While several studies have described the rate and pattern of involutional bone loss in women, far less information is available for men. Furthermore, the roles of lifestyle and body build in determining bone loss rate in both sexes have been largely extrapolated from cross-sectional studies. We addressed this issue in a population-based longitudinal study which sought to ascertain rates of bone loss at the femoral neck and lumbar spine in a cohort of men and women aged 60-75 years at baseline, and to relate this loss to anthropometric and lifestyle variables. We additionally investigated the capacity of biochemical markers of bone turnover to predict bone loss rates in these subjects. Women lost bone at all sites; this ranged from 0.20%/year at the lumbar spine to 1.43%/year at the femoral trochanteric region. By contrast, men lost only 0. 20%/year at the trochanteric region, and gained at the lumbar spine (0.33%/year) and at Ward's triangle (0.27%/year) over the 4-year period. Anthropometric measurements were associated with bone loss in both sexes; lower baseline body mass index (BMI) and a greater rate of loss of adiposity over the follow-up period were both associated with greater bone loss at all proximal femoral sites. These attained statistical significance after Bonferroni correction at the total proximal femur among both men (r = 0.29), p<0.01) and women (r = 0.31, p<0.05). Lifestyle factors associated with lower rates of bone loss (after adjustment for BMI) included alcohol consumption at the femoral neck among women (p = 0.007) and physical activity at the lumbar spine among men (p = 0.05). Serum parathyroid hormone, 25-hydroxyvitamin D and biochemical markers of bone turnover did not predict bone loss after adjustment for adiposity.

Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. Impaired conversion of cortisone (E) to cortisol (F) by the type 1 isoenzyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in obesity may represent a protective mechanism preventing ongoing weight gain and glucose intolerance. We have studied glucocorticoid metabolism in 33 male subjects with type 2 diabetes mellitus [age, 44.2 +/- 13 yr; body mass index (BMI), 31.1 +/- 7.5 kg/m(2) (mean +/- sd)] and 38 normal controls (age, 41.4 +/- 14 yr; BMI, 38.2 +/- 12.8 kg/m(2)). Circulating F:E ratios were elevated in the diabetic group and correlated with serum cholesterol and homeostasis model assessment-S. There was no difference in 11beta-HSD1 activity between diabetic subjects and controls. In addition, 11beta-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5alpha-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11beta-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11beta-HSD1 activity could not be explained by circulating levels of adipocytokines. Impaired E to F metabolism in obesity may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to down-regulate 11beta-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11beta-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.

Aims/hypothesis: We tested the hypothesis that NEFA concentrations are higher in obese subjects with fatty liver than in obese subjects without fatty liver. Materials and methods: We recruited 22 obese (BMI>30 kg/m 2 ) men aged 42-64 years, in whom liver fat was assessed by ultrasound and classified into categories of no, mild to moderate and severe fatty liver by two independent radiologists. Regional and visceral abdominal fat were assessed by dualenergy X-ray absorptiometry and magnetic resonance imaging, and endogenous glucose production, whole-body glucose disposal during an insulin clamp, and NEFA concentrations were measured, along with NEFA suppression (percent (%) suppression and insulin sensitivity index for NEFA during an OGTT). Results: Seven subjects had no evidence of fatty liver, nine had mild or moderate fatty liver and six had severe fatty liver. The amount of visceral fat was not associated with the degree of fatty liver. Whole-body glucose disposal was inversely associated with fatty liver (38.4, 26.5 and 23.9 μmol kg −1 min −1 for the groups with no fatty liver, mild to moderate fatty liver and severe fatty liver, respectively, p=0.004). NEFA suppression during the OGTT was decreased (62.5, 50.8 and 41%, p=0.03, for no, mild to moderate, and severe fatty liver, respectively) and the insulin sensitivity index for NEFA was decreased (0.80, 0.40 and 0.34, p<0.0001). Regression modelling suggested that NEFA concentrations were associated with fatty liver independently of whole-body glucose production and disposal measurements. Conclusions/interpretation: In obese men, NEFA concentrations during an OGTT are associated with fatty liver independently of classic measures of insulin sensitivity determined by the hyperinsulinaemic clamp. The contribution to this association by factors regulating NEFA concentrations requires further study.

Although excessive glucocorticoids are a well-recognized cause of osteoporosis, little is known about the role of endogenous glucocorticoids in determining skeletal mass. We have performed a detailed study of the hypothalamic-pituitary-adrenal (HPA) axis to explore the relationships between cortisol secretion and adult bone mass in 151 healthy men and 96 healthy women aged 61 to 73 years. At baseline and 4-year follow-up, bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) at the lumbar spine and proximal femur; a lifestyle questionnaire was completed; and height, weight, and waist and hip circumferences were measured. At follow-up subjects underwent a very low-dose (0.25 mg) dexamethasone suppression test, a low-dose (1 microg) short synacthen test, and a 24-hour urine collection for measurement of cortisol and its metabolites. In men, elevated peak plasma cortisol was associated with accelerated loss of mineral density in the lumbar spine (r = 0.16, P = 0.05). This relationship remained significant after adjustment for testosterone, estradiol, 25-hydroxyvitamin D, and parathyroid hormone levels (r = 0.22, P = 0.01) and after additional adjustment for age, (BM), activity, cigarette and alcohol consumption, and Kellgren/Lawrence score (r = 0.19, P = 0.03). In contrast in women, elevated peak plasma cortisol was associated with lower baseline BMD at the femoral neck (r = -0.23, P = 0.03) and greater femoral neck loss rate (r = 0.24, P = 0.02). There was no association between plasma cortisol concentrations after dexamethasone or urinary total cortisol metabolite excretion and bone density or bone loss rate at any site. These data provide evidence that circulating endogenous glucocorticoids influence the rate of involutional bone loss in healthy individuals.