ABSTRACT Measures of muscle mass, strength, and function predict risk of incident fractures, but it is not known whether this risk information is additive to that from FRAX (fracture risk assessment tool) probability. In the Osteoporotic Fractures in Men (MrOS) Study cohorts (Sweden, Hong Kong, United States), we investigated whether measures of physical performance/appendicular lean mass (ALM) by DXA predicted incident fractures in older men, independently of FRAX probability. Baseline information included falls history, clinical risk factors for falls and fractures, femoral neck aBMD, and calculated FRAX probabilities. An extension of Poisson regression was used to investigate the relationship between time for five chair stands, walking speed over a 6 m distance, grip strength, ALM adjusted for body size (ALM/height2), FRAX probability (major osteoporotic fracture [MOF]) with or without femoral neck aBMD, available in a subset of n = 7531), and incident MOF (hip, clinical vertebral, wrist, or proximal humerus). Associations were adjusted for age and time since baseline, and are reported as hazard ratios (HRs) for first incident fracture per SD increment in predictor using meta-analysis. 5660 men in the United States (mean age 73.5 years), 2764 men in Sweden (75.4 years), and 1987 men in Hong Kong (72.4 years) were studied. Mean follow-up time was 8.7 to 10.9 years. Greater time for five chair stands was associated with greater risk of MOF (HR 1.26; 95% CI, 1.19 to 1.34), whereas greater walking speed (HR 0.85; 95% CI, 0.79 to 0.90), grip strength (HR 0.77; 95% CI, 0.72 to 0.82), and ALM/height2 (HR 0.85; 95% CI, 0.80 to 0.90) were associated with lower risk of incident MOF. Associations remained largely similar after adjustment for FRAX, but associations between ALM/height2 and MOF were weakened (HR 0.92; 95% CI, 0.85 to 0.99). Inclusion of femoral neck aBMD markedly attenuated the association between ALM/height2 and MOF (HR 1.02; 95% CI, 0.96 to 1.10). Measures of physical performance predicted incident fractures independently of FRAX probability. Whilst the predictive value of ALM/height2 was substantially reduced by inclusion of aBMD requires further study, these findings support the consideration of physical performance in fracture risk assessment. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Background: Lumbar spine TBS, a texture index derived from lumbar spine dual-energy x-ray absorptiometry (DXA) images, enhances fracture prediction. No studies to date have studied a broad range of clinical variables to determine which patients might experience the greatest benefit from the use of TBS. Methods: Using the Manitoba BMD Registry, we identified 37,176 subjects with baseline DXA, FRAX (R)-based fracture probability, lumbar spine TBS, and minimum 5 years of observation. Subgroups considered were based on sex, age, body mass index (BMI), prior fracture, chronic obstructive lung disease (COPD), high alcohol use, rheumatoid arthritis (RA), high glucocorticoid use, osteoporotic femoral neck T-score, number of comorbidities, diabetes, secondary osteoporosis, and prior osteoporosis treatment. Non-traumatic major osteoporotic fractures (MOF, n = 3741) and hip fractures (HF, n = 1008) were identified using population-based health services data. We analyzed baseline TBS using analysis of covariance (ANCOVA). FRAX-adjusted hazard ratios (HR) per SD reduction in TBS were estimated and tested for interactions. Categorical net reclassification improvement (NRI) was estimated using fixed FRAX-based intervention cut-offs. Results: Adjusted baseline TBS was significantly lower (p <= 0.001) for women (-4.2%), osteoporotic hip T-score (-4.0%), COPD (-2.8%), diabetes (-2.6%), high alcohol use (-2.3%), prior fracture (-2.2%), glucocorticoid use (-15%), RA (-0.9%) and secondary osteoporosis (-0.8%), whereas recent osteoporosis therapy was associated with greater TBS (+1.5%). HRs per SD reduction in TBS for fracture prediction were larger for age < 65 vs 65 + (MOF p-interaction = 0.004, HF p-interaction < 0.001), without vs with prior fracture (MOF p-interaction = 0.003, HF p-interaction = 0.048), without vs with glucocorticoid use (HF p-interaction = 0.029), lower vs higher comorbidity score (HF p-interaction < 0.001), and without vs with osteoporosis treatment (MOF p-interaction = 0.005). NRI for using the TBS adjustment to FRAX in all subjects was 1.2% for MOF (p = 0.002) and 1.7% for HF (p = 0.016). NRI was greater in subjects age < 65 y (MOF:1.7%, HF:5.6%), no prior fracture (HF: 2.4%), non-osteoporotic T-score (HF: 3.0%), and high glucocorticoid use (MOF: 3.9%). Conclusion: TBS is sensitive to the effects of multiple risk factors for fracture. TBS-adjusted fracture risk assessment resulted in significant improvements for multiple subgroups.

Context: Areal bone mineral density (BMD) measurements are confounded by skeletal size. HipBMD is an input to the FRAX (R) tool (Centre for Metabolic Bone Diseases, University of Sheffield, United Kingdom), but it is unknown whether performance is affected by hip area. Objective: To examine whether fracture prediction by FRAX (R) is affected by hip area. Design and Setting: Cohort study using a population-based BMD registry. Patients: A total of 58,108 white women aged >= 40 years. Main Outcome Measures: Incident major osteoporotic fracture (MOF; n = 4913) and hip fracture (n = 1369), stratified by total hip area quintile, before and after adjustment for hip axis length (HAL). Results: Smaller hip area was associated with younger age and lower FRAX (R) scores, whereas incident fractures were greater in those with larger hip area (P for trend, 0.001). Larger hip area quintile increased risk for MOF and hip fracture when adjusted for FRAX (R) score with BMD (P for trend, 0.001). Each standard deviation increase in hip area was associated with greater risk for incident MOF [adjusted hazard ratio (HR), 1.08; 95% confidence interval (CI), 1.05 to 1.11] and hip fracture (HR, 1.16; 95% CI, 1.11 to 1.21), but not after adjustment for HAL. FRAX (R) with BMD underestimated MOF risk in the largest hip area quintile and underestimated hip fracture risk in the three largest hip area quintiles. Conclusions: In Canadian white women, skeletal size based on hip area affects fracture risk assessment based on FRAX (R) score with BMD, with risk underestimated in those with larger hip areas. Including HAL in the risk assessment compensates for this confounding by skeletal size and provides for more accurate assessment of fracture risk.

The characterization of risk factors for fracture that contribute significantly to fracture risk, over and above that provided by the bone mineral density, has stimulated the development of risk assessment tools. The more adequately evaluated tools, all available online, include the FRAX® tool, the Garvan fracture risk calculator and, in the United Kingdom only, QFracture®. Differences in the input variables, output, and model construct give rise to marked differences in the computed risks from each calculator. Reasons for the differences include the derivation of fracture probability (FRAX) rather than incidence (Garvan and QFracture), limited calibration (Garvan), and inappropriate source information (QFracture). These differences need to be taken into account in the evaluation of assessment guidelines.

IMPORTANCE Osteoporotic fractures are a leading cause of disability, costs, and mortality. FRAX is a tool used to assess fracture risk in the general population. Mental disorders and medications to treat them have been reported to adversely affect bone health, but, to date, they have not been systematically studied in relation to osteoporotic fractures.OBJECTIVE To examine the association of mental disorders and psychotropic medication use with osteoporotic fracture risk in routine clinical practice.DESIGN, SETTING, AND PARTICIPANTS In this population-based cohort study, bone mineral density and risk factors were used to calculate FRAX scores using data from the Manitoba Bone Density Program database of all women and men 40 years of age or older in Manitoba, Canada, referred for a baseline dual-energy x-ray absorptiometry scan from January 1, 1996, to March 28, 2013. Population-based health services data were used to identify primary mental disorders during the 3 prior years, psychotropic medication use during the prior year, and incident fractures. Cox proportional hazards regression models estimated the risk for incident fractures based on mental disorders and use of psychotropic medications. Data analysis was conducted from November 25, 2013, to October 15, 2016.MAIN OUTCOMES AND MEASURES Incident nontraumatic major osteoporotic fractures (MOFs) and hip fractures.RESULTS Of the 68 730 individuals (62 275 women and 6455 men; mean age, 64.2 [11.2] years) in the study, during 485 322 person-years (median, 6.7 years) of observation, 5750 (8.4%) sustained an incident MOF, 1579 (2.3%) sustained an incident hip fracture, and 8998 (13.1%) died. In analyses adjusted for FRAX score, depression was associated with MOF (adjusted hazard ratio [aHR], 1.39; 95% CI, 1.27-1.51; P<.05) and hip fracture (aHR, 1.43; 95% CI, 1.22-1.69; P<.05) before adjustment for medication use, but these associations were not significant after adjustment for medication use. In contrast, the use of selective serotonin reuptake inhibitors (aHR for MOF, 1.43; 95% CI, 1.27-1.60; P<.05; aHR for hip fracture, 1.48; 95% CI, 1.18-1.85; P<.05), antipsychotics (aHR for MOF, 1.43; 95% CI, 1.15-1.77; P<.05; aHR for hip fracture, 2.14; 95% CI, 1.52-3.02; P<.05), and benzodiazepines (aHR for MOF, 1.15; 95% CI, 1.04-1.26; P<.05; aHR for hip fracture, 1.24; 95% CI, 1.05-1.47; P<.05) were each independently associated with significantly increased risk for both MOF and hip fracture. FRAX significantly underestimated the 10-year risk of MOF by 29% and of hip fracture by 51% for those with depression. It also underestimated the 10-year risk of MOF by 36% for use of selective serotonin reuptake inhibitors, by 63% for use of mood stabilizers, by 60% for use of antipsychotics, and by 13% for use of benzodiazepines. FRAX underestimated the 10-year risk of hip fracture by 57% for use of selective serotonin reuptake inhibitors, by 98% for use of mood stabilizers, by 171% for use of antipsychotics, and by 31% for use of benzodiazepines. FRAX correctly estimated fracture risk in people without mental disorders and those not taking psychotropic medications.CONCLUSIONS AND RELEVANCE Mental disorders and medication use were associated with an increased risk for fracture, but in simultaneous analyses, only medication use was independently associated with fracture. Depression and psychotropic medication use are potential risk indicators that are independent of FRAX estimates.

The fracture risk assessment tool, FRAX, was released in 2008 and provides country-specific algorithms for estimating individualized 10-year probability of hip and major osteoporotic fracture (hip, clinical spine, distal forearm, and proximal humerus). Since its release, models are now available for 63 countries, covering 79% of the world population. The website receives approximately 3 million visits annually. Following independent validation, FRAX has been incorporated into more than 80 guidelines worldwide. However, the application of FRAX in guidelines has been heterogeneous with the adoption of several different approaches to setting intervention thresholds. The relationship between FRAX and efficacy of intervention has been explored and is expected to influence treatment guidelines in the future. A more unified approach to setting intervention thresholds with FRAX is a research priority.

ABSTRACT Daily subcutaneous (SC) injections of the investigational drug abaloparatide-SC (80 mcg) for 18 months significantly decrease the risk of vertebral and nonvertebral fracture compared with placebo in postmenopausal women. We examined the efficacy of abaloparatide-SC as a function of baseline fracture risk, assessed using the FRAX tool. Baseline clinical risk factors (age, body mass index [BMI], prior fracture, glucocorticoid use, rheumatoid arthritis, and smoking) were entered into country-specific FRAX models to calculate the 10-year probability of major osteoporotic fractures, with or without femoral neck bone mineral density (BMD). The interaction between probability of a major osteoporotic fracture and treatment efficacy was examined by a Poisson regression. A total of 821 women randomized to placebo and 824 women to abaloparatide-SC, mean age 69 years in both groups, were followed for up to 2 years. At baseline, the 10-year probability of major osteoporotic fractures (with BMD) ranged from 2.3% to 57.5% (mean 13.2%). Treatment with abaloparatide-SC was associated with a 69% (95% confidence interval [CI] 38–85%) decrease in major osteoporotic fracture (MOF) and a 43% (95% CI 9–64%) decrease in any clinical fracture compared with placebo. For all outcomes, hazard ratios tended to decrease (ie, greater efficacy) with increasing fracture probability. Whereas the interaction approached significance for the outcome of any fracture (p = 0.11), there was no statistically significant interaction for any of the fracture outcomes. Similar results were noted when FRAX probability was computed without BMD. Efficacy of abaloparatide-SC to decrease the risk of major osteoporotic fracture or any clinical fracture in postmenopausal women with low BMD and/or prior fracture appears independent of baseline fracture probability. © 2017 American Society for Bone and Mineral Research.

Introduction The aim of this study was to compare the intra-observer repeatability when using two different methods for estimating the volume of foetal urinary bladders.Method The urinary bladders of 20 foetuses were documented by three-dimensional ultrasound. Standard deviation was compared when the volumes of identical bladder images were repeatedly estimated using the Virtual Organ Computer-aided AnaLysis and the experimental SUM-OF-CYLINDERS methods.Results No systematic deviation was found between the estimated volumes when using these two methods. Standard deviation was smaller for the SUM-OF-CYLINDERS compared to the Virtual Organ Computer-aided AnaLysis method (p<0.0001). In relation to bladder volumes of 5-25ml, standard deviation was 11-14% for the Virtual Organ Computer-aided AnaLysis and 4-5% for the SUM-OF-CYLINDERS method.Conclusions Using three-dimensional ultrasound images adapted for the Virtual Organ Computer-aided AnaLysis method, foetal urinary bladder volumes can also be estimated using the SUM-OF-CYLINDERS method. The SUM-OF-CYLINDERS method employs technical advances which may result in a lower standard deviation and therefore higher intra-observer repeatability.

Measures of physical performance or function, but not appendicular lean mass, predict new fractures independently of FRAX probability : Findings from MrOS

CONTEXT:Type 2 diabetes is associated with a higher risk for major osteoporotic fracture (MOF) and hip fracture than predicted by the World Health Organization fracture risk assessment (FRAX) tool. OBJECTIVE:The objective of the study was to examine the impact of diabetes duration on fracture risk. METHODS:Using a clinical dual-energy x-ray absorptiometry registry linked with the Manitoba administrative databases, we identified all women age 40 years or older with 10 or more years of prior health care coverage undergoing hip dual-energy x-ray absorptiometry measurements (1996-2013). Incident MOF and incident hip fractures were each studied over 7 years. Cox proportional hazards models were adjusted for FRAX (FRAX adjusted) and then FRAX plus comorbidity, falls, osteoporosis therapy, or insulin (fully adjusted). FRAX calibration was assessed comparing observed vs predicted probabilities. RESULTS:There were 49 098 women without and 8840 women with diabetes (31.4% >10 y duration; 20.1% 5-10 y; 23.7% <5 y; 24.8% new onset). In FRAX-adjusted analyses, only duration longer than 10 years was associated with a higher risk for MOF (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.30-1.66), and this was similar in the fully adjusted models (HR 1.34, 95% CI 1.17-1.54). In contrast, a higher risk for hip fracture was seen for all durations in a dose-dependent fashion (eg, FRAX adjusted HR 2.10, 95% CI 1.71-2.59 for duration >10 y vs HR 1.32, 95% CI 1.03-1.69 for new onset). FRAX significantly underestimated the MOF risk (calibration ratio 1.24, 95% CI 1.08-1.39) and hip fracture risk (1.93, 95% CI 1.50-2.35) in those with a diabetes duration longer than 10 years. CONCLUSION:Diabetes is a FRAX-independent risk factor for MOF only in women with a long duration of diabetes, but diabetes increases hip fracture risk, regardless of duration. Those with diabetes longer than 10 years are at particularly high risk of fracture, and this elevated risk is currently underestimated by FRAX.

A Summary This systematic review identified assessment guidelines for osteoporosis that incorporate FRAX. The rationale for intervention thresholds is given in a minority of papers. Intervention thresholds (fixed or age-dependent) need to be country-specific.Introduction In most assessment guidelines, treatment for osteoporosis is recommended in individuals with prior fragility fractures, especially fractures at spine and hip. However, for those without prior fractures, the intervention thresholds can be derived using different methods. The aim of this report was to undertake a systematic review of the available information on the use of FRAX (R) in assessment guidelines, in particular the setting of thresholds and their validation.Methods We identified 120 guidelines or academic papers that incorporated FRAX of which 38 provided no clear statement on how the fracture probabilities derived are to be used in decision-making in clinical practice. The remainder recommended a fixed intervention threshold (n = 58), most commonly as a component of more complex guidance (e. g. bone mineral density (BMD) thresholds) or an age-dependent threshold (n = 22). Two guidelines have adopted both age-dependent and fixed thresholds.Results Fixed probability thresholds have ranged from 4 to 20% for a major fracture and 1.3-5 % for hip fracture. More than one half (39) of the 58 publications identified utilised a threshold probability of 20 % for a major osteoporotic fracture, many of which also mention a hip fracture probability of 3 % as an alternative intervention threshold. In nearly all instances, no rationale is provided other than that this was the threshold used by the National Osteoporosis Foundation of the USA. Where undertaken, fixed probability thresholds have been determined from tests of discrimination (Hong Kong), health economic assessment (USA, Switzerland), to match the prevalence of osteoporosis (China) or to align with pre-existing guidelines or reimbursement criteria (Japan, Poland). Age-dependent intervention thresholds, first developed by the National Osteoporosis Guideline Group (NOGG), are based on the rationale that if a woman with a prior fragility fracture is eligible for treatment, then, at any given age, a man or woman with the same fracture probability but in the absence of a previous fracture (i.e. at the 'fracture threshold') should also be eligible. Under current NOGG guidelines, based on age-dependent probability thresholds, inequalities in access to therapy arise especially at older ages (>= 70 years) depending on the presence or absence of a prior fracture. An alternative threshold using a hybrid model reduces this disparity.Conclusion The use of FRAX (fixed or age-dependent thresholds) as the gateway to assessment identifies individuals at high risk more effectively than the use of BMD. However, the setting of intervention thresholds needs to be country-specific.

This systematic review identified assessment guidelines for osteoporosis that incorporate FRAX. The rationale for intervention thresholds is given in a minority of papers. Intervention thresholds (fixed or age-dependent) need to be country-specific.

Scottish Intercollegiate Guidelines Network (SIGN) recently issued guidance on the management of osteoporosis and the prevention of fragility fractures. The aim of this paper was to critically review the guidance. The SIGN guidance utilises risk factors for fracture as an initial step for assessment, but recommends treatment only in individuals with a T-score of −2.5. There are many problems with the sole use of BMD as the sole gateway to treatment. Moreover, the assessment tools to determine risk (FRAX or QFracture) are not designed to detect osteoporosis but rather fracture risk. Whereas SIGN assumes that FRAX overestimates fracture probability, there are compelling reasons to believe that the disparity is related to the inadequate calibration of QFracture. The disparities make the use of a single threshold for BMD testing problematic. The SIGN guidance for men at high risk of fracture provides a set of confused and inconsistent recommendations that are in direct conflict with regulatory authorizations and is likely to increase further the large treatment gap in men. For women, the number of women eligible for treatment (i.e. with osteoporosis) is 81,700 with the use of FRAX but only 12,300 with QFracture representing 8.2 and 1.2 % of the total population at risk, respectively. We conclude that serious problems with the SIGN guidance preclude its implementation.

ObjectivesTo investigate the role of a fall risk assessment, using the Downton Fall Risk Index (DFRI), in predicting fall‐related injury, fall‐related head injury and hip fracture, and death, in a large cohort of older women and men residing in Sweden.DesignCross sectional observational study.SettingSweden.ParticipantsOlder adults (mean age 82.4 ± 7.8) who had a fall risk assessment using the DFRI at baseline (N = 128,596).MeasurementsInformation on all fall‐related injuries, all fall‐related head injuries and hip fractures, and all‐cause mortality was collected from the Swedish Patient Register and Cause of Death Register. The predictive role of DFRI was calculated using Poisson regression models with age, sex, height, weight, and comorbidities as covariates, taking time to outcome or end of study into account.ResultsDuring a median follow‐up of 253 days (interquartile range 90–402 days) (>80,000 patient‐years), 15,299 participants had a fall‐related injury, 2,864 a head injury, and 2,557 a hip fracture, and 23,307 died. High fall risk (DFRI ≥3) independently predicted fall‐related injury (hazard ratio (HR) = 1.43, 95% confidence interval (CI) = 1.39–1.49), hip fracture (HR = 1.51, 95% CI =1.38–1.66), head injury (HR = 1.12, 95% CI = 1.03–1.22), and all‐cause mortality (HR = 1.39, 95% CI = 1.35–1.43). DFRI more strongly predicted head injury (HR = 1.29, 95% CI = 1.21–1.36 vs HR = 1.08, 95% CI = 1.04–1.11) and hip fracture (HR = 1.41, 95% CI = 1.30–1.53 vs HR = 1.08, 95% CI = 1.05–1.11) in 70‐year old men than in 90‐year old women (P < .001).ConclusionFall risk assessment using DFRI independently predicts fall‐related injury, fall‐related head injury and hip fracture, and all‐cause mortality in older men and women, indicating its clinical usefulness to identify individuals who would benefit from interventions.

BACKGROUND/OBJECTIVES:Pregnancy is accompanied by fat gain and insulin resistance. Changes in adipose tissue morphology and function during pregnancy and factors contributing to gestational insulin resistance are incompletely known. We sought to characterize adipose tissue in trimesters 1 and 3 (T1/T3) in normal weight (NW) and obese pregnant women, and identify adipose tissue-related factors associated with gestational insulin resistance.SUBJECTS/METHODS:Twenty-two NW and 11 obese women were recruited early in pregnancy for the Pregnancy Obesity Nutrition and Child Health study. Examinations and sampling of blood and abdominal adipose tissue were performed longitudinally in T1/T3 to determine fat mass (air-displacement plethysmography); insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR); size, number and lipolytic activity of adipocytes; and adipokine release and density of immune cells and blood vessels in adipose tissue.RESULTS:Fat mass and HOMA-IR increased similarly between T1 and T3 in the groups; all remained normoglycemic. Adipocyte size increased in NW women. Adipocyte number was not influenced, but proportions of small and large adipocytes changed oppositely in the groups. Lipolytic activity and circulating adipocyte fatty acid-binding protein increased in both groups. Adiponectin release was reduced in NW women. Fat mass and the proportion of very large adipocytes were most strongly associated with T3 HOMA-IR by multivariable linear regression (R(2)=0.751, P<0.001).CONCLUSIONS:During pregnancy, adipose tissue morphology and function change comprehensively. NW women accumulated fat in existing adipocytes, accompanied by reduced adiponectin release. In comparison with the NW group, obese women had signs of adipocyte recruitment and maintained adiponectin levels. Body fat and large adipocytes may contribute significantly to gestational insulin resistance.

Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. (C) 2015 American Society for Bone and Mineral Research.