during exercise and recovery in men

The mechanism by which PTH is controlled during and after exercise is poorly understood due to insufficient temporal frequency of measurements. Objective: To examine the temporal pattern of PTH, PO4, ACa and Ca2+ during and after exercise. Design and setting: A laboratory-based study with a cross-over design, comparing 30 min of running at 55%, 65% and 75%VO2max, followed by 2.5-h of recovery. Blood was obtained at baseline, after 2.5, 5, 7.5, 10, 15, 20, 25 and 30 min of exercise and after 2.5, 5, 7.5, 10, 15, 20, 25, 30, 60, 90 and 150 min of recovery. Participants: Ten men (age 23±1 y, height 1.82±0.07 m, body mass 77.0±7.5 kg) participated. Main Outcome Measures: PTH, PO4, ACa and Ca2+ Results: Independent of intensity, PTH concentrations decreased with the onset of exercise (-21 to -33%; P≤0.001), increased thereafter and were higher than baseline by the end of exercise at 75%VO2max (+52%; P≤0.001). PTH peaked transiently after 5–7.5 min of recovery (+73 to +110%; P≤0.001). PO4 followed a similar temporal pattern to PTH and Ca2+ followed a similar but inverse pattern to PTH. PTH was negatively correlated with Ca2+ across all intensities (r=-0.739 to -0.790; P≤0.001). When PTH was increasing, the strongest cross-correlation was with Ca2+ at 0 lags (3.5 min) (r=-0.902 to -0.950); during recovery, the strongest cross-correlation was with PO4 at 0 lags (8 min) (r=0.987 to 0.995). Conclusions: PTH secretion during exercise and recovery is controlled by a combination of changes in Ca2+ and PO4 in men

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

SNPs in the vicinity of P2X7R, RANK/RANKL/OPG and Wnt signalling pathways and their association with bone phenotypes in academy footballers

Context: Genotype plays an important role in influencing bone phenotypes, such as bone mineral density, but the role of genotype in determining responses of bone to exercise has yet to be elucidated. Objective: To determine whether 10 SNPs associated with genes in the vicinity of P2X7R, RANK/RANKL/OPG and Wnt Signalling Pathways are associated with bone phenotypes in elite academy footballers (Soccer players) and to determine whether these genotypes are associated with training induced changes in bone. Design, participants, and methods: 99 elite academy footballers volunteered to participate. Peripheral computed tomography of the tibia (4%, 14%, 38% and 66% sites) was performed immediately before and 12 weeks after an increase in football training volume. Genotypes were determined using proprietary fluorescence-based competitive allele-specific PCR assays. Results: No significant genotype x time interactions were shown for any of the SNPs analysed (P > 0.05). A main effect of genotype was shown. SOST SNP rs1877632 (trabecular density), P2X7R SNPs rs1718119 (cortical thickness and CSA), rs3751143 (SSI, CSA, cortical CSA and periosteal circumference) RANK/RANKL/OPG SNPs rs9594738 (periosteal circumference), rs1021188 (cortical thickness and CSA) and rs9594759 (cortical density) were associated with bone phenotypes (P < 0.05). Conclusions: No association was shown between P2X7R, RANK/RANKL/OPG and Wnt Signalling SNPs and a change in bone phenotypes following 12 weeks of increased training volume in elite academy footballers. However, SNPs were associated with bone phenotypes pre training. These data highlight the complexity of SNPs in the vicinity of the RANK/RANKL/OPG, P2X7R and Wnt metabolic regulatory pathways with bone phenotypes in elite academy footballers

Does regional loss of bone density explain low trauma distal forearm fractures in men (The Mr F study)?

Summary The pathogenesis of low trauma wrist fractures in men is not fully understood. This study found that these men have lower bone mineral density at the forearm itself, as well as the hip and spine, and has shown that forearm bone mineral density is the best predictor of wrist fracture. Introduction Men with distal forearm fractures have reduced bone density at the lumbar spine and hip sites, an increased risk of osteoporosis and a higher incidence of further fractures. The aim of this case-control study was to investigate whether or not there is a regional loss of bone mineral density (BMD) at the forearm between men with and without distal forearm fractures. Methods Sixty-one men with low trauma distal forearm fracture and 59 age-matched bone healthy control subjects were recruited. All subjects underwent a DXA scan of forearm, hip and spine, biochemical investigations, health questionnaires, SF-36v2 and Fracture Risk Assessment Tool (FRAX). The non-fractured arm was investigated in subjects with fracture and both forearms in control subjects. Results BMD was significantly lower at the ultradistal forearm in men with fracture compared to control subjects, in both the dominant (mean (SD) 0.386 g/cm2 (0.049) versus 0.436 g/cm2 (0.054), p < 0.001) and non-dominant arm (mean (SD) 0.387 g/cm2 (0.060) versus 0.432 g/cm2 (0.061), p = 0.001). Fracture subjects also had a significantly lower BMD at hip and spine sites compared with control subjects. Logistic regression analysis showed that the best predictor of forearm fracture was ultradistal forearm BMD (OR = 0.871 (0.805–0.943), p = 0.001), with the likelihood of fracture decreasing by 12.9% for every 0.01 g/cm2 increase in ultradistal forearm BMD. Conclusions Men with low trauma distal forearm fracture have significantly lower regional BMD at the ultradistal forearm, which contributes to an increased forearm fracture risk. They also have generalised reduction in BMD, so that low trauma forearm fractures in men should be considered as indicator fractures for osteoporosis

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

The role of the central stellar cluster in active galactic nuclei. I. Semi-analytical model

The subject of the paper is the role of the massive stellar cluster in the activity phenomenon and in the structure of active galactic nuclei. We introduce a simple model of stellar dynamics in the internal part of the cluster, which allows us to include both the star-disk and the star-star interactions. It is shown that the properties of the distribution of stars in the vicinity of the black hole are determined both by the interaction of the stars with the accretion disk and by the pair gravitational and contact interaction between the stars. We calculate the distribution of stars in the central parts of the cluster and we discuss possible effects of stellar mass-loss due to the star-disk interaction. Finally, we study the implications of the central cluster for active galactic nuclei activity. We model the broad line region assuming that the gaseous wakes, following stars after each disk crossing, play the role of the broad line region clouds, and we calculate the corresponding line profiles. We also analyze the contribution of star-star and star-disk collisions to active galactic nuclei variability.Comment: Accepted for publication in Astronomy and Astrophysic