Prebiotic to Improve Calcium Absorption in Postmenopausal Women After Gastric Bypass: A Randomized Controlled Trial

Context The adverse skeletal effects of Roux-en-Y gastric bypass (RYGB) are partly caused by intestinal calcium absorption decline. Prebiotics, such as soluble corn fiber (SCF), augment colonic calcium absorption in healthy individuals. Objective We tested the effects of SCF on fractional calcium absorption (FCA), biochemical parameters, and the fecal microbiome in a post-RYGB population. Design, Setting, Participants : Randomized, double-blind, placebo-controlled trial of 20 postmenopausal women with history of RYGB mean 5 years prior. Intervention 2-month course of 20 g/day SCF or maltodextrin placebo orally. Main Outcomes Between-group difference in absolute change in FCA (primary outcome) was measured with a gold-standard dual stable isotope method. Other measures included tolerability, adherence, serum calciotropic hormones and bone turnover markers, and fecal microbial composition via 16S rRNA gene sequencing. Results Mean FCA ±SD at baseline was low at 5.5±5.1%. Comparing SCF to placebo, there was no between-group difference in mean (95% CI) change in FCA (+3.4 [-6.7,+13.6]%), nor in calciotropic hormones or bone turnover markers. The SCF group had a wider variation in FCA change than placebo (SD 13.4% vs. 7.0%). Those with greater change in microbial composition following SCF treatment had greater increase in FCA (r 2=0.72,p=0.05). SCF adherence was high, and GI symptoms similar between groups. Conclusions No between-group differences were observed in changes in FCA or calciotropic hormones, but wide confidence intervals suggest a variable impact of SCF that may be due to the degree of gut microbiome alteration. Daily SCF consumption was well-tolerated. Larger and longer-term studies are warranted.

New reference intervals for endocrinological biomarkers in pediatric patients: what can we learn from the LIFE child study?

Objectives We established reference intervals for serum concentrations of hormones from healthy pediatric subjects and investigated their associations with gender, body mass index (BMI), puberty and oral contraceptives (oC). Methods We calculated reference intervals for the thyroid parameters thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and calcitonin (Ct); the bone markers osteocalcin, procolagen type 1 N-propeptide, and carboxy-terminal cross-linking telopeptide of type 1 collagen; the calciotropic hormones 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone and the steroids cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, estradiol, dehydroepiandrosterone sulfate and aldosterone. Up to 10,002 blood serum samples from 3,229 healthy children and adolescents (age interval: 3 months to 20 years) were measured. To investigate the associations between the hormone levels with age, sex, weight status and the role of puberty-based changes, the measurement and BMI values were transformed into standard deviation scores. Results Most of the hormones depended on age- and gender. Puberty was linked to a, in part, temporary decrease in TSH, FT3 (for females), FT4, Ct, cortisol (for girls) and aldosterone (for boys) and peak in the bone marker and calciotropic hormones (excluding 25(OH)D) and nearly all remaining steroids. BMI had effects on the thyroid, bone, and calciotropic parameters, whereas oC led to increased cortisol, suppressed progesterone and estradiol values. Conclusions Age- and gender-specific reference intervals are essential for the interpretation of pediatric patients’ hormone measurements. Influencing factors as puberty, BMI, or oC should be taken into consideration for diagnosis and treatment monitoring.

Diagnosed changes of bone mineral density and level of calciotropic hormones in children with juvenile hyperthyroidism

The development of the skeletal system occur during childhood. Thyroid hormones play an important role in the skeleton's maturation and maintenance of the structure and mass of bones. Juvenile hyperthyroidism affects bone metabolism. This study aimed to identify abnormalities in bone mineral density and the level of calciotropic hormones in juvenile hyperthyroidism to further improve the diagnosis of complications of juvenile hyperthyroidism. Materials and methods. The study was conducted by 21 health controls and 71 children and adolescents with juvenile hyperthyroidism. Anthropometric indicators were calculated using the WHO Anthro Plus personal computer software. Thyroid status and thyroid antibodies, osteocalcin, parathyroid hormone, vitamin D, calcium, phosphorus, alkaline phosphatase were determined using a closed-type immunochemistry analyzer Cobas e 411 Hitachi company Hoffman Le Roche (Switzerland) and its reagents. Bone mineral density was evaluated by dual-energy absorptiometry on a Stratos X-ray densitometer from Diagnostic Medical Systems, France. Results. In juvenile hypertrichosis, in comparison with the control, significantly low values of vitamin D and calcium in the blood serum were noted, the mean values of osteocalcin and alkaline phosphatase were substantially higher. There was no significant difference in the levels of parathyroid hormone and phosphorus in the blood serum in the compared groups. In 45.1% of patients, a decrease in bone mass was diagnosed compared to the age norm. A reliable direct correlation of vitamin D and calcium with bone density was revealed in all X-ray densitometry parameters and a reliable inverse correlation of osteocalcin, alkaline phosphatase and bone mineral density. Osteocalcin had a stronger inverse correlation with all dual-energy X-ray absorptiometry parameters and became a better biomarker than alkaline phosphatase. Conclusions. There is a decrease in bone mineral density in children with juvenile hyperthyroidism. Changes in the level of calciotropic hormones indicate a deranged bone metabolism. Serum osteocalcin can be used as a biomarker of bone metabolism in children with juvenile hyperthyroidism. It is recommended to assess the bones' condition during the initial examination of children with juvenile hyperthyroidism. The study was carried out following the principles of the Declaration of Helsinki. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the parents of the children was obtained for the research. The author declares no conflicts of interest. Key words: juvenile hyperthyroidism, children, adolescents, bone mineral density; dual energy X-ray absorptiometry, osteocalcin, vitamin D.

Diagnosed Changes of Bone Mineral Density and Level of Calciotropic Hormones in Juvenile Hyperthyroidism

In childhood and adolescence, a genetically determined bone mass accumulates, which ensures the strength of the skeleton throughout life. But with thyrotoxicosis, a separation of the processes of bone resorption and synthesis and the formation of sites of osteoporosis and osteosclerosis occur, leading to the loss of 10% of bone mass in 1 cycle of remodeling. Because of the lack of information about this phenomenon, our work aimed to study the state of bone mineral density and levels of calciotropic hormones in children and adolescents with thyrotoxicosis. The study was conducted by 19 children and adolescents with thyrotoxicosis. The control group consisted of 23 healthy children and adolescents. All studies were conducted in the RSSPMCE. Thyroid status, PTH and vitamin D were determined using a closed-type immunochemistry analyser Cobas e 411 Hitachi company HoffmanLeRoche (Switzerland) and its reagents. Bone mineral density was evaluated by dual-energy absorptiometry on a Stratos X-ray densitometer from DMS, France. The results of the study showed that the average value of the level of vitamin D in the group with thyrotoxicosis was 12.3 ± 1.1 ng/ml, against 20.4 ± 6.2 ng/ml of the control group, while its deficiency was diagnosed in 84.2%, and its insufficiency - in 15.8% of pediatric patients. In the group with thyrotoxicosis, the average level of PTH was lower and amounted to 45.1 ± 23.9 ng/ml (p < 0.05) compared with the control (49.2 ± 21.3 ng/ml); hypoparathyroidism was found in 4.9 times more often than among healthy children, and 21.1% showed an increase in the level of PTH. In children and adolescents with thyrotoxicosis Z- index of the femoral neck, lumbar vertebrae and the general body were significantly lower than in the control group. 36.8% of children with thyrotoxicosis have osteoporosis. Conclusion: Thyrotoxicosis in children and adolescents causes a decrease in BMD and majorly increases the development of osteoporosis.

Memo1 gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones

Mediator of Cell Motility 1 (MEMO1) is an ubiquitously expressed modulator of cellular responses to growth factors including FGF23 signaling, and Memo1-deficient mice share some phenotypic traits with Fgf23- or Klotho-deficient mouse models. Here, we tested whether Memo1 gene expression is regulated by calciotropic hormones or by changing the dietary mineral load.MLO-Y4 osteocyte-like cells were cultured and treated with 1,25(OH)2-vitamin D3. Wildtype C57BL/6N mice underwent treatments with 1,25(OH)2-vitamin D3, parathyroid hormone (PTH), 17β-estradiol or vehicle. Other cohorts of C57BL/6N mice were fed diets varying in calcium or phosphate content. Expression of Memo1 and control genes was assessed by qPCR.1,25(OH)2-vitamin D3 caused an acute decrease in Memo1 transcript levels in vitro, but not in vivo. None of the hormones tested had an influence on Memo1 transcripts, whereas the assessed control genes reacted the expected way. Dietary interventions with calcium and phosphate did not affect Memo1 transcripts but altered the chosen control genes’ expression.We observed that Memo1 was not regulated by calciotropic hormones or change in mineral load, suggesting major differences between the regulation and physiological roles of Klotho, Fgf23 and Memo1.

Vitamin D and Reproductive Hormones Across the Menstrual Cycle

STUDY QUESTION How do the calciotropic hormones (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and intact parathyroid hormone (iPTH)) vary across the menstrual cycle and do cyclic patterns of reproductive hormones (estradiol, progesterone, LH, FSH) differ by vitamin D status? SUMMARY ANSWER Calciotropic hormones vary minimally across the menstrual cycle; however, women with 25-hydroxyvitamin D below 30 ng/ml have lower mean estradiol across the menstrual cycle. WHAT IS KNOWN ALREADY Prior human studies suggest that vitamin D status is associated with fecundability, but the mechanism is unknown. Exogenous estrogens and prolonged changes in endogenous estradiol (pregnancy or menopause) influence concentrations of 25-hydroxyvitamin D. In vitro, treatment with 1,25-dihydroxyvitamin D increases steroidogenesis in ovarian granulosa cells. There are little data about changes in calciotropic hormones across the menstrual cycle or cyclic patterns of reproductive hormones by categories of vitamin D status. STUDY DESIGN, SIZE, DURATION A prospective cohort study of 89 self-identified white women aged 18–44, across two menstrual cycles. Participants were a subset of the BioCycle Study, a community-based study conducted at the University of Buffalo, 2005–2007. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible participants had self-reported regular menstrual cycles between 21 and 35 days and were not using hormonal contraception or vitamins. Early morning fasting blood samples were drawn at up to eight study visits per cycle. Visits were timed to capture information in all cycle phases. Serum samples for 89 women (N = 163 menstrual cycles) were analyzed for estradiol, progesterone, LH, FSH and 25-hydroxyvitamin D (25(OH)D). Variability in calciotropic hormones within and across menstrual cycles was assessed using intraclass correlation coefficients and non-linear mixed models. Given the relative stability of the calciotropic hormones across the menstrual cycle, non-linear mixed models were used to examine differences in the cyclic patterns of estradiol, progesterone, LH and FSH by categories of each calciotropic hormone (split at the median). These models were conducted for all ovulatory cycles (N = 142 ovulatory menstrual cycles) and were adjusted for age, BMI (measured in clinic) and self-reported physical activity. MAIN RESULTS AND THE ROLE OF CHANCE Median 25(OH)D concentration was 29.5 ng/ml (SD 8.4), and only 6% of women had vitamin D deficiency (&lt;20 ng/ml). The mean concentration of 25(OH)D did not differ between the luteal and follicular phase; however, both 1,25(OH)2D and iPTH showed small fluctuations across the menstrual cycle with the highest 1,25(OH)2D (and lowest iPTH) in the luteal phase. Compared with women who had mean 25(OH)D ≥30 ng/ml, women with lower 25(OH)D had 13.8% lower mean estradiol (95% confidence interval: −22.0, −4.7) and 10.8% lower free estradiol (95% CI: −0.07, −0.004). Additionally, compared to women with iPTH ≤36 pg/ml, women with higher concentrations of iPTH had 12.7% lower mean estradiol (95% CI: −18.7, −6.3) and 7.3% lower progesterone (95% CI: −13.3, −0.9). No differences in the cyclic pattern of any of the reproductive hormones were observed comparing cycles with higher and lower 1,25(OH)2D. LIMITATIONS, REASONS FOR CAUTION Women included in this study had self-reported ‘regular’ menstrual cycles and very few were found to have 25(OH)D deficiency. This limits our ability to examine cycle characteristics, anovulation and the effects of concentrations of the calciotropic hormones found in deficient individuals. Additionally, the results may not be generalizable to women with irregular cycles, other races, or populations with a higher prevalence of vitamin D deficiency. WIDER IMPLICATIONS OF THE FINDINGS These findings support current clinical practice that does not time testing for vitamin D deficiency to the menstrual cycle phase. We find that women with lower vitamin D status (lower 25(OH)D or higher iPTH) have lower mean concentrations of estradiol across the menstrual cycle. Although this study cannot identify a mechanism of action, further in vitro work or clinical trials may help elucidate the biologic mechanisms linking calciotropic and reproductive hormones. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract numbers: HHSN275200403394C, HHSN275201100002I and Task 1 HHSN27500001) and the National Institute of Environmental Health Sciences. There are no competing interests.

Changes in Calciotropic Hormones and Bone Markers During Pregnancy in Response to a Nutrition + Exercise Intervention in the Be Healthy in Pregnancy RCT (P11-023-19)

Objectives Maternal bone health can be compromised in pregnancy if diet and exercise are inadequate. Our objective was to determine the changes of calciotropic hormones and bone biomarkers in response to a maternal high-dairy diet plus exercise intervention compared to usual care from early to late pregnancy. Methods As part of the Be Healthy in Pregnancy RCT (Southern Ontario, Canada) (NCT01689961), healthy pregnant women (≤ 17 wk gestation) were randomized to the control or treatment group (Nutrition: 25% protein energy with ∼50% from dairy and Exercise plan: 10,000 daily steps) for the duration of pregnancy. Calcium and vitamin D intakes were analyzed from 3-day diet and supplement records (Nutritionist Pro). Fasted serum was analyzed for 25(OH)D2 and D3 and 1,25(OH)2D by LC-MS/MS (Waters Corp.); procollagen type I N-terminal propeptide (PINP, Cloud Clone Corp., TX, USA) and insulin growth factor-1 (IGF-1, R&D Systems, MN, USA) by ELISA) at 12–17 and 36–38 wk gestation. T-tests were used to compare groups at baseline. Two-way ANOVA were performed to assess time and treatment effect. Results In 118 women (86% of European descent, mean (range) pre-pregnancy BMI 24.9 kg/m2 (17.9 – 39.6 kg/m2)), baseline median (Q1, Q3) vitamin D and calcium intakes (585 IU/d (453, 823) and 1192 mg/d (979, 1512)) and bone biomarkers were similar between control and treatment groups. Baseline 25(OH)D was 79.6 nmol/L (66.1, 97.7), 1,25(OH)2D was 71.5 pmol/L (62.3, 89.8), PINP was 57.0 ng/mL (37.4, 74.2) and IGF-1 was 178.0 ng/mL (132.0, 212.0). At the end of pregnancy, concentrations of 25(OH)D, 1,25(OH)2D and IGF-1 increased significantly (P < 0.001) by 19%, 34% and 82%, respectively, compared to early pregnancy. PINP remained unchanged and no treatment or interaction effects were observed. Calcium intake was higher in treatment vs control group in late pregnancy (1678 (1285, 2036) vs 1251 (951, 1565) mg/d, P < 0.005), but not vitamin D intake. Conclusions Serum concentrations of all biochemical measures except the bone formation biomarker PINP rose from early to late pregnancy. A high-dairy diet and exercise regimen providing higher calcium intakes did not modulate the changes in bone status induced by pregnancy. Funding Sources CIHR-Vanier and CCHCSP; Dairy Farmers of Canada, CIHR and DFC/AAFC Dairy Research Cluster; in-kind by GayLea Foods & Ultima Foods.