Melbourne Medical School Collected Works - Research Publications
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ItemNo Preview AvailableOsteoporosis in men: its pathophysiology and the role of teriparatide in its treatment(DOVE MEDICAL PRESS LTD, 2008)As the population ages, the burden of osteoporosis in men is expected to rise. Implementation of preventive measures such as falls prevention strategies, exercise and adequate calcium and vitamin D intake is recommended. However, when the diagnosis of osteoporosis is made, effective treatments need to be initiated to prevent fractures. As opposed to postmenopausal women, reduced bone formation is the predominant mechanism of age-related bone loss in men, making anabolic agents a logical treatment option for men with osteoporosis. Teriparatide is the only anabolic agent currently approved for treatment of osteoporosis in men. This paper summarizes the mechanism of action of teriparatide, as well as its tolerability and safety. Furthermore, the evidence supporting the efficacy of teriparatide treatment in men with osteoporosis is reviewed and its current role in the management of osteoporosis in men is discussed.
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ItemHip Structural Parameters over 96 Weeks in HIV-Infected Adults Switching Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine(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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ItemWhat is the clinical and ethical importance of incidental abnormalities found by knee MRI?(BMC, 2008)INTRODUCTION: Magnetic resonance imaging (MRI) is increasingly used to examine joints for research purposes. It may detect both suspected and unsuspected abnormalities. This raises both clinical and ethical issues, especially when incidental abnormalities are detected. The prevalence of incidental, potentially clinically significant abnormalities identified by MRI and their clinical significance in a population undergoing knee MRI in research studies are unknown. METHODS: We examined the prevalence of such lesions in healthy asymptomatic adults and those with symptomatic knee osteoarthritis (OA) undergoing knee MRI with limited sequences for the purpose of research. The MRI findings in 601 asymptomatic subjects and 132 with knee OA who underwent at least one limited knee MRI scan for cartilage volume measurement were examined by an MRI radiologist for the presence of potentially clinically significant abnormalities. RESULTS: These were present in 2.3% of healthy and 2.3% of OA subjects. All required further investigation to exclude non-benign disease, including four with bone marrow expansion (0.7%), requiring further investigation and management. A single potentially life-threatening lesion, a myeloma lesion, was identified in a subject with symptomatic knee OA on their second MRI scan in a longitudinal study. CONCLUSION: As musculoskeletal MRI is increasingly used clinically and for research purposes, the potential for detecting unsuspected abnormalities that require further investigation should be recognized. Incorporating a system to detect these, to characterize unexpected findings, and to facilitate appropriate medical follow-up when designing studies using this technology should be considered ethical research practice.
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ItemA case report of disabling bone pain after long-term kidney transplantation(SPRINGER LONDON LTD, 2014-02)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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ItemExamining the impact of reimbursement on referral to bone density testing for older adults: 8 years of data from the Barwon Statistical Division, Australia(SPRINGER LONDON LTD, 2013-12)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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ItemDeclining incidence of osteoporotic hip fracture in Australia.(Springer Science and Business Media LLC, 2012)UNLABELLED: Between 1997-1998 and 2006-2007 in Australia, the age-standardised incidence rates of hip fractures declined by 20 and 13 %, in females and males, respectively. Although this may be related to the rollout of public health campaigns and strategies addressing osteoporosis, absolute numbers of hip fractures continued to increase. BACKGROUND: Previous reports described an increasing trend in osteoporotic hip fracture incidence in Australia in the 1980s with a stabilisation over the 1990s. AIM: The aim of this study was to describe national trends in the incidence of osteoporotic hip fracture in Australia between 1997-1998 and 2006-2007. METHODS: Data on low-trauma hip fractures in persons aged 50 years and over were obtained from the National Hospital Morbidity Database. Cases where the patient was transferred in from another hospital were excluded. Age-standardised incidence rates were calculated and a linear test for trend applied. RESULTS: Although the absolute number of hip fracture cases has continued to increase, from 14,769 in 1997-1998 to 16,412 in 2006-2007, these numbers are lower than previous predictions based on population ageing. Over the 10-year period, the age-standardised incidence rates in females declined by 20 %, from 370 to 295 per 100,000, while the age-standardised incidence rates in males declined by 13 %, from 200 to 174 per 100,000. Both declines were statistically significant. The sex difference in incidence rates narrowed between 1997-1998 (females 85 % higher) and 2006-2007 (females 70 % higher). CONCLUSIONS: The age-standardised incidence of osteoporotic hip fracture in Australia is falling. This may be related to the uptake of bisphosphonates as well as the rollout of public health campaigns and strategies addressing osteoporosis.
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ItemA global representation of vitamin D status in healthy populations.(Springer Science and Business Media LLC, 2012)PURPOSE: This paper visualizes the available data on vitamin D status on a global map, examines the existing heterogeneities in vitamin D status and identifies research gaps. METHODS: A graphical illustration of global vitamin D status was developed based on a systematic review of the worldwide literature published between 1990 and 2011. Studies were eligible if they included samples of randomly selected males and females from the general population and assessed circulating 25-hydroxyvitamin D [25(OH)D] levels. Two different age categories were selected: children and adolescents (1-18 years) and adults (>18 years). Studies were chosen to represent a country based on a hierarchical set of criteria. RESULTS: In total, 200 studies from 46 countries met the inclusion criteria, most coming from Europe. Forty-two of these studies (21 %) were classified as representative. In children, gaps in data were identified in large parts of Africa, Central and South America, Europe, and most of the Asia/Pacific region. In adults, there was lack of information in Central America, much of South America and Africa. Large regions were identified for which the mean 25(OH)D levels were below 50 nmol/L. CONCLUSIONS: This study provides an overview of 25(OH)D levels around the globe. It reveals large gaps in information in children and adolescents and smaller but important gaps in adults. In view of the importance of vitamin D to musculoskeletal growth, development, and preservation, and of its potential importance in other tissues, we strongly encourage new research to clearly define 25(OH)D status around the world.
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ItemOperational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults(SPRINGER LONDON LTD, 2014-01)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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ItemEffects 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(WILEY, 2014-01)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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ItemThe Effect of Acute Exercise on Undercarboxylated Osteocalcin and Insulin Sensitivity in Obese Men(WILEY, 2014-12)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.