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Summary: Childhood fracture may predict persistent skeletal fragility, but it may also reflect high physical activity which is beneficial to bone development. We observe a difference in the relationship between previous fracture and bone outcome across physical activity level and sex. Further elaboration on this variation is needed.Purpose: Childhood fracture may be an early marker of skeletal fragility, or increased levels of physical activity (PA), which are beneficial for bone mineral accrual. This study investigated the association between a previous history of childhood fracture and adolescent bone mineral outcomes by various PA levels.Methods: We recruited 469 girls and 492 boys aged 15–18 years to this study. We assessed PA levels by questionnaire and measured areal bone mineral density (aBMD) and bone mineral content (BMC) using dual-energy X-ray absorptiometry (DXA) at arm, femoral neck (FN), total hip (TH), and total body (TB) and calculated bone mineral apparent density (BMAD, g/cm3). Fractures from birth to time of DXA measurements were retrospectively recorded. We analyzed differences among participants with and without fractures using independent sample t test. Multiple linear regression was used to examine the association between fractures and aBMD and BMC measurements according to adolescent PA.Results: Girls with and without a previous history of fracture had similar BMC, aBMD, and BMAD at all sites. In multiple regression analyses stratified by physical activity intensity (PAi), there was a significant negative association between fracture and aBMD-TH and BMC-FN yet only in girls reporting low PAi. There was a significant negative association between forearm fractures, BMAD-FN, and BMAD-arm among vigorously active boys.Conclusion: Our findings indicate a negative association between childhood fractures and aBMD/BMC in adolescent girls reporting low PAi. In boys, such an association appears only in vigorously active participants with a history of forearm fractures. [ABSTRACT FROM AUTHOR]

Summary: Serum parathyroid hormone (PTH) was associated with increased bone turnover markers and cortical porosity of the inner transitional zone at the proximal femur. These results suggest that PTH through increased intracortical bone turnover leads to trabecularisation of inner cortical bone in postmenopausal women.Introduction: Vitamin D deficiency leads to secondary hyperparathyroidism and increased risk for fractures, whereas its association with cortical porosity is less clear. We tested (i) whether serum 25-hydroxyvitamin D (25(OH)D) and PTH were associated with cortical porosity and (ii) whether the associations of 25(OH)D) and PTH with fracture risk are dependent on cortical porosity.Methods: This case-control study included 211 postmenopausal women, 54–94 years old, with prevalent fractures and 232 controls from the Tromsø Study. Serum 25(OH)D, PTH, and bone turnover markers (procollagen type I N-terminal propeptide [PINP] and C-terminal cross-linking telopeptide of type I collagen [CTX]) were measured. Femoral subtrochanteric cortical and trabecular parameters were quantified using computed tomography, and femoral neck areal bone mineral density (FN aBMD) was quantified using dual-energy X-ray absorptiometry.Results: Compared with controls, fracture cases exhibited reduced serum 25(OH)D and increased PTH, PINP, and CTX, increased femoral subtrochanteric cortical porosity, and reduced cortical thickness and FN aBMD (all, p < 0.05). Serum 25(OH)D was not associated with cortical parameters (all, p > 0.10). PTH was associated with increased PINP, CTX, and cortical porosity of the inner transitional zone and reduced trabecular bone volume/tissue volume and FN aBMD (p ranging from 0.003 to 0.054). Decreasing 25(OH)D and increasing PTH were associated with increased odds for fractures, independent of age, height, weight, calcium supplementation, serum calcium, cortical porosity, and thickness.Conclusions: These data suggest that serum PTH, not 25(OH)D, is associated with increased intracortical bone turnover resulting in trabecularisation of the inner cortical bone; nevertheless, decreasing 25(OH)D) and increasing PTH are associated with fracture risk, independent of cortical porosity and thickness. [ABSTRACT FROM AUTHOR]

Summary: The rationale of this study was to determine the effect of high-dose vitamin D supplementation on bone mineral density (BMD). Prediabetic males given vitamin D had significantly less reduction in BMD at the femoral neck compared to the controls. The clinical implications of our findings require further investigation. Introduction: Type 2 diabetes mellitus is associated with increased fracture risk, and recent studies show crosstalk between bone and glucose metabolism. Few studies have investigated the effect of vitamin D supplementation on the bone without additional calcium. In the present study, we aimed to determine whether a high dose of vitamin D could improve bone mass density (BMD) in prediabetic subjects. Methods: The current study was conducted as a secondary research on a previously performed trial, in which 511 subjects with prediabetes were randomized to vitamin D (20,000 IU per week) versus placebo for 5 years. BMD was measured using dual-energy X-ray absorptiometry (DEXA). Results: Two hundred and fifty-six subjects were randomized to vitamin D and 255 to placebo. Mean baseline serum 25-hydroxyvitamin D (25(OH)D) level was 60 nmol/L. Two hundred and two and 214 in the vitamin D and placebo groups, respectively, completed BMD measurements, whereas one in each group was excluded due to use of bisphosphonates. Males given vitamin D had significantly less reduction in BMD at the femoral neck measurement site compared to the controls (0.000 versus − 0.010 g/cm, p = 0.008). No significant differences between intervention groups were seen at the total hip measurement site, regarding both males and females. Conclusions: Vitamin D supplementation alone may be beneficial in males with prediabetes, but confirmatory studies are needed. [ABSTRACT FROM AUTHOR]

Objective: Vitamin D deficiency is associated with an unfavorable metabolic profile in observational studies. The intention was to compare insulin sensitivity (the primary end point) and secretion and lipids in subjects with low and high serum 25(OH)D (25-hydroxyvitamin D) levels and to assess the effect of vitamin D supplementation on the same outcomes among the participants with low serum 25(OH)D levels.Research Design and Methods: Participants were recruited from a population-based study (the Tromsø Study) based on their serum 25(OH)D measurements. A 3-h hyperglycemic clamp was performed, and the participants with low serum 25(OH)D levels were thereafter randomized to receive capsules of 20,000 IU vitamin D(3) or identical-looking placebo twice weekly for 6 months. A final hyperglycemic clamp was then performed.Results: The 52 participants with high serum 25(OH)D levels (85.6 ± 13.5 nmol/L [mean ± SD]) had significantly higher insulin sensitivity index (ISI) and lower HbA(1c) and triglycerides (TGs) than the 108 participants with low serum 25(OH)D (40.3 ± 12.8 nmol/L), but the differences in ISI and TGs were not significant after adjustments. After supplementation, serum 25(OH)D was 142.7 ± 25.7 and 42.9 ± 17.3 nmol/L in 49 of 51 completing participants randomized to vitamin D and 45 of 53 randomized to placebo, respectively. At the end of the study, there were no statistically significant differences in the outcome variables between the two groups.Conclusions: Vitamin D supplementation to apparently healthy subjects with insufficient serum 25(OH)D levels does not improve insulin sensitivity or secretion or serum lipid profile. [ABSTRACT FROM AUTHOR]

PURPOSE: The serum 25-hydroxyvitamin D (25(OH)D) levels are lower in obese than lean subjects. The present study examines the cross-sectional and longitudinal relations between body mass index (BMI) and serum 25(OH)D, and the serum 25(OH)D response to vitamin D supplementation in relation to BMI. METHODS: The Tromsø study is a longitudinal population-based multipurpose study. The fourth survey was conducted in 1994 and the sixth in 2008. The intervention study was a 1-year placebo-controlled randomized intervention trial, where the results from the 93 subjects given 40,000 IU per week are presented. RESULTS: A total of 10,229 subjects were included in the 2008 cross-sectional study. There was a significant negative association between serum 25(OH)D levels and BMI which was also present during the winter months. Serum 25(OH)D levels varied through seasons, but not BMI. In the longitudinal study from 1994 to 2008 which included 2,656 subjects, change in BMI was a significant negative predictor of change in 25(OH)D. In the intervention study, there was a significant and negative correlation between BMI and serum 25(OH)D both at baseline and at the end of the study. The increase in serum 25(OH)D after 1 year was significantly and inversely related to baseline BMI. CONCLUSIONS: We have confirmed the strong association between serum 25(OH)D and BMI. The very obese need higher vitamin D doses than lean subjects to achieve the same serum 25(OH)D levels. [ABSTRACT FROM AUTHOR]

Background: In meta-analyses supplementation with vitamin D appears to reduce incidence of fractures, and in cross-sectional studies there is a positive association between serum 25-hydroxyvitamin D (25(OH)D) levels and bone mineral density (BMD). However, the effect of supplementation with high doses of vitamin D on BMD is more uncertain and could in theory have both positive and negative effects.Methods: The study was a one year, double blind placebo-controlled intervention trial performed at the University Hospital of North Norway. 421 subjects, 21 - 70 years old, were included and 312 completed the study. The subjects were randomized to vitamin D3 40.000 IU per week (DD group), vitamin D3 20.000 IU per week (DP group), or placebo (PP group). All subjects were given 500 mg calcium daily. Serum 25(OH)D, osteoprotegrin (OPG), receptoractivator of nuclear factor-kappaB ligand (RANKL), and BMD at the lumbar spine and the hip were measured before and at the end of the study.Results: At baseline the mean serum 25(OH)D levels were 58 nmol/L (all subjects) and increased to 141 and 100 nmol/L in the DD and DP groups, respectively. After one year, no significant differences were found between the three groups regarding change in BMD, serum OPG or RANKL.Conclusions: Supplementation with high doses of vitamin D for one year does not appear to have a negative effect on BMD in healthy subjects. In order to disclose a positive effect, subjects with low BMD and/or low serum 25(OH)D levels need to be studied.Trial Registration: The trial was registered at ClinicalTrials.gov (NCT00243256). [ABSTRACT FROM AUTHOR]

Examining fracture dynamics by socioeconomic status may inform healthcare and prevention. We found a higher risk of hip fracture in men and women with lower educational level in Norway. However, by age 90 + years, the cumulative incidence was higher in those with higher education, due to their higher life expectancy., Purpose: Socioeconomic gradients are seen for several health outcomes in high-income countries. We aimed to examine possible educational gradients in risk of hip fracture in Norway and to describe the cumulative incidence of hip fracture by educational level., Methods: In a population-wide cohort of Norwegians aged ≥ 50 years, information on attained education from Statistics Norway was linked to hospital-treated hip fractures and deaths during 2002-2019. We estimated relative fracture risk by educational level (primary, secondary or tertiary) in Cox proportional hazards regression. We also examined the cumulative incidence over attained age by gender and educational level in competing risk regression., Results: The population included N = 1,389,858 individuals with 135,938 incident hip fractures. Compared with men who had attained tertiary education, hazard ratios (95% confidence intervals) for hip fracture were 1.44 (1.40, 1.49) in men with primary education only and 1.26 (1.22, 1.29) in men with secondary education. In women, the corresponding estimates were 1.28 (1.25, 1.31) and 1.16 (1.13, 1.19). In the age range 50 to 90 years, the highest cumulative incidence of hip fracture was seen in those with primary education. The gradient gradually diminished with advancing age and was reversed in the oldest (> 90 years) in both genders., Conclusions: There was a clear educational gradient in hip fracture incidence in both men and women in Norway, with a higher risk in people with lower education. Despite this, the cumulative incidence of hip fracture in old age was highest among people with higher education, due to their higher life expectancy., (© 2024. The Author(s).)

In a Norwegian youth cohort followed from adolescence to young adulthood, bone mineral density (BMD) levels declined at the femoral neck and total hip from 16 to 27 years but continued to increase at the total body indicating a site-specific attainment of peak bone mass., Purpose: To examine longitudinal trends in bone mineral density (BMD) levels in Norwegian adolescents into young adulthood., Method: In a prospective cohort design, we followed 980 adolescents (473 (48%) females) aged 16-19 years into adulthood (age of 26-29) on three occasions: 2010-2011 (Fit Futures 1 (FF1)), 2012-2013 (FF2), and 2021-2022 (FF3), measuring BMD (g/cm 2 ) at the femoral neck, total hip, and total body with dual x-ray absorptiometry (DXA). We used linear mixed models to examine longitudinal BMD changes from FF1 to FF3., Results: From the median age of 16 years (FF1), femoral neck BMD (mean g/cm 2 (95% CI)) slightly increased in females from 1.070 (1.059-1.082) to 1.076 (1.065-1.088, p = 0.015) at the median age of 18 years (FF2) but declined to 1.041 (1.029-1.053, p < 0.001) at the median age of 27 years (FF3). Similar patterns were observed in males: 16 years, 1.104 (1.091-1.116); 27 years, 1.063 (1.050-1.077, p < 0.001); and for the total hip in both sexes (both p < 0.001). Total body BMD increased from age 16 to 27 years in both sexes (females: 16 years, 1.141 (1.133-1.148); 27 years, 1.204 (1.196-1.212), p < 0.001; males: 16 years, 1.179 (1.170-1.188); 27 years, 1.310 (1.296-1.315), p < 0.001)., Conclusion: BMD levels increased from 16 to 18 years at the femoral and total hip sites in young Norwegian females and males, and a small decline was observed at the femoral sites when the participants were followed up to 27 years. Total body BMD continued to increase from adolescence to young adulthood., (© 2024. The Author(s).)

Aim: We aimed to investigate changes in pre-diagnostic concentrations of classic and 11-oxygenated androgens in type 2 diabetes (T2DM) cases and healthy controls, associations between androgen concentrations and T2DM, and the potential for androgens to improve the prediction of T2DM when considered in combination with established risk factors., Methods: Androgen concentrations were analysed in serum samples from 116 T2DM cases and 138 controls at 3, pre-diagnostic time-points: 1986/87 (T1), 1994/95 (T2), and 2001 (T3). Generalised estimating equations were used to longitudinally examine androgen concentrations, and logistic regression models were used to estimate the odds ratios (OR) of T2DM at each time-point. Logistic regression models were also used to calculate area under the receiver operating characteristics curve (AROC) from models including established risk factors alone (ERF model) and established risk factors plus each androgen, respectively, which were compared to identify improvements in predictive ability., Results: For women, no significant associations were observed between any of the investigated androgens and T2DM after adjusting for confounders. For men, after adjusting for confounders, concentrations of all investigated 11-oxygenated androgens were higher in cases than controls at one or several time-points. We observed associations between T2DM and concentrations of 11-ketoandrostenedione (OR: 1.59) and 11-ketotestosterone (OR: 1.62) at T1; and 11-hydroxyandrostenedione (OR: 2.00), 11-hydroxytestosterone (OR: 1.76), 11-ketoandrostenedione (OR: 1.84), 11-ketotestosterone (OR: 1.78) and testosterone (OR: 0.45) at T3 in men. The addition of these androgens (including 11-hydroxytestosterone at T2) to the ERF model resulted in an improved ability to predict T2DM in men (AROC: 0.79-0.82). We did not observe significant differences in changes in androgen concentrations over time between cases and controls in either sex., Conclusion: Our results demonstrate that testosterone and 11-oxygenated androgens are associated with T2DM in men before diagnosis and may be potential biomarkers in T2DM risk assessment., (© 2024. The Author(s).)

Context: Longitudinal data regarding vitamin D status in adolescence is scarce. This study presents population-based data from an Arctic adolescent population (n = 589) at 16 and 18 years., Objective: The aims of this study were to investigate changes in vitamin D status during 2 years in adolescence, and whether lifestyle changes were associated with serum 25-hydroxyvitamin D (s-25(OH)D) at follow-up., Methods: Fit Futures is a longitudinal study at 69°N in Norway. Participants had their s-25(OH)D levels analyzed in their first and third year of upper secondary school (median age 16 and 18 years), in Fit Futures 1 (FF1) and Fit Futures 2 (FF2), respectively. Self-reported lifestyle habits were registered through questionnaires. The association between lifestyle changes and s-25(OH)D levels at follow-up were calculated by regression analyses, controlling for baseline s-25(OH)D levels., Results: Longitudinal data were available for 309 girls and 280 boys. The proportion of adolescents with s-25(OH)D <50 nmol/L were 73.7% in FF1 and 77.1% in FF2, while the proportion <30 nmol/L constituted 35.7% in FF1 and 40.9% in FF2. Of those with s-25(OH)D <30 nmol/L (severe vitamin D deficiency) in FF1, 73.3% remained severely deficient in FF2. Among boys, an increase in UV exposure was significantly associated with higher s-25(OH)D levels in FF2 (beta; CI [nmol/L] 12.9; 9.1, 16.7). In girls, decreased vitamin/mineral supplement intake was significantly associated with lower s-25(OH)D at FF2 (-6.7; -10.2, -3.1), while increased UV (10.8; 7.0, 14.7) and combined hormonal contraceptive exposure (12.1; 6.0, 18.1) in FF2 was significantly associated with higher s-25(OH)D levels in FF2., Conclusion: Severe vitamin D deficiency was prevalent throughout adolescence. Lifestyle changes may alter s-25(OH)D levels in this age group., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Per- and polyfluoroalkyl substances (PFAS) comprise a large group of chemicals that are ubiquitous in the environment and include recognized persistent organic pollutants. The aim of this cross-sectional study was to investigate possible endocrine disrupting effects of different PFAS in adolescents., Methods: Serum concentrations of PFAS, thyroid, parathyroid and steroid hormones were measured in 921 adolescents aged 15-19 years in the Fit Futures study, Northern Norway. The questionnaire included data on self-reported age at menarche and puberty development score (PDS). Multiple linear and logistic regression analyses and principle component analyses (PCA) were used to assess associations of PFAS with hormones concentrations and puberty indices., Results: In girls, total PFAS (∑PFAS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA) were positively associated with dehydroepiandrosterone sulfate (DHEAS) and negatively associated with 11-deoxycorticosterone (11-DOC)/DHEAS ratio. In boys, the associations with 11-DOC/DHEAS ratio were positive for ∑PFAS, perfluoroheptanoate (PFHpA), perfluoroheptane sulfonate (PFHpS), PFOA, and PFOS. Perfluoroundecanoate (PFUnDA) was negatively associated with free thyroxine (fT4) and free triiodothyronine (fT3) in boys. PFNA and PFDA were also negatively associated with fT3 in boys. Serum parathyroid hormone concentration (PTH) was negatively associated with ∑PFAS and perfluorohexane sulfonate (PFHxS) in girls, and with PFOS in boys. PFDA and PFUnDA were positively associated with early menarche, while ∑PFAS and PFOA were positively associated with PDS in boys. No associations of PFAS with serum testosterone, follicle-stimulating hormone, or luteinizing hormone were found in either sex. In girls, PFOA was positively associated with free testosterone index (FTI). In boys, PFOA was positively associated with androstendione and 17-OH-progesterone, while PFHpA was positively associated with estradiol., Conclusions: Serum concentrations of several PFAS were associated with parathyroid and steroid hormones in both sexes, and with thyroid hormones in boys, as well as with early menarche in girls and higher PDS in boys., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood., Design: Cross-sectional study., Methods: We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH., Results: Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively)., Conclusions: We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)