Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Associations between ultra-distal forearm bone mineral density and incident fracture in women.

Bone mineral density measured at the ultra-distal forearm site was associated with any fracture, as well as distal radius fracture in women from a longitudinal cohort study. PURPOSE: Femoral neck (BMDhip) and lumbar spine (BMDspine) bone mineral density (BMD) are routinely used to assess fracture risk. More data are needed to understand how ultra-distal forearm BMD (BMDUDforearm) may assist fracture prediction. METHODS: Using a Lunar DPX-L, Geelong Osteoporosis Study women (n = 1026), aged 40-90 years, had BMD measured. Incident low-trauma fractures were radiologically verified. Using Cox proportional hazard models, hazard ratios (HR) were calculated for BMDUDforearm as a continuous variable (expressed as a one-unit decrease in T-score) and a categorical variable (normal/osteopenia/osteoporosis). Areas under receiver operating characteristics (AUROC) curves were calculated. Analyses were conducted for any fracture and distal radius fractures. RESULTS: During 14,270 person-years of follow-up, there were 318 fractures (85 distal radius). In adjusted models, continuous BMDUDforearm was associated with any (HR 1.26;95%CI 1.15-1.39) and distal radius fractures (HR 1.59;95%CI 1.38-1.83). AUROCs for continuous BMDUDforearm, 33% forearm(BMD33%forearm), BMDhip, BMDspine, and FRAX without BMD were similar for any fracture (p > 0.05). For distal radius fracture, the AUROC for BMDUDforearm was higher than other sites and FRAX (p < 0.05). In adjusted models, those with osteoporosis had a higher likelihood of any fracture (HR 2.12; 95%CI 1.50-2.98). For distal radius fractures, both osteopenia and osteoporosis had a higher risk (HR 4.31; 95%CI 2.59-7.15 and 4.81; 95%CI 2.70-8.58). AUROCs for any fracture were similar for categorical BMD at all sites but lower for FRAX (p < 0.05). For distal radius fractures, the AUROC for BMDUDforearm, was higher than other sites and FRAX (p < 0.05). CONCLUSION: Ultra-distal forearm BMD may aid risk assessments for any distal radius fractures.

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Emergency presentations for farm-related injuries in older adults residing in south-western Victoria, Australia.

INTRODUCTION: Farm workers are at high risk for injuries, and epidemiological data are needed to plan resource allocation. OBJECTIVE: This study identified regions with high farm-related injury rates in the Barwon South West region of Victoria, Australia, for residents aged ≥50 yr. DESIGN: Retrospective synthesis using electronic medical records of emergency presentations occurring during 2017-2019 inclusive for Local Government Areas (LGA) in the study region. For each LGA, age-standardised incidence rates (per 1000 population/year) were calculated. FINDINGS: For men and women combined, there were 31 218 emergency presentations for any injury, and 1150 (3.68%) of these were farm-related. The overall age-standardised rate for farm-related injury presentations was 2.6 (95% CI 2.4-2.7); men had a higher rate than women (4.1, 95% CI 3.9-4.4 versus 1.2, 95% CI 1.0-1.3, respectively). For individual LGAs, the highest rates of farm-related emergency presentations occurred in Moyne and Southern Grampians, both rural LGAs. Approximately two-thirds of farm-related injuries occurred during work activities (65.0%), and most individuals arrived at the hospital by transport classified as "other" (including private car, 83.3%). There were also several common injury causes identified: "other animal related injury" (20.2%), "cutting, piercing object" (19.5%), "fall ⟨1 m" (13.1%), and "struck by or collision with object" (12.5%). Few injuries were caused by machinery (1.7%) and these occurred mainly in the LGA of Moyne (65%). DISCUSSION AND CONCLUSION: This study provides data to inform future research and resource allocation for the prevention of farm-related injuries.

Negative back beliefs are associated with increased odds of low back pain and disability: a 10-year cohort study in men.

OBJECTIVE: Although negative back beliefs are associated with high-intensity low back pain (LBP)/disability, whether they influence incident high-intensity LBP/high-disability over the long-term is unknown. This study aimed to investigate whether negative back beliefs were associated with developing high-intensity LBP and/or high-disability over 10 years in men. METHODS: Men with no or low-intensity LBP and/or disability attending the Geelong Osteoporosis Study between 2006-2010 were included. Data on age, body mass index, mobility, education, back beliefs (Back Beliefs Questionnaire), LBP and disability (Graded Chronic Pain Scale) were collected between 2006-2010. Beliefs, LBP and disability were re-assessed in 2016-2021. Binary logistic regression was used to examine the association between negative back beliefs and incident high-intensity pain and/or high-disability, adjusting for age, body mass index, mobility, and education. RESULTS: At baseline, 705 participants (mean age 53.8 years) had no or low LBP and no or low-disability; 441 (62.6%) participants completed a 10-year follow-up. Of these, 37 (8.4%) developed high-intensity pain and/or high-disability. In multivariate analyses, participants with more negative back beliefs at baseline were more likely to develop high-intensity pain and/or high-disability (Odds ratio 1.05, 95% CI 1.00-1.11). Developing more negative back beliefs was also associated with incident high-intensity pain and/or high-disability (Odds Ratio 1.20, 95% CI 1.12-1.30). CONCLUSION: In a male community-based population, negative beliefs regarding the consequences of LBP were associated with an increased likelihood of developing high-intensity pain and/or high-disability. Addressing negative back beliefs in the community may reduce the incidence of high-intensity pain and/or high-disability over 10 years in men.

Lipopolysaccharide-binding protein and bone health: data from a population-based sample of men.

We aimed to investigate the association between serum lipopolysaccharide-binding protein (LBP) and bone health in men. LBP was associated with lower bone density at the mid-forearm and the quantitative heel ultrasound measure, broadband ultrasound attenuation, for heavier participants. Data do not support clear associations between serum LBP and bone health. INTRODUCTION: The objective of this study was to investigate the association between serum lipopolysaccharide-binding protein (LBP) and potential downstream effects on skeletal density, quality, and turnover in a population-based sample of men. METHODS: This cross-sectional study utilised data from 1149 men (aged 20-96 year) enrolled in the Geelong Osteoporosis Study. Blood samples were obtained and lipopolysaccharide-binding protein (LBP), bone resorption marker, C-telopeptide (CTx), and formation marker, type 1 procollagen amino-terminal-propeptide (P1NP), were measured. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Stiffness Index (SI), broadband ultrasound attenuation (BUA), and speed of sound (SOS) were derived from quantitative heel ultrasound (QUS). Linear regression models were developed to test associations between log-transformed LBP (ln-LBP), BMD, QUS, and bone turnover, after adjusting for potential covariates. RESULTS: Serum LBP ranged from 1.07-208.53 ng/mL (median 16.53 ng/mL). Those with higher levels were older, less mobile, and had lower BMD at the mid-forearm, otherwise, groups were similar. Before and after adjustment for age, ln-LBP was associated with lower BMD at the spine, total body, and mid-forearm. Further adjustment for weight attenuated associations at the spine and total body, yet the relationship at the mid-forearm was sustained (ß - 0.014 ± 0.004, p = 0.001). SOS and SI were not associated with ln-LBP either before or after adjustment for age; however, weight was identified as an effect modifier in the relationship between ln-LBP and BUA. An association was observed for those weighing greater than 82.7 kg (ß 3.366 ± 0.929, p < 0.001), after adjustment for potential covariates. Neither bone turnover marker was associated with ln-LBP. CONCLUSION: Our data do not support a clear association between serum LBP and measures of bone health in this sample of men.

Mean Bone Material Strength Index Values for Women are Lower Than Those for Men: Data from a Single Geographical Location.

Bone material strength index (BMSi) values are obtained using impact microindentation, which assesses the ability of bone to resist indentation. Differences in BMSi between men and women are unclear, and to date, BMSi sex differences have not been compared for individuals from the same population. Therefore, we compared BMSi values for men and women drawn from the same geographical location in Australia. Participants (n = 220) were from the Geelong Osteoporosis Study. BMSi was measured, following international published guidelines, using an OsteoProbe for participants at recent follow-up phases (women 2022-2023 and men 2016-2022). Women (n = 55) were age matched to men (n = 165) in a 1:3 ratio. A two-sample t test was used to determine the intergroup difference in mean BMSi. Linear regression was also performed, adjusting for weight and height. Median (IQR) ages for men and women were 67.0 (61.7-71.5) and 67.4 (62.0-71.2) years (p = 0.998). Men were heavier (81.0 ± 10.9 vs 71.0 ± 13.9 kg, p < 0.001) and taller (173.9 ± 6.4 vs 161.5 ± 7.5 cm, p < 0.001) than women. Mean (± SD) BMSi for women (75.7 ± 7.4) was lower than for men (82.8 ± 6.8) (p < 0.001). The difference persisted after adjustment for weight and height (mean ± SE: 76.5 ± 1.1 vs 82.5 ± 0.6, p < 0.001). Given the higher fracture risk observed for women, the higher mean BMSi values in men are consistent with cross sectional data suggesting this measure may be useful in fracture prediction.

Reference Intervals for Bone Impact Microindentation in Healthy Adults: A Multi-Centre International Study.

Impact microindentation (IMI) is a novel technique for assessing bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. The aim of this study was to define the reference intervals for men and women by evaluating healthy adults from the United States of America, Europe and Australia. Participants included community-based volunteers and participants drawn from clinical and population-based studies. BMSi was measured on the tibial diaphysis using an OsteoProbe in 479 healthy adults (197 male and 282 female, ages 25 to 98 years) across seven research centres, between 2011 and 2018. Associations between BMSi, age, sex and areal bone mineral density (BMD) were examined following an a posteriori method. Unitless BMSi values ranged from 48 to 101. The mean (± standard deviation) BMSi for men was 84.4 ± 6.9 and for women, 79.0 ± 9.1. Healthy reference intervals for BMSi were identified as 71.0 to 97.9 for men and 59.8 to 95.2 for women. This study provides healthy reference data that can be used to calculate T- and Z-scores for BMSi and assist in determining the utility of BMSi in fracture prediction. These data will be useful for positioning individuals within the population and for identifying those with BMSi at the extremes of the population.

Associations Between Aldosterone-Renin-Ratio and Bone Parameters Derived from Peripheral Quantitative Computed Tomography and Impact Microindentation in Men.

Components of the renin-angiotensin-aldosterone system (RAAS) are present on bone cells. One measure of RAAS activity, the aldosterone-renin-ratio (ARR), is used to screen for primary aldosteronism. Associations between ARR and bone mineral density are conflicting. This study investigated associations between ARR and peripheral quantitative computed tomography (pQCT) and impact microindentation (IMI). Male participants (n = 431) were from the Geelong Osteoporosis Study. "Likely" primary aldosteronism was defined as ARR ≥ 70 pmol/mIU. Another group, "possible" primary aldosteronism, was defined as either ARR ≥ 70 pmol/mIU or taking a medication that affects the RAAS, but not a beta blocker, and renin < 15 mU/L. Using pQCT, images at 4% and 66% of radial (n = 365) and tibial (n = 356) length were obtained. Using IMI measurements, bone material strength index (BMSi; n = 332) was determined. Associations between ARR or likely/possible primary aldosteronism and IMI or pQCT-derived bone parameters were tested using median regression. ARR and aldosterone values were not associated with any of the pQCT-derived bone variables in either unadjusted or adjusted analyses. Men with likely primary aldosteronism (n = 16), had lower adjusted total bone area (radial 66% site, - 12.5%). No associations were observed for men with possible primary aldosteronism (unadjusted or adjusted). No associations with BMSi were observed (p > 0.05). There were no associations between ARR or aldosterone and pQCT-derived bone parameters. Men with likely primary aldosteronism had lower bone area, suggesting clinically high levels of ARR may have a negative impact on bone health.

Peripheral quantitative computed tomography-derived bone parameters in men with impaired fasting glucose and diabetes.

INTRODUCTION: Individuals with type 2 diabetes mellitus (T2DM) are at higher risk of fracture, but paradoxically do not have reduced bone mineral density. We investigated associations between peripheral quantitative computed tomography (pQCT) and glycaemia status. MATERIALS AND METHODS: Participants were men (n = 354, age 33-92 year) from the Geelong Osteoporosis Study. Diabetes was defined by fasting plasma glucose (FPG) ≥ 7.0 mmol/L, self-report of diabetes and/or antihyperglycaemic medication use and impaired fasting glucose (IFG) as FPG 5.6-6.9 mmol/L. Bone measures were derived using pQCT (XCT2000) at 4% and 66% radial and tibial sites. Linear regression was used, adjusting for age, body mass index and socio-economic status. RESULTS: At the 4% site, men with T2DM had lower adjusted bone total area, trabecular area and cortical area at the radius (all - 6.2%) and tibia (all - 6.4%) compared to normoglycaemia. Cortical density was higher for T2DM at the radius (+ 5.8%) and tibia (+ 8.0%), as well as adjusted total bone density at the tibial site (+ 6.1%). At the 66% site, adjusted total bone area and polar stress strain index were lower for T2DM at the radius (- 4.3% and - 8.0%). Total density was also higher for T2DM (+ 1.2%). Only cortical density at the 4% tibial site was different between IFG and normoglycaemia in adjusted analyses (+ 4.5%). CONCLUSION: Men with T2DM had lower total bone area, trabecular area, cortical area and polar stress strain index than the other two groups; however, total density and cortical density were higher. Only one difference was observed between IFG and normoglycaemia; increased tibial cortical density.

Estimation of Whole-Body and Appendicular Lean Mass from Spine and Hip Dual Energy X-ray Absorptiometry: A Cross-Sectional Study.

Whole-body dual X-ray absorptiometry (DXA) accurately measures lean mass but is not routinely used in clinical practice. Hip and spine DXA are used in the diagnosis of osteoporosis, and with the common co-occurrence of sarcopenia with osteoporosis, regional DXA scans provide an opportunity for assessment of lean mass. The aim of this study is to develop predictive equations for the estimation of whole-body lean mass (WBLM), appendicular lean mass (ALM) and whole-body fat mass (WBFM) from regional DXA scans. A total of 2427 participants (ages 20-96 year; 57.7% men) from the Geelong Osteoporosis Study who underwent both regional and whole-body DXA were included in the analysis. Using forward stepwise multivariable linear regression, percentage fat (spine%fat, hip%fat) values from lumbar spine and femoral neck DXA were used in combination with clinical data to develop and validate equations for the estimation of WBLM, WBFM and ALM. Mean age was 53.5 year (± 19.2), weight 78.2 kg (± 15.4), height 169.6 cm (± 9.4), WBLM 50.4 kg (± 11.1), ALM 22.8 kg (± 5.4) and WBFM 24.3 kg (± 10.4). Spine%fat (r = 0.21) and hip%fat (r = - 0.34) were correlated with whole-body lean mass (p < 0.001). Final predictive equations included age, sex, weight, height, spine%fat, and hip%fat and possessed high predictive value (Adj R2 0.91-0.94, RMSE 1.60-2.84 kg). K-fold cross-validation methods produced median root mean square error (RMSE) ranging from 1.59 to 2.81 kg for the three models. Regional DXA scans of the spine and hip can be used to estimate whole-body and appendicular lean mass, to assist in the identification of low muscle mass.

Fatty Liver Index and Skeletal Muscle Density.

Accumulation of fat in the liver and skeletal muscle is associated with obesity and poor health outcomes. Liver steatosis is a characteristic of non-alcoholic fatty liver disease (NAFLD) and myosteatosis, of poor muscle quality in sarcopenia. In this study of 403 men (33-96 years), we investigated associations between the fatty liver index (FLI) and muscle density, as markers of fat accumulation in these organs. We also investigated associations between the FLI and parameters of sarcopenia, including DXA-derived appendicular lean mass (ALM) and handgrip strength by dynamometry. Muscle density was measured using pQCT at the radius and tibia. FLI was calculated from BMI, waist circumference, and levels of triglycerides and gamma-glutamyltransferase. There was a pattern of decreasing muscle density across increasing quartiles of FLI. After adjusting for age and lifestyle, mean radial muscle density in Q4 was 2.1% lower than Q1 (p < 0.001) and mean tibial muscle density was 1.8% lower in Q3 and 3.0% lower in Q4, compared to Q1 (p = 0.022 and < 0.001, respectively). After adjusting for age and sedentary lifestyle, participants in the highest FLI quartile were sixfold more likely to have sarcopenia. In conclusion, our results suggest that fat accumulation in the liver co-exists with fat infiltration into skeletal muscle.

Fracture Risk and Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers.

Medications used to treat hypertension may affect fracture risk. This study investigated fracture risk for users of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). Participants (899 men, median age 70.3 yr (59.9-79.1), range 50.0-96.6 yr; 574 women, median age 65.5 yr (58.1-75.4), range 50.1-94.6 yr) were from the Geelong Osteoporosis Study. Medication use was self-reported and incident fractures were ascertained using radiological reports. Bone mineral density (BMD) was measured at the femoral neck. Participants were divided into four groups: (1) non-users without hypertension, (2) non-users with hypertension, (3) ACEI users and (4) ARB users. Dosage was calculated using the defined daily dose (DDD) criteria. Participants were followed from date of visit to first fracture, death or 31 December 2016, whichever occurred first. Cox proportional hazards models were used for analyses. At least one incident fracture was sustained by 156 men and 135 women over a median(IQR) of 11.5(6.2-13.2) and 10.9(6.3-11.6) years of follow-up, respectively. In unadjusted analyses, compared to non-users without hypertension, men in all three other groups had a higher risk of fracture (Hazard Ratio (HR, 95%CI) 1.54, 1.00-2.37; 1.90, 1.18-3.05; 2.15, 1.26-3.66), for non-users with hypertension, ACEI and ARB users, respectively). Following adjustment for age, prior fracture and BMD, these associations became non-significant. A dose effect for ARB use was observed; men using lower doses had a higher risk of fracture than non-users without hypertension, in both unadjusted (2.66, 1.34-5.29) and adjusted (2.03, 1.01-4.08) analyses, but this association was not observed at higher doses. For women, unadjusted analyses showed a higher risk for ACEI users compared to non-users without hypertension (1.74, 1.07-2.83). This was explained after adjustment for age, alcohol consumption, prior fracture and BMD (1.28, 0.74-2.22). No other differences were observed. In men, lower dose (0 < DDD ≤ 1) ARB use was associated with an increased risk of fracture. ACEI or ARB use was not associated with increased risk of incident fracture in women. These findings may be important for antihypertensive treatment decisions in individuals with a high risk of fracture.

The Predictability of Frailty Associated with Musculoskeletal Deficits: A Longitudinal Study.

We investigated and quantified the predictability of frailty associated with musculoskeletal parameters. This longitudinal study included 287 men aged ≥ 50 yr at baseline (2001-2006) from the Geelong Osteoporosis Study. Baseline musculoskeletal measures included femoral neck bone mineral density (BMD), appendicular lean mass index (ALMI, kg/m2) and whole-body fat mass index (FMI, kg/m2) and lower-limb strength. Frailty at the 15 yr-follow-up (2016-2019) was defined as ≥ 3 and non-frail as < 3, of the following: unintentional weight loss, weakness, low physical activity, exhaustion, and slowness. Binary regression models and AUROC curves quantified the attributable risk of musculoskeletal factors to frailty and their predictive ability. Potential confounders included anthropometry, smoking, alcohol, FMI, socioeconomic status and comorbidities. Forty-eight (16.7%) men were frail at 15 yr-follow-up. Musculoskeletal models were better predictors of frailty compared to the referent (confounders only) model (AUROC for musculoskeletal factors 0.74 vs 0.67 for the referent model). The model with the highest AUROC (0.74; 95% CI 0.66-0.82) included BMD, ALMI and muscle strength (hip abductors) and was better than the referent model that included only lifestyle factors (p = 0.046). Musculoskeletal parameters improved the predictability model as measured by AUROC for frailty after 15 years. In general, muscle models performed better compared to bone models. Musculoskeletal parameters improved the predictability of frailty of the referent model that included lifestyle factors. Muscle deficits accounted for a greater proportion of the risk for frailty than did bone deficits. Targeting musculoskeletal health could be a possible avenue of intervention in regards to frailty.

Patients with end-stage kidney disease have markedly abnormal cortical hip parameters by dual-energy X-ray absorptiometry.

BACKGROUND: Patients with end-stage kidney disease (ESKD) have higher fracture rates and post-fracture mortality than the general population, but bone mineral density by dual-energy X-ray absorptiometry (DXA) is less predictive of fracture in this patient group. Bone biopsy and high-resolution imaging indicate that cortical thickness (CT) is reduced and cortical porosity is increased in ESKD. The aim of this study was to assess cortical parameters using DXA in patients with ESKD. It was hypothesized that these parameters would show deterioration and be associated with fracture. METHODS: Using advanced hip analysis, normal age-related ranges were determined from 752 female and 861 male femur scans and were compared with scans of 226 patients with ESKD at the time of transplantation. RESULTS: Compared with controls, female patients had lower mean±SD CT (mms) at the femoral neck (FN) (2.59 ± 1.42 versus 5.23 ± 1.85), calcar (3.46 ± 1.07 versus 5.09 ± 1.30) and shaft (4.42 ± 1.21 versus 7.44 ± 2.07; P < 0.001 for each), and buckling ratios were higher (8.21 ± 4.6 versus 3.63 ± 1.42; P < 0.001), indicating greater FN instability. All findings were similar for men. Prevalent fracture was documented in 28.8% of patients; 12.4% vertebral only, 8.4% non-vertebral only and 8% vertebral plus non-vertebral. In adjusted models, each 1 SD reduction in FN CT and increase in the buckling ratio was associated with a respective 1.73 (1.22-2.46)- and 1.82 (1.49-2.86)-fold increase in the risk of prevalent vertebral fracture. CONCLUSIONS: In patients with ESKD, DXA-derived cortical parameters are markedly abnormal compared with age- and sex-matched controls. These parameters should be assessed for incident fracture prediction and targeting treatment.

Lean mass as a risk factor for intensive care unit admission: an observational study.

PURPOSE: Intensive care unit (ICU) survivors have reduced physical function likely due to skeletal muscle wasting and weakness acquired during critical illness. However, the contribution of pre-morbid muscle mass has not been elucidated. We aimed to examine the association between pre-ICU muscle mass and ICU admission risk. Secondary outcomes include the relationship between muscle mass and ICU outcomes. METHODS: ICU admissions between June 1, 1998, and February 1, 2019, were identified among participants of Geelong Osteoporosis Study (GOS), a population-based cohort study. Cox proportional hazard regression models estimated hazard ratios (HR) for ICU admission across T-score strata and continuous values of DXA-derived lean mass measures of skeletal mass index (SMI, lean mass/body mass %) and appendicular lean mass corrected for height (ALM/h2, kg/m2). Multivariable regression was used to determine the relationship between lean mass and ICU outcomes. RESULTS: One hundred and eighty-six of 3126 participants enrolled in GOS were admitted to the ICU during the follow-up period. In adjusted models, lean mass was not predictive of ICU admission (SMI: HR 0.99 95%CI 0.97-1.01, p = 0.32; ALM/h2: HR 1.11 95%CI 0.94-1.31, p = 0.23), while greater appendicular lean mass was related to reduced 28-day mortality (ALM/h2 adjOR: 0.25, 95%CI 0.10-0.63, p = 0.003, SMI adjOR: 0.91, 95%CI 0.82-1.02, p = 0.09). CONCLUSION: Lean mass was not associated with ICU admission in this population-based cohort study; however, greater appendicular lean mass was associated with reduced mortality. This suggests pre-ICU muscle status may not predict development of critical illness but is associated with better survival after critical illness occurs.

Impact of subclinical hypothyroidism on health-related quality of life: a narrative review.

A biochemical diagnosis of subclinical hypothyroidism (SCH) is defined by an elevated serum thyroid-stimulating hormone (TSH) with a normal serum free thyroxine (FT4). This paper discusses SCH in the Australian population, the impact of SCH on health-related quality of life (HRQoL), and the evidence for thyroid hormone therapy as well as exercise therapy to improve HRQoL in SCH. The prevalence of SCH in Australia is approximately 4-5% and is higher in females and the elderly. Current evidence suggests thyroid hormone therapy is not associated with an improvement in HRQoL. However, there does appear to be a subgroup of those with SCH that experience an impairment in HRQoL who may potentially benefit from treatment. Because the majority of research to date has been done in elderly, largely asymptomatic individuals, this may not be representative of the entire SCH population. In addition, alternative treatments, such as exercise therapy, have not been well explored in the literature, despite exercise therapy's effects on HRQoL in other populations. Further research is required to define clearly which individuals with SCH are likely to experience an impaired HRQoL, as well as explore the effects of thyroid hormone therapy and exercise therapy in these individuals.

The contribution of musculoskeletal factors to physical frailty: a cross-sectional study.

BACKGROUND: Musculoskeletal conditions and physical frailty have overlapping constructs. We aimed to quantify individual contributions of musculoskeletal factors to frailty. METHODS: Participants included 347 men and 360 women aged ≥60 yr (median ages; 70.8 (66.1-78.6) and 71.0 (65.2-77.5), respectively) from the Geelong Osteoporosis Study. Frailty was defined as ≥3, pre-frail 1-2, and robust 0, of the following; unintentional weight loss, weakness, low physical activity, exhaustion, and slowness. Measures were made of femoral neck BMD, appendicular lean mass index (ALMI, kg/m2) and whole-body fat mass index (FMI, kg/m2) by DXA (Lunar), SOS, BUA and SI at the calcaneus (Lunar Achilles Insight) and handgrip strength by dynamometers. Binary and ordinal logistic regression models and AUROC curves were used to quantify the contribution of musculoskeletal parameters to frailty. Potential confounders included anthropometry, smoking, alcohol, prior fracture, FMI, SES and comorbidities. RESULTS: Overall, 54(15.6%) men and 62(17.2%) women were frail. In adjusted-binary logistic models, SI, ALMI and HGS were associated with frailty in men (OR = 0.73, 95%CI 0.53-1.01; OR=0.48, 0.34-0.68; and OR = 0.11, 0.06-0.22; respectively). Muscle measures (ALMI and HGS) contributed more to this association than did bone (SI) (AUROCs 0.77, 0.85 vs 0.71, respectively). In women, only HGS was associated with frailty in adjusted models (OR = 0.30 95%CI 0.20-0.45, AUROC = 0.83). In adjusted ordinal models, similar results were observed in men; for women, HGS and ALMI were associated with frailty (ordered OR = 0.30 95%CI 0.20-0.45; OR = 0.56, 0.40-0.80, respectively). CONCLUSION: Muscle deficits appeared to contribute more than bone deficits to frailty. This may have implications for identifying potential musculoskeletal targets for preventing or managing the progression of frailty.

Prevalence of Frailty in Older Men and Women: Cross-Sectional Data from the Geelong Osteoporosis Study.

Few studies have investigated the prevalence of frailty in the Australian general population. This study determined the prevalence of frailty in a population-based sample of older adults and examined the relationship between frailty and comorbid conditions. Men (n = 347) and women (n = 360) aged ≥ 60 year from the Geelong Osteoporosis Study (GOS) were assessed between 2016-2019 and 2011-2014, respectively. Frailty was identified using a modified Fried frailty phenotype. Prevalence estimates were standardised to the 2011 Australian population. Kruskal-Wallis test and χ2 test were used to analyse data. For women, mean standardised prevalence estimates were 18.3% (14.1-22.5) for frail, 54.1% (47.3-60.8) pre-frail and 22.9% (18.9-26.8) robust. Corresponding estimates for men were 13.1% (9.8-16.3) frail, 47.8% (42.0-53.6) pre-frail and 27.3% (22.7-31.8) robust. Women who were frail were older, shorter, tended to have a higher body mass index (BMI) and used more medications compared to other groups. Compared to robust women, those who were frail were more likely to have cardio-metabolic (OR 3.5 (0.7-20.0)), pulmonary (OR 3.5 (1.5-8.4)) and musculoskeletal (OR 10.1 (2.1-48.0)) conditions. Frail men were older, had a higher BMI and were more likely to have musculoskeletal conditions (OR 5.8 (2.8-12.3)) and tended to be from a lower SES. No further associations were observed. This study reported the prevalence of frail and pre-frail individuals in a population-based sample of Australian men and women. Frailty was associated with musculoskeletal conditions for both men and women; however, associations with cardio-metabolic and pulmonary comorbidities were evident in women only.

The association between a fracture risk tool and frailty: Geelong Osteoporosis Study.

BACKGROUND: Frailty is characterised by age-related declines in physical, psychological and social functioning. Features of frailty overlap with risk factors for fragility fractures. The aim of this study was to investigate the association between the fracture risk assessment tool (FRAX®) and frailty. METHODS: In cross-sectional analysis, frailty status was determined for participants aged 60-90 yr at 15-year follow-up of the Geelong Osteoporosis Study, using a modified Fried frailty phenotype. Using the FRAX on-line tool, scores for hip and major osteoporotic fracture (MOF) were calculated with and without bone mineral density (BMD). Using the area under Receiver Operating Characteristic (AUROC) curves, and FRAX scores calculated at the baseline visit for these participants, we investigated the association of FRAX and frailty 15 years later. RESULTS: Forty-seven of 303 women (15.5%) and 41 of 282 men (14.5%) were frail at the 15-year visit. There was a gradient of increasing median FRAX scores from robust to frail. For example, for women, median MOF-FRAX without BMD increased from 5.9 for the robust to 7.5 for the pre-frail and 14.0 for the frail (p < 0.001). In secondary analyses, an association was observed between FRAX and frailty over 15 years, with the highest AUROC for women being 0.72 for MOF-FRAX with BMD, and for men, 0.76 hip-FRAX without BMD. CONCLUSION: An association was observed between FRAX and frailty where frail men and women had higher FRAX-scores compared to the other groups. Preliminary data suggest that FRAX, with or without BMD, may be useful in enhancing the information on frailty. Further research using larger datasets will be required to explore this.