Changes in thyroid function and evolution of subclinical thyroid disease in older men.

OBJECTIVE: Prevalence of subclinical thyroid disease increases with age, but optimal detection and surveillance strategies remain unclear particularly for older men. We aimed to assess thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations and their longitudinal changes, to determine the prevalence and incidence of subclinical thyroid dysfunction in older men. DESIGN, PARTICIPANTS AND MEASUREMENTS: Longitudinal study of 994 community-dwelling men aged ≥70 years without known or current thyroid disease, with TSH and FT4 concentrations assessed at baseline and follow-up (after 8.7 ± 0.9 years). Factors associated with incident subclinical thyroid dysfunction were examined by logistic regression and receiver operating characteristic analyses. RESULTS: At baseline, 85 men (8.6%) had subclinical hypothyroidism and 10 (1.0%) subclinical hyperthyroidism. Among 899 men euthyroid at baseline (mean age 75.0 ± 3.0 years), 713 (79.3%) remained euthyroid, 180 (20.0%) developed subclinical/overt hypothyroidism, and 6 (0.7%) subclinical/overt hyperthyroidism. Change in TSH correlated with baseline TSH (r = .16, p < .05). Change in FT4 correlated inversely with baseline FT4 (r = -0.35, p < .05). Only higher age and baseline TSH predicted progression from euthyroid to subclinical/overt hypothyroidism (fully-adjusted odds ratio [OR] per year=1.09, 95% confidence interval [CI] = 1.02-1.17, p = .006; per 2.7-fold increase in TSH OR = 65.4, CI = 31.9-134, p < .001). Baseline TSH concentration ≥2.34 mIU/L had 76% sensitivity and 77% specificity for predicting development of subclinical/overt hypothyroidism. CONCLUSIONS: In older men TSH concentration increased over time, while FT4 concentration showed little change. Subclinical or overt hypothyroidism evolved in one fifth of initially euthyroid men, age and higher baseline TSH predicted this outcome. Increased surveillance for thyroid dysfunction may be justified in older men, especially those with high-normal TSH.

Serum bicarbonate concentration and the risk of death in type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIMS: To examine whether all-cause mortality is independently associated with serum bicarbonate concentration below the laboratory reference interval in a representative, well-characterised community-based cohort of people with type 2 diabetes. METHODS: 1478 FDS2 participants with type 2 diabetes (mean age 65.8 years, 51.6% males, median diabetes duration 9.0 years) from the longitudinal, observational Fremantle Diabetes Study Phase II (FDS2) were followed from study entry to death or end-2016. Independent associates of a low baseline serum bicarbonate (< 22 mmol/L) were determined using multiple logistic regression. The role of important covariates in influencing the association between bicarbonate and mortality was assessed by a stepwise Cox regression approach. RESULTS: A low serum bicarbonate was associated with increased all-cause mortality in unadjusted analysis (hazard ratio (HR) 1.90 (95% confidence limits (CL) 1.39, 2.60 per mmol/L). Mortality remained significantly associated with low serum bicarbonate (HR 1.40 (95% CL 1.01, 1.94) per mmol/L) in a Cox regression model with adjustment for factors associated with mortality but not low serum bicarbonate, but inclusion of estimated glomerular filtration rate categories rendered the association non-significant (HR 1.16 (95% CL 0.83, 1.63) per mmol/L). CONCLUSIONS: A low serum bicarbonate is not an independent prognostic marker in people with type 2 diabetes but it may be a manifestation of the pathway between the development of impaired renal function and death.

Reference intervals for plasma ß-CTX and P1NP in children: A systematic review and pooled estimates.

OBJECTIVE: Reference intervals for plasma P1NP and ß-CTX in children and adolescents from several studies have recently been published. The aim of this study was to combine the available data into a set of reference intervals for use in clinical laboratories. DESIGN AND METHODS: A systematic literature search for primary studies reporting reference intervals for plasma P1NP and ß-CTX in infants, children and adolescents using the Roche methods was carried out. Reference limits were extracted. For each year of age, mean upper and lower reference limits were calculated, weighted by the number of subjects in each study, and were plotted against age. Proposed reference limits were developed from the weighted mean data with age partitions determined pragmatically. RESULTS: Reference limits for clinical use for females to 25 years and males to 18 years, based on the weighted mean reference data, are presented. Ten studies contributed to the pooled analysis. The proposed reference limits are identical for males and females <9 years age, prior to the pubertal growth spurt. For ß-CTX, the weighted mean reference limits showed relatively constant values during the pre-pubertal years but a marked increase during puberty before a rapid decline towards adult values. Those for P1NP showed high values declining rapidly in the first 2 years of life, followed by a modest increase during early puberty. Limited published information for late adolescent and young adult subjects was noted. CONCLUSIONS: The proposed reference intervals may be useful for clinical laboratories reporting these bone turnover markers measured by the Roche assays.

The relationship between thyroid dysfunction, cardiovascular morbidity and mortality in type 2 diabetes: The Fremantle Diabetes Study Phase II.

AIMS: It is uncertain whether subclinical thyroid dysfunction is associated with cardiovascular disease (CVD) events and mortality in people with type 2 diabetes. The aim of this study was to determine whether undetected thyroid disease increases the risk of incident CVD and death in type 2 diabetes. METHODS: One thousand two hundred fifty participants with type 2 diabetes (mean age 65.3 years, 56.5% males, median diabetes duration 8.0 years) without known thyroid disease and not taking medications known to affect thyroid function were categorised, based on baseline serum free thyroxine (FT4) and thyrotropin (TSH) concentrations, as euthyroid, overt hypothyroid (increased TSH, low FT4), subclinical hypothyroid (increased TSH, normal FT4), overt thyrotoxic (decreased TSH, raised FT4) or subclinical thyrotoxic (decreased TSH, normal FT4). Incident myocardial infarction, incident stroke, all-cause and cardiovascular mortality were ascertained during a mean 6.2-6.7 years of follow-up. RESULTS: Most participants with newly-detected thyroid dysfunction had subclinical hypothyroidism (77.2%) while overt/subclinical thyrotoxicosis was infrequent. Compared to participants with TSH 0.34-2.9 mU/L, those with TSH > 5.1 mU/L were not at increased risk of incident myocardial infarction (adjusted hazard ratio (95% confidence limits) 1.77 (0.71, 2.87)), incident stroke (1.66 (0.58, 4.78)), all-cause mortality (0.78 (0.44, 1.37)) or cardiovascular mortality (1.16 (0.38, 3.58)). Independent baseline associates of subclinical hypothyroidism included estimated glomerular filtration rate and systolic blood pressure. CONCLUSIONS: Subclinical hypothyroidism was not independently associated with CVD events or mortality in community-dwelling people with type 2 diabetes despite its associations with CVD risk factors, questioning strategies to identify and/or treat mild thyroid dysfunction outside usual care.

Changes in the Epidemiology of Hepatobiliary Disease Complicating Type 2 Diabetes over 25 Years: The Fremantle Diabetes Study.

OBJECTIVE: To determine whether the incidence/outcome of hepatobiliary disease (HBD) has increased over recent decades in community-based Australians with and without type 2 diabetes (T2D). METHODS: Longitudinal data from the Fremantle Diabetes Study Phase I (FDS1; recruitment 1993-1996; n = 1291 with T2D) and Phase II (FDS2; 2008-2011; n = 1509) were analyzed. Participants with T2D from both Phases were age-, sex-, and postcode-matched 1:4 to people without diabetes. Incident HBD and associated mortality were ascertained from hospitalization, cancer registration, and/or death certification codes. Incidence rates (IRs) and IR ratios (IRRs) for those with versus without diabetes in FDS1 and FDS2 were calculated. RESULTS: HBD IRs for people without diabetes did not change between Phases. The IRR (95% CI) for people with T2D in FDS2 versus FDS1 was 1.30 (1.01-1.68) with the highest IRRs in participants aged <65 years. Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) events were 54% greater in FDS2 than FDS1 in the presence of greater abdominal adiposity. NAFLD/NASH was coded in one in 11 HBD events in FDS2 and in 10% of HBD deaths (<4% of total mortality). CONCLUSIONS: HBD is more frequent in people with versus without T2D and this discrepancy is increasing. Hospitalizations/deaths due to NAFLD/NASH remain uncommon.

U-Shaped Association of Plasma Testosterone, and no Association of Plasma Estradiol, with Incidence of Fractures in Men.

PURPOSE: Whether androgens, distinct from estrogen, maintain bone health during male aging has implications for understanding osteoporosis. We assessed associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. PARTICIPANTS AND METHODS: Analysis of 3307 community-dwelling men aged 76.8 ± 3.5 years, median follow-up period of 10.6 years. Plasma testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) assayed by mass spectrometry, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) using immunoassay. Incident fractures determined via data linkage. We analyzed probability of fracture and performed Cox regression adjusted for age, medical comorbidities, and frailty. RESULTS: Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested nonlinear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher plasma T, lower E2, higher SHBG, and higher LH. In fully adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Quartile 2 [Q2] versus Q1: fully adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] 0.51-0.94, P = .020; Q3: HR 0.59, 95% CI 0.42-0.83, P = .002) and hip fracture (Q2 versus Q1: HR 0.60, 95% CI 0.37-0.93, P = .043; Q3: HR 0.52, 95% CI 0.31-0.88, P = .015). DHT, E2, and LH were not associated with fracture. Higher SHBG was associated with hip fracture (Q4 versus Q1: HR 1.76, 95% CI 1.05-2.96, P = .033). CONCLUSIONS: Midrange plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk.

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Sex hormones and incident dementia in older men: The health in men study.

BACKGROUND: Low circulating testosterone has been associated with dementia in older men but existing evidence from prospective studies is inconsistent. METHODS: We conducted a prospective longitudinal study of 4069 community-dwelling older men free of dementia aged 71-88 years at baseline. The main objective of the study was to determine if men with low circulating sex hormones were more likely to develop dementia over time. The main biochemical exposures of interest were collected at baseline between 2001 and 2004 and men were assessed for incident dementia via an electronic health records database to the 31 st of December 2013. RESULTS: Dementia developed in 499 men over a median of 10.5 years (range 9.4-12.2 years). The risk of developing dementia increased with decreasing total (hazard ratio [HR] 1.14, 95% confidence interval [95%CI] 1.03-1.26 per standard deviation decrease) and calculated free testosterone (HR 1.18, 95%CI 1.06-1.31 per standard deviation decrease) after adjustment for age, baseline cognitive function, depression, body mass, hypertension, cardiovascular disease and total plasma homocysteine. Men in the lowest quartiles of total (adjusted HR 1.39, 95%CI 1.04-1.85) and calculated free testosterone (adjusted HR 1.43, 95%CI 1.08-1.90) had increased risk of developing dementia compared to those in the highest quartiles. CONCLUSIONS: Lower plasma total and calculated free testosterone were associated with increased risk of developing dementia independent of relevant measured clinical and biochemical factors and was not explained due to differential mortality in those with lower testosterone levels. The association between low testosterone and dementia is biologically plausible but data on the role of testosterone treatment in preventing dementia is lacking and adequately powered trials in men at risk would be welcome.

A 10-Year Prospective Study of Bone Mineral Density and Bone Turnover in Males and Females With Type 1 Diabetes.

Context: In a previous community-based, cross-sectional study, males with type 1 diabetes (T1D) had lower bone mineral density (BMD) than did matched people without diabetes but females with T1D had normal BMD. Objective: To determine whether BMD in the males continued to decline, the neutral effect of T1D on BMD in females persisted, and whether temporal BMD changes reflected changes in bone turnover markers. Design: Longitudinal observational study. Setting: Urban community. Patients: Forty-eight of the original 102 original cross-sectional study participants (20 males, 28 females) of mean age 42.0 years and median diabetes duration 14.6 years at baseline who were restudied a mean of 10.3 years later. Main Outcome Measures: BMD at total hip, femoral neck, lumbar spine (L1 to L4), and distal forearm. Biochemical bone turnover markers. Results: After adjustment for age, body mass index (BMI), and renal function, there was no temporal change in BMD at the hip or forearm in the males (P ≥ 0.12), but lumbar spine BMD increased (P = 0.009). Females exhibited no statistically significant change in BMD in similar multivariable models that also included postmenopausal status, except a mild increase at the forearm (P = 0.046). Age- and sex-related changes in bone turnover markers paralleled those in general population studies. Conclusions: There is a reduction in BMD in males with T1D that occurs early in the course of the disease but then stabilizes. BMD in females with T1D remains similar to that expected for age, BMI, and postmenopausal status.

Subclinical thyroid dysfunction and circulating thyroid hormones are not associated with bone turnover markers or incident hip fracture in older men.

OBJECTIVE: Overt thyroid dysfunction is a risk factor for osteoporosis and fractures. Subclinical hyperthyroidism has also been associated with fracture. It remains unclear whether variation in thyroid hormones within the euthyroid range modulates bone health, particularly among older men. We assessed whether thyroid stimulating hormone (TSH) and free thyroxine (FT4) are associated with bone turnover markers (BTMs) and predict hip fracture risk in community-dwelling older men without known thyroid disease. DESIGN: Prospective cohort study. PATIENTS: Four thousand two hundred forty-eight men aged 70-89 years. MEASUREMENTS: Baseline blood samples were assayed for TSH, FT4, total osteocalcin (TOC), undercarboxylated osteocalcin (ucOC), N-terminal propeptide of type I collagen (P1NP) and collagen type I C-terminal cross-linked telopeptide (CTX). Incidence of hip fracture events was ascertained to 2012. Associations of TSH and FT4 with BTMs were analysed at baseline using Pearson correlation coefficients, and with incident hip fracture using Cox proportional hazards regression. RESULTS: After excluding men with pre-existing thyroid or bone disease, there were 3, 338 men for analysis. Of these, 3, 117 were euthyroid, 135 had subclinical hypothyroidism, and 86 had subclinical hyperthyroidism. Men with subclinical thyroid disease were older, and those with subclinical hyperthyroidism had lower creatinine than the other groups. After multivariate analysis, there were no associations found between FT4, TSH or subclinical thyroid dysfunction and BTMs at baseline. Neither subclinical thyroid dysfunction, TSH nor FT4 were predictive of incident hip fracture in our study population. CONCLUSIONS: In euthyroid older men, TSH and FT4 were not associated with BTMs or incident hip fracture. Our findings differ from those previously described in postmenopausal women.

Clinical utility of bone turnover markers in the management of common metabolic bone diseases in adults.

Bone turnover marker (BTMs) concentrations in blood and urine reflect bone-remodelling activity, and may be useful adjuncts in the diagnosis and management of metabolic bone diseases. Newer biomarkers, mainly bone regulatory proteins, are currently being investigated to elucidate their role in bone metabolism and disease and may in future be useful in clinical diagnosis and management of metabolic bone disease. BTM concentrations increase around menopause in women, and at a population level the degree of increase in BTMs reflect bone loss. However, lack of adequate data precludes their use in individual patients for fracture risk assessment in clinical practice. The rapid and large changes in BTMs following anti-resorptive and anabolic therapies for osteoporosis treatment indicate they may be useful for monitoring therapy in clinical practice. The offset of drug effect on BTMs could be helpful for adjudicating the duration of bisphosphonate drug holidays. BTMs may offer useful additional data in skeletal diseases that are typically characterised by increased bone remodelling: chronic kidney disease (CKD), primary hyperparathyroidism (PHPT) and Paget's disease. In CKD, bone specific alkaline phosphatase (bAP) is currently endorsed for use for the assessment of mineral bone disease. The role of BTMsin predicting the bone mineral density response to successful parathyroidectomy in PHPT shows some utility but the data are not consistent and studies are limited in size and/or duration. In Paget's disease of bone, BTMs are used to confirm diagnosis, evaluate extent of disease or degree of activity and for monitoring the response to bisphosphonate treatment. Whilst BTMs are currently used in specific clinical practice instances when investigating or managing metabolic bone disease, further data are needed to consolidate their clinical use where evidence of utility is limited.

Progressive impairment of testicular endocrine function in ageing men: Testosterone and dihydrotestosterone decrease, and luteinizing hormone increases, in men transitioning from the 8th to 9th decades of life.

CONTEXT: Sex hormone trajectories in ageing men and their health implications remain unclear. We examined longitudinal trajectories and associations of testosterone (T), dihydrotestosterone (DHT), oestradiol (E2), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) in oldest old men. DESIGN: Prospective cohort study. PARTICIPANTS: We studied 1025 community-dwelling men median age 75.1 years at baseline with 8.6 years of follow-up. MEASUREMENTS: Baseline and follow-up T, DHT and E2 were assayed using mass spectrometry. Physical performance was assessed at follow-up. Correlations and covariate-adjusted P-values were determined. RESULTS: Longitudinal change in T was -2.0%/year, DHT -7.2%/year, LH +7.5%/year, SHBG +5.6%/year while E2 remained stable. Annualized increases in LH correlated with decreases in T and DHT (r = -.20, P < .0001 and r = -.12, P = .0035, respectively). Higher baseline T correlated with better physical performance at follow-up (eg, Step test r = .07, P = .03), as did higher baseline DHT (eg, time to sit-stand [TSS] r = -.07, P = .01). Larger annualized increases in LH predicted poorer physical performance at follow-up (eg, TSS r = .14, P = .001). Higher T at follow-up was associated with better physical performance (eg, TSS r = -.07, P = .04), as were higher DHT and lower LH. At baseline, 24 men (2.4%) had abnormally high LH (>16 IU/L); at follow-up, 175 (17.4%) had high LH of whom 70 had low T (<6.4 nmol/L). CONCLUSIONS: Annualized increases in LH are associated with declines in T and DHT, and predict poorer subsequent physical performance in oldest old men. Men transitioning from 8th to 9th decades exhibit biochemical evidence of progressively impaired testicular endocrine function, warranting further evaluation.

Risk of prevalent and incident dementia associated with insulin-like growth factor and insulin-like growth factor-binding protein 3.

Insulin-like growth factor 1 (IGF-1) influences cell proliferation and survival. In the extracellular environment, IGF-1 circulates bound to proteins (IGF-binding proteins; IGFBP), some of which have physiological effects that seem independent of IGF-1, including the brain (for example, IGFBP-3). We completed a systematic review of the association between dementia and IGF-1 and IGFBP-3, and a cross-sectional and longitudinal study designed to investigate if lower plasma concentration of these proteins increased the risk of prevalent and incident dementia. A total of 3967 men aged 71-89 years joined the study, of whom 535 (13.5%) showed evidence of prevalent cognitive impairment. The plasma concentrations of IGF-1 and IGFBP-3 were similar for men with and without cognitive impairment. The 3432 men free of cognitive impairment were then followed for up to 13 years. During this time 571 (16.6%) developed dementia. The plasma concentration of IGF-1 had no association with incident dementia. The doubling of the plasma concentration of IGFBP-3 decreased the hazard ratio of dementia by 23% (95% confidence interval=5-37%). The results were not affected by age, body mass index and history of smoking, diabetes, hypertension, coronary heart disease or stroke. If these findings are confirmed by others, the plasma concentration of IGFBP-3 could be used to improve the accuracy of predictive models of dementia and as a potential new factor to assist in the development of prevention and treatment strategies.

Higher Dihydrotestosterone Is Associated with the Incidence of Lung Cancer in Older Men.

Advancing age is associated with increased cancer incidence, but the role of sex hormones as risk predictors for common cancers in older men remains uncertain. This study was performed to assess associations of testosterone (T), dihydrotestosterone (DHT) and estradiol (E2), with incident prostate, lung and colorectal cancer in community-dwelling older men. Plasma T, DHT and E2 were assayed using liquid chromatography-mass spectrometry between 2001 and 2004 in 3690 men. Cancer outcomes until 20 June 2013 were ascertained using data linkage. Analyses were performed using proportional hazards competing-risks models, and adjustments were made for potential confounding factors including smoking status. Results are expressed as subhazard ratios (SHR). There were 348, 107 and 137 cases of prostate, lung and colorectal cancers respectively during a median of 9.1-year follow-up. Mean T was comparable in current and non-smokers, whilst mean DHT was lower in ex- and current smokers compared to non-smokers. After adjusting for confounders including smoking, higher T or DHT was associated with an increased incidence of lung cancer (SHR = 1.30, 95% CI 1.06-1.60; p = 0.012 per 1 SD increase in T and SHR = 1.29, 95% CI 1.08-1.54; p = 0.004 for DHT). Sex hormones were not associated with prostate or colorectal cancer. In older men, higher T or DHT predict increased incidence of lung cancer over the next decade. Sex hormones are not associated with incident prostate or colorectal cancer. Further studies are warranted to determine if similar associations of sex hormones with lung cancer are present in other populations and to investigate potential underlying mechanisms.

Clinical usefulness of bone turnover marker concentrations in osteoporosis.

Current evidence continues to support the potential for bone turnover markers (BTM) to provide clinically useful information particularly for monitoring the efficacy of osteoporosis treatment. Many of the limitations identified earlier remain, principally in regard to the relationship between BTM and incident fractures. Important data are now available on reference interval values for CTX and PINP across a range of geographic regions and for individual clinical assays. An apparent lack of comparability between current clinical assays for CTX has become evident indicating the possible limitations of combining such data for meta-analyses. Harmonization of units for reporting serum/plasma CTX (ng/L) and PINP (µg/L) is recommended. The development of international collaborations continues with an important initiative to combine BTM results from clinical trials in osteoporosis in a meta-analysis and an assay harmonization program are likely to be beneficial. It is possible that knowledge derived from clinical studies can further enhance fracture risk estimation tools with inclusion of BTM together with other independent risk factors. Further data of the relationships between the clinical assays for CTX and PINP as well as physiological and pre-analytical factors contributing to variability in BTM concentrations are required.

Profile of diabetes in men aged 79-97 years: the Western Australian Health in Men Study.

AIMS: To investigate behavioural, physical and biochemical characteristics associated with diabetes in the oldest age group of elderly men. METHODS: We conducted a cross-sectional analysis of community-dwelling men aged 79-97 years from Perth, Western Australia. Lifestyle behaviours, self-rated health, physical function, and fasting glucose and HbA1c levels were assessed. RESULTS: Of 1426 men, 315 had diabetes (22%). Men with diabetes were of similar age to men without (84.9 vs 84.5 years; P = 0.14). Only 26.5% of men with diabetes self-rated their health as excellent or very good, compared with 40.6% of men without diabetes (P < 0.001). Diabetes was associated with less involvement with recreational walking (32.7 vs 41.0%; P < 0.01) and leisure activities (19.0 vs 26.5%; P < 0.01). Men with diabetes had poorer physical function on multiple measures, including longer times for the Timed Up-and-Go test (15.0 ± 6.9 s vs 13.4 ± 5.3 s; P < 0.001) and weaker knee extension (20.2 vs 21.9 kg; P < 0.001). In multivariate analyses, diabetes was associated with an increased prevalence of myocardial infarction (odds ratio 1.80, 95% CI 1.25-2.60; P < 0.001) and falls resulting in injury (odds ratio 1.55, 95% CI 1.06-2.26; P = 0.02). Average HbA1c was 49 ± 8 mmol/mol (6.6 ± 0.8%) in men with diabetes, with 90.6% of these men on diet or oral hypoglycaemic therapy. CONCLUSIONS: In older men, diabetes is associated with poorer self-perceived health, reduced healthy lifestyle behaviours and physical function, heart disease and injurious falls. The majority of these men with diabetes had good glycaemic control. Encouraging healthy lifestyle behaviours and improving physical function should be evaluated as interventions to improve quality-of-life and health outcomes.

Reference Ranges for Thyroid-Stimulating Hormone and Free Thyroxine in Older Men: Results From the Health In Men Study.

Background: In older adults, thyroid-stimulating hormone (TSH) concentrations are raised and higher free thyroxine (FT4) is associated with poorer health outcomes. As use of nonage-appropriate reference ranges could lead to suboptimal management, we aimed to define reference intervals for TSH and FT4 in older men. Methods: We conducted the study on community-dwelling men aged 70-89 years. Baseline TSH and FT4 levels were assayed (Elecsys 2010, Roche Diagnostics). Conventional reference intervals for TSH and FT4 were 0.4-4.0 mIU/L and 10-23 pmol/L, respectively. Incident deaths were ascertained using data linkage. Results: Of the 3,885 men included in the analysis, the 2.5th and 97.5th centiles for TSH and FT4 were 0.64-5.9 mIU/L and 12.1-20.6 pmol/L (0.94-1.60ng/dL), respectively. Of the 411 very healthy men defined by excellent or very good self-rated health and absence of major medical comorbidities, 2.5th to 97.5th centiles for TSH and FT4 were 0.67-4.98 mIU/L and 12.1-20.5 pmol/L (0.94-1.59ng/dL), respectively. TSH was not associated with mortality, whereas higher FT4 was associated with increased mortality. Applying intervals based on very healthy older men to the cohort as a whole led to the reclassification of 310 men (8.0%). More men were classified as being hyperthyroid or hypothyroid, or having subclinical hyperthyroidism, and fewer as having subclinical hypothyroidism. Conclusions: In older men, the reference interval for TSH in older men is shifted upward, whereas the reference interval for FT4 is compressed compared with the conventional reference ranges. Applying reference intervals based on healthy older men identifies a substantial number of older men as having overt thyroid disease or subclinical hyperthyroidism and reduces the number classified as having subclinical hypothyroidism.

Serum bicarbonate concentration and the risk of cardiovascular disease and death in type 2 diabetes: the Fremantle Diabetes Study.

BACKGROUND: Serum bicarbonate is associated with mortality, heart failure (HF) and progression of renal failure in studies of healthy people and patients with chronic kidney disease, but the significance of these observations in unselected patients with diabetes in the general population is unknown. The aim of this study was to determine whether serum bicarbonate was associated with mortality and cardiovascular disease risk in type 2 diabetes. METHODS: Baseline serum bicarbonate was available for 1283 well-characterized community-based patients (mean ± SD age 64.1 ± 11.3 years, 48.7 % males) from the longitudinal observational Fremantle Diabetes Study followed for a mean of 12 years. Associations between serum bicarbonate and mortality, coronary heart disease (CHD) and incident HF were analysed using Cox proportional hazards regression. RESULTS: Serum bicarbonate was independently and negatively associated with incident CHD. For each 1 mmol/L increase in bicarbonate, the hazard ratio for CHD was 0.95 (95 % confidence interval 0.92-0.99) after adjustment for age as time scale, age at baseline, sex, English fluency, diabetes duration, loge(serum triglycerides), loge(urinary albumin: creatinine ratio), peripheral sensory neuropathy and peripheral arterial disease. There were no independent associations between serum bicarbonate and all-cause mortality [0.98 (0.95-1.004)] or incident HF [0.99 (0.95-1.03)]. CONCLUSIONS: Serum bicarbonate was a significant independent predictor of incident CHD but not death or HF in community-based patients with type 2 diabetes. This supports intervention trials of bicarbonate replacement in type 2 patients at risk of CHD and who have a low serum bicarbonate concentration.