Educational gradient in hip fracture incidence in Norway. The Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

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.

Early menarche and other endocrine disrupting effects of per- and polyfluoroalkyl substances (PFAS) in adolescents from Northern Norway. The Fit Futures study.

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.

Cause-specific excess mortality after hip fracture: the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

BACKGROUND: Information on cause of death may help appraise the degree to which the high excess mortality after hip fracture reflects pre-existing comorbidities or the injury itself. We aimed to describe causes of death and cause-specific excess mortality through the first year after hip fracture. METHODS: For studying the distribution of causes of death by time after hip fracture, we calculated age-adjusted cause-specific mortality at 1, 3, 6 and 12 months in patients hospitalized with hip fracture in Norway 1999-2016. Underlying causes of death were obtained from the Norwegian Cause of Death Registry and grouped by the European Shortlist for Causes of Death. For estimating excess mortality, we performed flexible parametric survival analyses comparing mortality hazard in patients with hip fracture (2002-2017) with that of age- and sex matched controls drawn from the Population and Housing Census 2001. RESULTS: Of 146,132 Norwegians with a first hip fracture, a total of 35,498 (24.3%) died within one year. By 30 days post-fracture, external causes (mainly the fall causing the fracture) were the underlying cause for 53.8% of deaths, followed by circulatory diseases (19.8%), neoplasms (9.4%), respiratory diseases (5.7%), mental and behavioural disorders (2.0%) and diseases of the nervous system (1.3%). By one-year post-fracture, external causes and circulatory diseases together accounted for approximately half of deaths (26.1% and 27.0%, respectively). In the period 2002-2017, cause-specific one-year relative mortality hazard in hip fracture patients vs. population controls ranged from 1.5 for circulatory diseases to 2.5 for diseases of the nervous system in women, and correspondingly, from 2.4 to 5.3 in men. CONCLUSIONS: Hip fractures entail high excess mortality from all major causes of death. However, the traumatic injury of a hip fracture is the most frequently reported underlying cause of death among older patients who survive less than one year after their fracture.

Circulating sex-steroids and Staphylococcus aureus nasal carriage in a general male population.

Male sex is associated with higher risk of both colonisation and infection with Staphylococcus aureus (S. aureus). However, the role of sex-steroids in colonisation among men is largely unknown. Thus, the aim of this study was to investigate possible associations between circulating sex-steroids and nasal carriage of S. aureus in a general male population. The population-based Tromsø6 study (2007-2008) included 752 males aged 31-87 years with serum sex-steroids measured by liquid chromatography tandem mass spectrometry and two nasal swab samples for the assessment of S. aureus carriage. Multivariable logistic regression models were used to study the association between sex-steroid concentrations and S. aureus persistent nasal carriage (two positive swabs vs. others), while adjusting for potential confounding factors.S. aureus persistent nasal carriage prevalence was 32%. Among men aged 55 years and above (median age 65 years), there was an inverse dose-response relationship between serum concentration of testosterone and persistent nasal carriage, and carriers had significantly lower mean levels of testosterone (P = 0.028, OR = 0.94 per nmol/l change in testosterone; 95% CI = 0.90-0.98). This association was attenuated when adjusting for body mass index and age (OR = 0.96 per nmol/l change in testosterone; 95% CI = 0.91-1.01). There was no association in the total population. This large population-based study suggests that testosterone levels may be inversely related to S. aureus persistent nasal carriage in older men. Future studies addressing biological mechanisms underlying the male predisposition to S. aureus colonisation and infection may foster preventive interventions that take sex-differences into account.

A man in his sixties with dyspnoea and oedema. / Mann i 60-årene med tungpustethet og ødemer.

BACKGROUND/CASE PRESENTATION: A man in his sixties with chronic obstructive pulmonary disease was hospitalised due to oedema and dyspnoea during the previous weeks. He was hypertensive, with 10 kg weight gain, generalised oedema, proximal myopathy and moon face. The assessment was consistent with ectopic ACTH-dependent Cushing's syndrome. A 15 mm lung tumour was detected on CT, with inconclusive cytological examination, and negative FDG/PET CT and octreotide scintigraphy. He developed necrotising pancreatitis and a duodenal perforation, which were surgically treated. His cortisol levels and Cushingoid appearance normalised after surgery, and it was concluded that his hypercortisolism was part of a physiological response. He remained clinically in habitual shape until two years later, when he again developed Cushingoid stigmata. A new octreotide scintigraphy was negative, but FDG/PET CT revealed increased FDG uptake in the lung lesion. Before a lung biopsy was performed, the patient developed necrotising pancreatitis. He was treated conservatively and died in respiratory failure. Autopsy revealed a NET in the lung and necrotising pancreatitis. INTERPRETATION: The case demonstrates diagnostic challenges in the assessment of ectopic ACTH-dependent cyclic Cushing's syndrome. Is also suggests that pancreatitis could be triggered by hypercortisolism.

Lost relation between blood pressure and serum 25-hydroxyvitamin D.

BACKGROUND: Low serum 25-hydroxyvitamin D (25(OH)D) levels have consistently been associated with hypertension. During the last decades there has been an unexplained reduction in blood pressure (BP) in Western countries. We therefore examined the relation between serum 25(OH)D and BP in the 7th survey of the Tromsø study 2015/2016. METHODS: Blood pressure and serum 25(OH)D were measured and life-style factors registered in 15,951 subjects not using BP medication. RESULTS: In unadjusted analyses there was a significant negative association between serum 25(OH)D and systolic and diastolic BP that disappeared after adjusting for relevant confounders. This finding is in contrast to our previous reports on 25(OH)D and BP. We therefore cross-sectionally re-analyzed non-smoking (due to interference by smoking in the 25(OH)D assay) subjects not using BP medication from the 4th survey in 1994/1995 (n = 4108), 6th survey in 2007/2008 (n = 7553) and 7th survey 2015/2016 (n = 13,413). Adjusting for age and BMI, there were significant inverse relations between BP and 25(OH)D in the 4th, to a lesser degree in the 6th, and none in the 7th survey. For males the age- and BMI-adjusted differences in systolic BP between those with serum 25(OH)D < 25 nmol/L versus serum 25(OH)D > 100 nmol/L were 6.2 mmHg, 4.1 mmHg and -0.1 mmHg, for the 4th, 6th and 7th surveys, respectively. CONCLUSIONS: Concomitant with a substantial reduction in BP from 1994 to 2015, there has been a loss of relation between 25(OH)D and BP which is hard to explain.

Bone mineral density at the hip and its relation to fat mass and lean mass in adolescents: the Tromsø Study, Fit Futures.

BACKGROUND: Positive association between body weight and bone mass is well established, and the concept of body mass index (BMI) is associated with higher areal bone mineral density (aBMD) and reduced fracture risk. BMI, that comprises both fat mass (FM) and lean mass (LM) may contribute to peak bone mass achievement in different ways. This study explored the influence of body composition in terms of total body LM and FM on hip aBMD-values in adolescence. METHODS: In 2010/2011, 93% of the region's first-year upper-secondary school students (15-17 years old) in Tromsø, Norway attended the Tromsø Study, Fit Futures. Areal BMD at femoral neck (aBMDFN) and total hip (aBMDTH) (g/cm2), total body LM and FM (g) were measured by dual energy X-ray absorptiometry (DXA). Height and weight were measured, and BMI calculated. Lifestyle variables were collected by self-administered questionnaires and interviews, including questions on time spent on leisure time physical activity. Stratified analyses of covariance and regression models included 395 girls and 363 boys. Crude results were adjusted for age, height, sexual maturation, physical activity levels, vitamin D levels, calcium intake, alcohol consumption and smoking habits. RESULTS: Unadjusted distribution indicated higher aBMD-levels at higher LM-levels in both genders (p < 0.001), but higher aBMD at higher FM-levels were found only in girls (p < 0.018). After multiple adjustments, aBMDFN-levels in girls were associated by 0.053 g/cm2 and 0.032 g/cm2 per standard deviation (SD) change in LM and FM (p < 0.001). Corresponding values in boys were 0.072 and 0.025 (p < 0.001). The high LM groups accounted for the highest aBMD-levels, while aBMD-levels at the LM/FM-combinations indicated different patterns in girls compared to boys. The adjusted odds ratio (95% CI) for low levels of aBMDFN was 6.6 (3.4,13.0) in boys, compared to 2.8 (1.6,4.9) in girls per SD lower LM. CONCLUSIONS: LM and FM should be regarded as strong predictors for bone mass and hence bone strength in adolescents. A gender specific difference indicated that high lean mass is of crucial importance prominently in boys. In adolescents with low lean mass, especially in girls, high fat mass may partially ameliorate the effect of deficient lean mass levels.

Association between serum 25-hydroxyvitamin D concentration and symptoms of respiratory tract infection in a Norwegian population: the Tromsø Study.

OBJECTIVE: Previous studies have suggested anti-infection effects of vitamin D, although the associations reported between vitamin D (serum 25-hydroxyvitamin D (25(OH)D) concentration) and respiratory tract infection (RTI) are conflicting. The main aim of the present study was to explore this association in a Norwegian population. DESIGN: We examined the association between serum 25(OH)D and recent RTI symptoms in 6350 middle-aged and elderly participants in the Tromsø Study 6. The main outcome measurement was self-reported RTI symptoms in the previous week. SETTING: Tromsø, Norway, 69 °N. SUBJECTS: Six thousand three hundred and fifty middle-aged and elderly residents of Tromsø. RESULTS: Of the 6350 included, 791 (12.5%) reported RTI symptoms in the previous week. We classified serum 25(OH)D concentrations into quartiles and adjusted the data for current smoking habit and month of attendance. The prevalence of RTI symptoms did not increase with decreasing serum 25(OH)D level, was highest in quartile 3 (15.0%) followed by quartile 4 (12.4%), and was lowest in quartiles 1 and 2 (11.1% and 11.4%). There was no trend for increasing duration of illness with decreasing serum 25(OH)D. The prevalence of RTI symptoms was not significantly associated with the intake of fish, n-3 capsules or vitamin and/or mineral supplements, or sun exposure. Only use of cod-liver oil or fish oil capsules daily or sometimes was significantly associated with fewer RTI symptoms during the preceding 7 d (P = 0.04). CONCLUSIONS: Low serum 25(OH)D was not associated with increased prevalence of recent RTI symptoms. Our findings do not support the idea that vitamin D supplementation can reduce the incidence of RTI in Norway.

Serum free and bio-available 25-hydroxyvitamin D correlate better with bone density than serum total 25-hydroxyvitamin D.

In the circulation 25-hydroxyvitamin D (25(OH)D) is bound to vitamin D-binding protein (DBP) and albumin. Only a small fraction is in the unbound, free form. According to the 'free-hormone-hypothesis' only the free form is biologically active. Genetic differences in DBP may affect the binding to 25(OH)D and thereby the amount of free 25(OH)D. In the present study sera were obtained from 265 postmenopausal women with low bone mass density (BMD). Serum 25(OH)D, DBP and albumin were measured and the free and bio-available (free + albumin-bound) 25(OH)D calculated. Based on genotyping of the polymorphisms rs7041 and rs4588, the six common DBP phenotypes were identified and the free and bio-available 25(OH)D calculated according to the corresponding binding coefficients. Relations between measures of 25(OH)D and PTH and BMD were evaluated with linear regression adjusted for age and BMI. The calculated amount of free and bio-available 25(OH)D was 0.03% and 13.1%, respectively, of the measured total serum 25(OH)D. Adjusting for DBP phenotype affected the calculated free and bio-available 25(OH)D levels up to 37.5%. All measures of 25(OH)D correlated significantly with PTH, whereas a significant association with BMD was only seen for the free and bio-available 25(OH)D measures. Adjusting for the DBP phenotypes improved the associations. These relations were almost exclusively seen in subjects not using vitamin D and/or calcium supplements. In conclusion, the free and bio-available forms of 25(OH)D may be a more informative measure of vitamin D status than total 25(OH)D. Adjustment for DBP phenotype may improve this further.

Vitamin D deficiency and lifestyle risk factors in a Norwegian adolescent population.

AIM: The aim was to study vitamin D status in a healthy adolescent Norwegian population at 69°N. METHODS: The data presented come from The Tromsø Study: Fit Futures, during the school year 2010/2011 (not including the summer months), where 1,038 (92% of those invited) participated. Physical examinations, questionnaires and blood samples were collected, and serum 25-hydroxyvitamin D (25(OH)D) were analyzed using LC-MS/MS. RESULTS: RESULTS are presented from 475 boys and 415 girls (15-18 years old) with available blood samples. A total of 60.2% had vitamin D deficiency or insufficiency (serum 25(OH)D <50 nmol/l), 16.5% were deficient (<25 nmol/l) and 1.6% had severe vitamin D deficiency (<12.5 nmol/l). Only 12.4% had levels >75 nmol/l. A significant gender difference with a mean (SD) serum 25(OH)D level of 40.5 (20.5) nmol/l in boys and 54.2 (23.2) nmol/l in girls (p <0.01) was present. Furthermore, 51.3% of girls had levels >50 nmol/l in comparison to 29.7% of boys (p <0.01). There was an inverse correlation between parathyroid hormone levels and 25(OH)D, rs= -0.30 (p<0.01). Explanatory factors that were significantly associated with serum 25(OH)D levels in multivariate models were use of snuff, consumption of vitamin D fortified milk, cod liver oil and vitamin/mineral supplements, physical activity, sunbathing holiday and use of solarium in boys, and vitamin/mineral supplements, physical activity, sunbathing holiday and use of solarium in girls . CONCLUSIONS: Vitamin D deficiency is prevalent during the school year among adolescents in northern Norway, particularly among boys.

Cohort profile: Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

AIMS: This paper describes the history, purpose, data collection and contributions in the research collaboration Norwegian Osteoporosis Epidemiologic Studies (NOREPOS). METHODS: NOREPOS encompasses almost 85,000 bone mineral density measurements within Cohort of Norway and data on almost 140,000 hip fractures in Norway 1994-2008. Included are anthropometric measurements, blood pressure, lipids and glucose, and 50 standard questions on sociodemographic factors, diseases and risk factors. Blood samples/DNA are stored. The main research question posed in NOREPOS is why hip fracture rates in Norway are the highest in the world. Data on hip fractures 2009-2013 will be added in 2014. RESULTS: Main findings include: Every hour a Norwegian suffers a hip fracture; hip fracture incidence rates declined after 1999; only 16% of patients used anti-osteoporosis drugs 1 year after hip fracture; 25% of patients died within 1 year after the fracture; 12% suffered a new hip fracture within 10 years; rural dwellers had lower hip and forearm fracture incidence than city dwellers; magnesium in tap water may be protective whereas bacterial contamination, cadmium and lead may be harmful to bone health; low serum vitamin D and E levels were associated with higher hip fracture risk; vitamin A was not associated with fracture risk; and abdominal obesity increased the risk of hip fracture when BMI was accounted for. CONCLUSIONS: NOREPOS encompasses a unique source of information for aetiological research, genetic studies as well as for biomarkers of osteoporosis and fractures. Because of the increasing number of elderly people in Europe, hip fractures will continue to pose an international public health and health care challenge.

Vitamin D Status During Adolescence and the Impact of Lifestyle Changes: 2 Years' Follow-up From the Fit Futures Study.

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.

Longitudinal assessment of classic and 11-oxygenated androgen concentrations and their association with type 2 diabetes mellitus development: the Tromsø study.

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.

Acquisition of peak bone mass in a Norwegian youth cohort: longitudinal findings from the Fit Futures study 2010-2022.

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/cm2) 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/cm2 (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.

Serum calcium and the calcium-sensing receptor polymorphism rs17251221 in relation to coronary heart disease, type 2 diabetes, cancer and mortality: the Tromsø Study.

Serum calcium measured in 27,158 subjects in 1994 and the calcium-sensing receptor polymorphism rs17251221 genotyped in 9,404 subjects were related to cardiovascular risk factors, incident myocardial infarction (MI), type 2 diabetes (T2DM), cancer and death during follow-up until 2008-2010. In a Cox regression model with adjustment for age, gender, smoking and body mass index, subjects with serum calcium 2.50-2.60 mmol/L had a significantly increased risk of incident MI [n = 1,802, hazards ratio (HR) 1.40, 95 % confidence interval (CI) 1.18, 1.66] and T2DM (n = 705, HR 1.49, 95 % CI 1.15, 1.94) and a significantly reduced risk of cancer (n = 2,222, HR 0.73, 95 % CI 0.62, 0.86) as compared to subjects with serum calcium 2.20-2.29 mmol/L. For rs17251221 there was a mean difference in serum calcium of 0.05 mmol/L between major and minor homozygote genotypes. No consistent, significant relation between rs17251221 and risk factors or the major hard endpoints were found. The minor homozygote genotype (high serum calcium) had a significant twofold increased risk (HR 2.32, 95 % CI 1.24, 4.36) for prostate cancer, as compared to the major homozygote. This may be clinically important if confirmed in other cohorts.

Plasma-Metanephrines in Patients with Autoimmune Addison's Disease with and without Residual Adrenocortical Function.

PURPOSE: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison's disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. METHODS: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). RESULTS: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. CONCLUSION: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.

Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study.

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.

Associations between polymorphisms related to calcium metabolism and human height: the Tromsø Study.

A number of single nucleotide polymorphisms (SNPs) related to height have been detected. Calcium metabolism is important for the skeleton and accordingly also for adult height. Therefore, in the present study, nine SNPs related to the vitamin D receptor (VDR) gene and serum levels of 25-hydroxyvitamin D (25(OH)D), calcium, phosphate and parathyroid hormone (PTH) were related to height in 9471 subjects. Relation with height was evaluated with linear regression for trend across SNP genotypes with age and gender as covariates. After correcting for multiple testing, significant associations with height were found for two SNPs related to the VDR gene (rs1544410 (Bsml) and rs7975232 (Apal)), one SNP related to serum 25(OH)D (rs3829251 at the DHCR7/NADSYN1 gene), one SNP related to serum calcium (rs1459015 at the PTH gene) and one SNP related to serum phosphate (rs1697421 at the ALPL gene). For rs3829251, the mean differences in height between major and minor homozygotes were 1.5-2.0 cm (P < 0.01) and were seen in both genders and all age groups tested, whereas for the other SNPs, the differences were less than 1 cm. In conclusion, several SNPs related to calcium metabolism are associated with height, in particular rs3829251 at the DHCR7/NADSYN1 gene.