Melbourne Medical School Collected Works - Research Publications

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    Hip Structural Parameters over 96 Weeks in HIV-Infected Adults Switching Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine
    Haskelberg, H ; Pocock, N ; Amin, J ; Ebeling, PR ; Emery, S ; Carr, A ; Hsu, Y-H (PUBLIC LIBRARY SCIENCE, 2014-04-10)
    BACKGROUND: Therapy with tenofovir is associated with lower bone mineral density (BMD), higher markers of bone turnover and increased fracture risk in HIV-infected adults. Bone structural parameters generated by hip structural analysis may represent a separate measure of bone strength, but have not been assessed in HIV. METHODS: Dual-energy X-ray absorptiometry (DXA) scans from 254 HIV-infected adults randomised to simplify their existing dual nucleoside analogue reverse transcriptase inhibitor therapy to coformulated tenofovir-emtricitabine or abacavir-lamivudine were analysed using DXA-derived hip structural analysis software. Hip structural parameters included femoral strength index, section modulus, cross-sectional area, and cross-sectional moment of inertia. We used one-way ANOVA to test the relationship between nucleoside analogue type at baseline and structural parameters, multivariable analysis to assess baseline covariates associated with femoral strength index, and t-tests to compare mean change in structural parameters over 96 weeks between randomised groups. RESULTS: Participants taking tenofovir at baseline had lower section modulus (-107.3 mm2, p = 0.001), lower cross-sectional area (-15.01 mm3, p = 0.001), and lower cross-sectional moment of inertia (-2,036.8 mm4, p = 0.007) than those receiving other nucleoside analogues. After adjustment for baseline risk factors, the association remained significant for section modulus (p = 0.008) and cross-sectional area (p = 0.002). Baseline covariates significantly associated with higher femoral strength index were higher spine T-score (p = 0.001), lower body fat mass (p<0.001), lower bone alkaline phosphatase (p = 0.025), and higher osteoprotegerin (p = 0.024). Hip structural parameters did not change significantly over 96 weeks and none was significantly affected by treatment simplification to tenofovir-emtricitabine or abacavir-lamivudine. CONCLUSION: In this population, tenofovir use was associated with reduced composite indices of bone strength as measured by hip structural analysis, but none of the structural parameters improved significantly over 96 weeks with tenofovir cessation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00192634.
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    A case report of disabling bone pain after long-term kidney transplantation
    Myint, TMM ; Vucak-Dzumhur, M ; Ebeling, PR ; Elder, GJ (SPRINGER LONDON LTD, 2014-02-01)
    A 77-year-old man, who received a renal transplant 13 years before for IgA glomerulonephritis, was referred after he developed bilateral mid-tibial aching pain that did not improve with simple analgesia. He had recently been changed from low-dose cyclosporine to tacrolimus, but the pain did not improve when this was reversed. He had a history of focal prostatic adenocarcinoma, cryptococcal lung infection, osteoporosis treated with alendronate for 2 years and multiple squamous cell carcinomas, including one requiring left neck dissection and radiotherapy. Upon physical examination, he had gouty tophi and marked bilateral tibial tenderness but had no other clinical findings. Laboratory investigations included an elevated intact parathyroid hormone value of 7.9 pmol/L (1.6 to 6.9), bone specific alkaline phosphatase of 22 µg/L (3.7 to 20.9), urinary deoxypyridinoline/creatinine ratio of 7.2 nmol/mmol (2.5 to 5.4) and C-reactive protein. Chest X-ray and tibial X-rays were normal, but there was marrow oedema and a prominent periosteal reaction on magnetic resonance imaging. A radionuclide bone scan showed increased symmetrical, linear uptake in both tibiae and the left femur, and uptake was also noted in both clinically asymptomatic humeri. Tibial bone biopsy disclosed small deposits of poorly differentiated metastatic cancer and a follow-up chest CT revealed a lung lesion. It was concluded that the bone pain and periostitis was caused by primary lung cancer with metastatic disease to bone, and an associated hypertrophic osteoarthropathy.
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    Examining the impact of reimbursement on referral to bone density testing for older adults: 8 years of data from the Barwon Statistical Division, Australia
    Brennan, SL ; Kotowicz, MA ; Sarah, B ; Leslie, WD ; Ebeling, PR ; Metge, CJ ; Dobbins, AG ; Pasco, JA (SPRINGER LONDON LTD, 2013-12-01)
    UNLABELLED: In 2007, Medicare Australia revised rei:mbursement guidelines for dual energy X-ray absorptiometry (DXA) for Australians aged ≥70 years; we examined whether these changes increased DXA referrals in older adults. Proportions of DXA referrals doubled for men and tripled for women from 2003 to 2010; however, rates of utilization remained low. INTRODUCTION: On April 1, 2007 Medicare Australia revised reimbursement guidelines for DXA for Australians aged ≥70 year; changes that were intended to increase the proportion of older adults being tested. We examined whether changes to reimbursement increased DXA referrals in older adults, and whether any sex differences in referrals were observed in the Barwon Statistical Division. METHODS: Proportions of DXA referrals 2003-2010 based on the population at risk ascertained from Australian Census data and annual referral rates and rate ratios stratified by sex, year of DXA, and 5-year age groups. Persons aged ≥70 years referred to the major public health service provider for DXA clinical purposes (n = 6,096; 21 % men). RESULTS: DXA referrals. Proportions of DXA referrals for men doubled from 0.8 % (2003) to 1.8 % (2010) and tripled from 2.0 to 6.3 % for women (all p < 0.001). For 2003-2006, referral ratios of men/women ranged between 1:1.9 and 1:3.0 and for 2007-2010 were 1:2.3 to 1:3.4. Referral ratios <2007:≥2007 were 1:1.7 for men aged 70-79 years (p < 0.001), 1:1.2 for men aged 80-84 years (p = 0.06), and 1:1.3 for men 85+ years (p = 0.16). For women, the ratios <2007:≥2007 were 1:2.1 (70-79 years), 1.1.5 (80-84 years), and 1:1.4 (85+ years) (all p < 0.001). CONCLUSIONS: DXA referral ratios were 1:1.6 (men) and 1:1.8 (women) for 2007-2010 vs. 2003-2006; proportions of referrals doubled for men and tripled for women from 2003 to 2010. Overall, rates of DXA utilization remained low. Policy changes may have had minimal influence on referral; thus, ongoing evaluation over time is warranted.
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    Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults
    Scott, D ; Hayes, A ; Sanders, KM ; Aitken, D ; Ebeling, PR ; Jones, G (SPRINGER LONDON LTD, 2014-01-01)
    UNLABELLED: Sarcopenia may be diagnosed in the clinic using operational definitions based on low muscle mass or function. This prospective, population-based study revealed that sex-specific associations may exist between operational definitions of sarcopenia and falls in community-dwelling middle-aged and older adults. INTRODUCTION: The objective of this study is to verify associations between sarcopenia and falls risk and to determine changes in sarcopenia prevalence over 5 years in middle-aged and older men and women according to different anthropometric and performance-based operational definitions. METHODS: N = 681 volunteers (48% female; mean ± SD age 61.4 ± 7.0 years) participated in baseline and follow-up assessments (mean 5.1 ± 0.5 years later). Appendicular lean mass (ALM) was assessed by dual-energy X-ray absorptiometry, hand grip (HGS) and lower-limb (LLS) strength were assessed by dynamometry, and falls risk was determined using the physiological profile assessment. Anthropometric definitions (ALM/height squared [ALM-H], ALM/weight × 100 and a residuals method [ALM-R]) and performance-based definitions (HGS, LLS and upper- and lower-limb muscle quality [LMQ]) of sarcopenia were examined. The lowest 20% of the sex-specific distribution for each definition at baseline was classified as sarcopenia. RESULTS: Sarcopenia prevalence increased after 5 years for all operational definitions except ALM-H (men: -4.0%; women: -5.5%). Men classified with sarcopenia according to anthropometric definitions, and women classified with sarcopenia according to performance-based definitions, had significant increases in falls risk over 5 years (all P < 0.05) compared to individuals without sarcopenia. Significant sex interactions were observed for ALM-R, LLS and LMQ (all P < 0.05) definitions. CONCLUSIONS: Sarcopenia prevalence generally increases at a higher rate when assessed using performance-based definitions. Sarcopenia is associated with increases in falls risk over 5 years in community-dwelling middle-aged and older adults, but sex-specific differences may exist according to different anthropometric or performance-based definitions.
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    Effects of a Targeted Multimodal Exercise Program Incorporating High-Speed Power Training on Falls and Fracture Risk Factors in Older Adults: A Community-Based Randomized Controlled Trial
    Gianoudis, J ; Bailey, CA ; Ebeling, PR ; Nowson, CA ; Sanders, KM ; Hill, K ; Daly, RM (WILEY, 2014-01-01)
    Multimodal exercise programs incorporating traditional progressive resistance training (PRT), weight-bearing impact training and/or balance training are recommended to reduce risk factors for falls and fracture. However, muscle power, or the ability to produce force rapidly, has emerged as a more crucial variable to functional decline than muscle strength or mass. The aim of this 12-month community-based randomized controlled trial, termed Osteo-cise: Strong Bones for Life, was to evaluate the effectiveness and feasibility of a multimodal exercise program incorporating high-velocity (HV)-PRT, combined with an osteoporosis education and behavioral change program, on bone mineral density (BMD), body composition, muscle strength and functional muscle performance in older adults. Falls incidence was evaluated as a secondary outcome. A total of 162 older adults (mean ± SD; 67 ± 6 years) with risk factors for falls and/or low BMD were randomized to the Osteo-cise program (n = 81) or a control group (n = 81). Exercise consisted of fitness center-based HV-PRT, weight-bearing impact and challenging balance/mobility activities performed three times weekly. After 12 months, the Osteo-cise program led to modest but significant net gains in femoral neck and lumbar spine BMD (1.0% to 1.1%, p < 0.05), muscle strength (10% to 13%, p < 0.05), functional muscle power (Timed Stair Climb, 5%, p < 0.05) and dynamic balance (Four Square Step Test 6%, p < 0.01; Sit-to-Stand, 16%, p < 0.001) relative to controls. There was no effect on total body lean mass or mobility (timed-up-and-go), and no difference in falls rate (incidence rate ratio [IRR], 1.22; 95% confidence interval [CI], 0.72-2.04). In conclusion, this study demonstrates that the Osteo-cise: Strong Bones for Life community-based, multimodal exercise program represents an effective approach to improve multiple musculoskeletal and functional performance measures in older adults with risk factors for falls and/or low BMD. Although this did not translate into a reduction in the rate of falls, further large-scale trials are needed to evaluate the efficacy of this multimodal approach on reducing falls and fracture.
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    The Effect of Acute Exercise on Undercarboxylated Osteocalcin and Insulin Sensitivity in Obese Men
    Levinger, I ; Jerums, G ; Stepto, NK ; Parker, L ; Serpiello, FR ; McConell, GK ; Anderson, M ; Hare, DL ; Byrnes, E ; Ebeling, PR ; Seeman, E (WILEY, 2014-12-01)
    Acute exercise improves insulin sensitivity for hours after the exercise is ceased. The skeleton contributes to glucose metabolism and insulin sensitivity via osteocalcin (OC) in its undercarboxylated (ucOC) form in mice. We tested the hypothesis that insulin sensitivity over the hours after exercise is associated with circulating levels of ucOC. Eleven middle-aged (58.1 ± 2.2 years mean ± SEM), obese (body mass index [BMI] = 33.1 ± 1.4 kg/m(2) ) nondiabetic men completed a euglycemic-hyperinsulinemic clamp at rest (rest-control) and at 60 minutes after exercise (4 × 4 minutes of cycling at 95% of HRpeak ). Insulin sensitivity was determined by glucose infusion rate relative to body mass (GIR, mL/kg/min) as well as GIR per unit of insulin (M-value). Blood samples and five muscle biopsies were obtained; two at the resting-control session, one before and one after clamping, and three in the exercise session, at rest, 60 minutes after exercise, and after the clamp. Exercise increased serum ucOC (6.4 ± 2.1%, p = 0.013) but not total OC (p > 0.05). Blood glucose was ∼6% lower and insulin sensitivity was ∼35% higher after exercise compared with control (both p < 0.05). Phosphorylated (P)-AKT (Ak thymoma) was higher after exercise and insulin compared with exercise alone (no insulin) and insulin alone (no exercise, all p < 0.05). In a multiple-linear regression including BMI, age, and aerobic fitness, ucOC was associated with whole-body insulin sensitivity at rest (β = 0.59, p = 0.023) and after exercise (β = 0.66, p = 0.005). Insulin sensitivity, after acute exercise, is associated with circulating levels of ucOC in obese men. Whether ucOC has a direct effect on skeletal muscle insulin sensitivity after exercise is yet to be determined.
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    Femoral shaft strains during daily activities: Implications for atypical femoral fractures
    Martelli, S ; Pivonka, P ; Ebeling, PR (ELSEVIER SCI LTD, 2014-09-01)
    BACKGROUND: Atypical femoral fractures are low-energy fractures initiating in the lateral femoral shaft. We hypothesized that atypical femoral fracture onset is associated with daily femoral strain patterns. We examined femoral shaft strains during daily activities. METHODS: We analyzed earlier calculations of femoral strain during walking, sitting and rising from a chair, stair ascent, stair descent, stepping up, and squatting based on anatomically consistent musculoskeletal and finite-element models from a single donor and motion recordings from a body-matched volunteer. Femoral strains in the femoral shaft were extracted for the different activities and compared. The dependency between femoral strains in the lateral shaft and kinetic parameters was studied using multi-parametric linear regression analysis. FINDINGS: Tensile strain in the lateral femoral shaft varied from 327 με (squatting) to 2004 με (walking). Walking and stair descent imposed tensile loading on the lateral shaft, whereas the other activities mainly imposed tensile loads on the anterior shaft. The multi-parametric linear regression showed a moderately strong correlation between tensile strains in the lateral shaft and the motion kinetic (joint moments and ground reaction force) in the proximal (R(2)=0.60) and the distal shaft (R(2)=0.46). INTERPRETATION: Bone regions subjected to tensile strains are associated with atypical femoral fractures. Walking is the daily activity that induces the highest tensile strain in the lateral femoral shaft. The kinetics of motion explains 46%-50% of the tensile strain variation in the lateral shaft, whereas the unexplained part is likely to be attributed to the way joint moments are decomposed into muscle forces.
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    Serum selenium status in Graves' disease with and without orbitopathy: a case-control study
    Khong, JJ ; Goldstein, RF ; Sanders, KM ; Schneider, H ; Pope, J ; Burdon, KP ; Craig, JE ; Ebeling, PR (WILEY, 2014-06-01)
    OBJECTIVE: Selenium is effective in improving quality of life and reducing the progression of active Graves' orbitopathy. The effect of correcting relative selenium deficiency on improving Graves' orbitopathy is unknown, as baseline selenium levels have not previously been measured. The study aims to determine whether serum selenium levels are reduced in patients with Graves' disease with orbitopathy (GO) compared with without orbitopathy (GD). DESIGN: A prospective, case-control study performed between 2009 and 2012 at endocrine and ophthalmology clinics in Australia. PATIENTS: A total of 198 patients with Graves' disease participated in the study: 101 with Graves' orbitopathy and 97 without Graves' orbitopathy. MEASUREMENTS: Serum selenium levels in both groups. RESULTS: Mean serum selenium levels were significantly lower in GO (1·10 ± 0·18 μm) than in GD (1·19 ± 0·20 μm) (P = 0·001). Mean selenium levels appeared to decrease in parallel with increasing severity of GO; selenium level was 1·19 ± 0·20 μm in GD, 1·10 ± 0·19 μm in moderate-to-severe GO and 1·09 ± 0·17 μm in sight-threatening GO (P = 0·003). Serum selenium levels remained significantly lower in GO after adjusting for age, smoking status, thyroidectomy, radioactive iodine treatment and residential location. CONCLUSION: Serum selenium levels are lower in patients with GO compared with GD in an Australian study population with marginal selenium status. Relative selenium deficiency may be an independent risk factor for orbitopathy in patients with Graves' disease.
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    Shining the Light on Sunshine: a systematic review of the influence of sun exposure on type 2 diabetes mellitus-related outcomes
    Shore-Lorenti, C ; Brennan, SL ; Sanders, KM ; Neale, RE ; Lucas, RM ; Ebeling, PR (WILEY, 2014-12-01)
    Prospective observational studies uniformly link vitamin D deficiency with the incidence of type 2 diabetes mellitus (T2DM), yet trials supplementing participants at risk of T2DM with vitamin D to reduce progression to T2DM have yielded inconsistent results. Inconsistencies between supplementation trials may be due to insufficient dosing or small sample sizes. Observational studies may also have reported spurious associations due to uncontrolled confounding by lifestyle or genetic factors. Alternatively, observational and intervention studies may not be entirely comparable. Observational studies show an association between higher vitamin D status, which is predominantly derived from sun exposure, and decreased incidence of T2DM. Trials intervene with vitamin D supplementation, and therefore may be missing alternate causes of the effect of sun exposure, as seen in observational studies. We propose that sun exposure may be the driving force behind the associations seen in observational studies; sun exposure may have additional benefits beyond increasing serum 25-hydroxyvitamin D (25OHD) levels. We performed an electronic literature search to identify articles that examined associations between sun exposure and T2DM and/or glucose metabolism. A best evidence synthesis was then conducted using outcomes from analyses deemed to have high methodological quality. Ten eligible full-text articles were identified, yielding 19 T2DM-related outcomes. The best evidence analysis considered 11 outcomes which were grouped into six outcome types: T2DM, fasting glucose, glucose tolerance, fasting insulin, insulin secretion and insulin sensitivity. There was moderate evidence to support a role of recreational sun exposure in reducing odds of T2DM incidence. High-level evidence was lacking; evidence presented for other outcomes was of low or insufficient level. This review highlights significant gaps in research pertaining to sun exposure and T2DM-related outcomes. Further research is encouraged as we aim to identify novel preventative strategies for T2DM.