Venkat Parameswaran

Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study

CONTEXT IL-1, IL-6, and TNF-alpha play an important role in the pathogenesis of osteoporosis in animals; however, evidence that these play a similar role in bone loss in human studies is limited. OBJECTIVE Our objective was to determine the associations between serum markers of inflammation and changes in bone mineral density (BMD) and urinary pyridinoline (PYR) to creatinine (Cr) ratio over 2.9 yr in older adults. METHODS A total of 168 randomly selected subjects (mean 63 yr, range 52-78, 48% female) was studied. BMD was measured by dual-energy x-ray absorptiometry at baseline (mean T score: -0.18 to -0.61) and 2.9 yr later. Serum high-sensitivity (hs) C-reactive protein (CRP), IL-6, TNF-alpha, and the urinary PYR/Cr ratio were measured on both occasions. RESULTS The mean annual loss of BMD was 0.15, 0.15, and 0.34% at total body, spine, and hip, respectively. Change in total body BMD was associated with baseline hs-CRP, IL-6, and TNF-alpha, as well as change in hs-CRP (beta: -0.41%/U, 95% confidence interval -0.68%, -0.15%) and IL-6 (beta: -0.62%/U, 95% confidence interval -1.01%, -0.23%). If these markers were put in the same predictive model, only IL-6 remained largely unchanged. Changes in other BMD sites were significantly predicted by IL-6 (hip and spine) and TNF-alpha (spine only). Finally, change in the PYR/Cr ratio was positively associated baseline IL-6, hs-CRP, and their changes (all P < 0.05) in women, but not men. CONCLUSIONS Variation within the low levels of inflammatory markers observed in this study, especially IL-6, predicts bone loss and resorption, suggesting that targeted antiinflammatory therapy has potential for the prevention of osteoporosis.

Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults

OBJECTIVE The role of inflammation in osteoarthritis (OA) pathogenesis is unclear, and the associations between inflammatory cytokines and cartilage loss have not been reported. We determined the associations between serum levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), knee radiographic OA (ROA) and cartilage loss over 2.9 years in older adults. METHODS A total of 172 randomly selected subjects (mean 63 years, range 52-78, 47% female) were studied at baseline and approximately 3 (range 2.6-3.3) years later. IL-6 and TNF-α were assessed by radioimmunoassay. T1-weighted fat-suppressed magnetic resonance imaging of the right knee was performed at baseline and follow-up to determine knee cartilage volume. Knee ROA of both knees was assessed at baseline. RESULTS At baseline, quartiles of IL-6 and TNF-α were associated with increased prevalence of medial tibiofemoral joint space narrowing (OARSI grade ≥ 1) in multivariate analyses [odds ratio (OR): 1.42 and 1.47 per quartile, respectively, both P<0.05]. Longitudinally, baseline IL-6 predicted loss of both medial and lateral tibial cartilage volume (β: -1.19% and -1.35% per annum per quartile, P<0.05 and P<0.01, respectively), independently of TNF-α. Change in IL-6 was associated with increased loss of medial and lateral tibial cartilage volume (β: -1.18% and -1.06% per annum per quartile, both P<0.05) and change in TNF-α was also negatively associated with change in medial cartilage volume (β: -1.27% per annum per quartile, P<0.05). CONCLUSIONS Serum levels of IL-6 and TNF-α are associated with knee cartilage loss in older people suggesting low level inflammation plays a role in the pathogenesis of knee OA.

Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: The Tasmanian older adult cohort study

OBJECTIVE To determine the associations between serum levels of vitamin D, sunlight exposure, and knee cartilage loss cross-sectionally and longitudinally in older adults. METHODS A total of 880 randomly selected subjects (mean age 61 years [range 51-79 years], 50% women) were studied at baseline, and 353 of these subjects were studied 2.9 years later. Serum levels of 25-hydroxyvitamin D (25[OH]D) were assessed by radioimmunoassay, and sunlight exposure was assessed by questionnaire. T1-weighted fat-suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine knee cartilage volume and defects. Knee radiographic osteoarthritis (OA) and knee pain were also assessed. RESULTS The mean 25(OH)D serum level was 52.8 nmoles/liter at baseline (range 13-119 nmoles/liter). Winter sunlight exposure and serum 25(OH)D level were both positively associated with medial and lateral tibial cartilage volume, and a serum 25(OH)D level<50 nmoles/liter was associated with increased medial tibiofemoral joint space narrowing (all P<0.05). Longitudinally, baseline serum 25(OH)D level predicted change in both medial and lateral tibial cartilage volume (beta=+0.04% per annum per nmole/liter for both; P<0.05), and change in serum 25(OH)D level was positively associated with change in medial tibial cartilage volume. These associations were consistent in subjects with radiographic OA and knee pain and/or in women, but not in men or in subjects without radiographic OA or knee pain. CONCLUSION Sunlight exposure and serum 25(OH)D levels are both associated with decreased knee cartilage loss (assessed by radiograph or MRI). This is best observed using the whole range of 25(OH)D levels rather than predefined cut points and implies that achieving vitamin D sufficiency may prevent and/or retard cartilage loss in knee OA.

Vitamin D levels in prepubertal children in Southern Tasmania: prevalence and determinants.

Objective: To describe the prevalence and determinants of 25-hydroxy D3(25(OH)D) in children.Design: Cross-sectional study.Setting: Southern Tasmania between June and November 1997.Subjects: Two hundred and one 8-y old male and female children taking part in a cohort study whose principal endpoints were blood pressure and high-density lipoprotein (HDL) cholesterol.Results: The mean 25(OH)D level was 79 nmol/l (s.d. 29.5, median 73, range 12–222). Boys had higher levels than girls (82.1 vs 72.8 nmol/l, P=0.02). 25(OH)D was associated with sunlight exposure in winter school holidays (r=0.20, P=0.005) and winter weekends (r=0.16, P=0.02), the month after school holidays (87.5 vs 69.5 nmol, P<0.0001) and body mass index (r=−0.23, P=0.001). Dietary intake of vitamin D was low (mean 40 IU/day, range 5.2–384) and was not associated with 25(OH)D levels (r=0.01, P=0.91). Variation in skin melanin density was weakly associated with 25(OH)D (r=0.09, P=0.19).Conclusions: Sunlight is the major determinant of vitamin D stores in our population. Neither variation in skin type within Caucasians nor diet modified this association to any significant extent. Extrapolation of these findings to sunlight bone mass associations in a very similar population suggests that a minimum level of around 50 nmol/l in the population is required for optimal bone development in prepubertal children but this needs to be confirmed with further controlled trials of vitamin D supplementation and bone mass.Sponsorship: Arthritis Foundation of Australia, Roche Pharmaceuticals.

Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study

OBJECTIVE To describe the associations between leptin, body composition, sex and knee cartilage volume/defects in older adults. METHODS A cross-sectional sample of 190 randomly selected subjects (mean 63 years, range 52-78, 48% female) were studied. Knee cartilage volume and defects were determined using T1-weighted fat saturation MRI. Serum leptin levels were measured by radioimmunoassay. Fat and lean mass were measured by dual energy x ray absorptiometry (DXA). Body mass index (BMI) was calculated. RESULTS In multivariable analysis, serum levels of leptin were negatively associated with total cartilage volume (beta: -541 mm3/log transformed unit, 95% CI -861 to -221) but not with prevalent knee cartilage defects. BMI was negatively associated with cartilage volume after adjustment for total lean mass and positively with prevalent knee cartilage defects. However, the association between BMI and cartilage volume disappeared after adjustment for leptin while the association between BMI and cartilage defects remained unchanged. Lastly, sex differences in total cartilage volume decreased substantially after adjustment for leptin (R2 from 51% to 30%). CONCLUSIONS This cross-sectional study suggests cartilage volume loss with obesity and female sex is related to leptin and, thus, is hormonally mediated in older adults. By contrast, obesity related knee focal cartilage defects may be more related to non-hormonal factors.

The influence of gestational stage on urinary iodine excretion in pregnancy

INTRODUCTION Median urinary iodine concentration (UIC) is the most commonly used indicator of population iodine nutrition. However, its validity as an indicator of dietary intake relies on a stable relationship between dietary iodine intake and urinary excretion. Physiological alterations in normal pregnancy, such as increased glomerular filtration rate, potentially invalidate UIC as an assessment tool in pregnancy. OBJECTIVE The objective of the study was to document the impact of advancing gestation on UIC in normal pregnancy and determine whether the current reference intervals for general population iodine monitoring are appropriate for use in the context of pregnancy. DESIGN Tasmania has a well-described history of mild iodine deficiency (school-age median UIC of 84 microg/liter). We assessed UIC in 759 urine samples from 431 women attending the Antenatal Clinic at the Royal Hobart Hospital, Tasmanias primary teaching hospital. MAIN OUTCOME The overall median UIC during pregnancy was 75 microg/liter (95% confidence interval 70.03-79.97 microg/liter) at a median gestation of 19.4 wk. Stratification by gestation, however, revealed a dynamic relationship between ioduria and gestation. Median UIC was elevated in early pregnancy and subsequently declined with advancing gestation. CONCLUSION In this mildly iodine-deficient population, current reference intervals for UIC overestimated the adequacy of iodine nutrition during the first and early second trimester of pregnancy. Gestation-specific UIC reference intervals are required to classify iodine nutrition during pregnancy. This is particularly important in populations with borderline iodine deficiency.

A population-based study of the relationship between salt intake, bone resorption and bone mass

Objective: To explore the relationship between urinary sodium (the best measure of salt intake), urinary calcium, urinary deoxypyridinoline (DPYR) and bone mass. Design: Cross-sectional study. Setting: Population based sample of healthy Hobart residents. Subjects: One hundred and fifty-four (M=34, F=120) subjects invited to take part from a systematic sample of the electoral roll and a single newspaper advertisement. Results: In both sexes, urinary sodium correlated moderately with urinary DPYR (r=0.32, P<0.0001) and urinary calcium (r=0.37, P<0.0001). In multivariate analysis, the combination of urinary sodium, total body bone area, age and sex explained 22% of the variation in log-transformed DPYR (P<0.00001). In univariate analysis, both urinary sodium and urinary DPYR were strongly associated with bone mineral content and bone mineral density at all sites but this association disappeared after adjustment for confounders particularly body weight. Conclusions: This study has shown that salt intake is associated with markers of bone resorption in a population-based sample of males and females and appears likely to be a risk factor for osteoporosis despite the lack of a demonstrable association between bone mass and a single measure of urinary sodium excretion. Further studies are needed to define the effect of salt intake on bone mass and fractures more clearly. These studies will need to be either longitudinal or interventional in design with repeated measures of urinary sodium so that habitual sodium intake can be accurately assessed and regression dilution bias can be minimised. Sponsorship: Arthritis Foundation of Australia, Royal Hobart Hospital Acute Care Program.

Not a simple fat-soluble vitamin: Changes in serum 25-(OH)D levels are predicted by adiposity and adipocytokines in older adults.

Abstract.  Ding C, Parameswaran V, Blizzard L, Burgess J, Jones G (Menzies Research Institute, University of Tasmania, Hobart, Tas.; Monash University, Melbourne, Vic.; Royal Hobart Hospital, Hobart, Tas., Australia). Not a simple fat soluble vitamin: changes in serum 25‐(OH)D levels are predicted by adiposity and adipocytokines in older adults. J Intern Med 2010; 268: 501–510.

Methylglyoxal, Cognitive Function and Cerebral Atrophy in Older People

BACKGROUND The effects of advanced glycation endproducts on cognition and brain structure are poorly understood. We studied associations of the advanced glycation endproduct precursor methylglyoxal (MGO) with cognitive function and brain volumes in older people. METHODS Nondemented participants in the Tasmanian Study of Cognition and Gait underwent cognitive testing and brain magnetic resonance imaging scans. Brain volumes were obtained by magnetic resonance imaging scan segmentation and statistical parametric mapping procedures. Serum MGO was measured after derivatization to methylquinoxaline by high pressure liquid chromatography and UV detection. Linear regression was used to examine associations of log-transformed MGO with cognitive scores and brain volumes adjusting for potential confounding by age, sex, education, mood, insulin resistance, history of stroke, vascular risk factors, alcohol intake, and psychoactive medication use. RESULTS There were 378 participants, mean age 72.1 years (SD 7.1), 55% male. Greater MGO was associated with poorer memory (β = -.12, 95% confidence interval: -0.22, -0.02, p = .02) and executive function, the latter being greater among those with a history of stroke (MGO × stroke β = .48, 95% confidence interval: 0.17, 0.79, p = .002). Greater MGO was associated with lower grey matter volume (β = -6.42, 95% confidence interval -11.82, -1.11, p = .02) but not with white matter volume, white matter lesion volume, or hippocampal volume. CONCLUSIONS These results support the investigation of the role of the advanced glycation endproduct precursor methylglyoxal in cognitive decline and neurodegeneration in older people.

Multiple endocrine neoplasia type 1 (MEN 1) is associated with an increased prevalence of diabetes mellitus and impaired fasting glucose

Objective  Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant syndrome characterized by primary hyperparathyroidism, pituitary neoplasia and foregut lineage neuroendocrine tumours. It has also been associated with premature cardiovascular death. As diabetes is a risk factor for increased cardiovascular mortality we investigated the prevalence and clinical correlates of glycaemic abnormalities in a large MEN 1 kindred.