Sarcopenia definitions and their association with injurious falls in older Swedish women from the Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone fractures (SUPERB) study.

Associations between different sarcopenia definitions and the risk of injurious falls were investigated in 75-80-year-old women in the Swedish SUPERB cohort. Only sarcopenia according to the Sarcopenia Definitions and Outcomes Consortium (SDOC) definition was associated with incident injurious falls with and without fractures in older women. PURPOSE: To investigate the association between three commonly used sarcopenia definitions and the risk of injurious falls in a population of older Swedish women. METHODS: A total of 2,883 75-80-year-old women with complete data on relevant sarcopenia definitions from the Swedish SUPERB cohort were studied. Sarcopenia was defined based on the Sarcopenia Definitions and Outcomes Consortium (SDOC: low handgrip strength and gait speed), revised European Working Group on Sarcopenia in Older People (EWGSOP2: low appendicular lean mass index (ALMI, dual-energy X-ray absorptiometry (DXA)-derived), appendicular lean mass (kg)/height (m2), hand grip strength (kg), or low chair stand time (s)), and Asian Working Group for Sarcopenia (AWGS: low ALMI and hand grip strength (kg) or low gait speed (m/s)). Questionnaires captured the occurrence of falls in the past 12 months. Incident injurious falls were identified using national registers. Cox regression (hazard ratios (HR) and 95% confidence intervals (CI)) analyses were performed without adjustment and after adjustment for age, body mass index, previous falls, and the Charlson comorbidity index. RESULTS: During a median (IQR) follow-up time of 7.06 (6.2-7.9) years, there were 491 injurious falls without fracture and 962 injurious falls when also including falls resulting in a fracture. Sarcopenia according to EWGSOP2 and AWGS was not associated with an increased risk of injurious falls. Individuals with sarcopenia defined by SDOC had a higher risk of injurious falls with and without fracture (HR 2.11; 95% CI, 1.63-2.73 and HR, 2.16; 95% CI, 1.55-3.02, respectively). CONCLUSION: Sarcopenia definitions confined to muscle function and strength such as SDOC, rather than including DXA-determined ALMI (EWGSOP2 and AWGS), are associated with incident injurious falls with and without fractures in older women.

Normal Bone Microstructure and Density But Worse Physical Function in Older Women Treated with Selective Serotonin Reuptake Inhibitors, a Cross-Sectional Population-Based Study.

Depression in the elderly is today often treated with selective serotonin reuptake inhibitors (SSRIs) because of their favorable adverse effect profile. However, treatment with SSRIs is associated with increased risk of fractures. Whether this increased risk depends on reduced bone strength or increased fall risk due to reduced physical function is not certain. The aim was therefore to investigate if treatment with SSRIs is associated with impaired bone microstructure, bone density, or physical function in older women. From an ongoing population-based study, 1057 women (77.7 ± 1.5 years) were included. Validated questionnaires were used to assess information regarding medical history, medications, smoking, mental and physical health, and physical activity. Physical function was measured using clinically used tests: timed up and go, walking speed, grip strength, chair stand test, and one leg standing. Bone mineral density (BMD) was measured at the hip and spine with dual-energy X-ray absorptiometry (Hologic Discovery A). Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT). Treatment with SSRIs was associated with higher BMD at the femoral neck, total hip, and lumbar spine, whereas no associations were found for any HR-pQCT-derived measurements. The use of SSRIs was associated with lower grip strength, walking speed, and fewer chair stand rises. These associations were valid also after adjustments for known risk factors for falls. Treatment with SSRIs was, independently of covariates, associated with worse physical function without any signs of inferior bone geometry and microstructure.

The role of different physical function tests for the prediction of fracture risk in older women.

BACKGROUND: Physical function is an important risk factor for fracture. Previous studies found that different physical tests (e.g., one-leg standing [OLS] and timed up and go [TUG]) predict fracture risk. This study aimed to determine which physical function test is the most optimal independent predictor of fracture risk, together with clinical risk factors (CRFs) used in fracture risk assessment (FRAX) and bone mineral density (BMD). METHODS: In total, 2321 women out of the included 3028 older women, aged 77.7 ± 1.6 (mean ± SD), in the Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures study had complete data on all physical function tests and were included in the analysis. At baseline, hand grip strength, OLS, TUG, walking speed and chair stand tests were performed. All incident fractures were confirmed by X-ray or review of medical records and subsequently categorized as major osteoporotic fractures (MOFs), hip fractures and any fracture. Multivariate Cox regression (hazard ratios [HRs] and 95% confidence intervals [CIs]) analyses were performed with adjustments for age, body mass index (BMI), FRAX CRFs, femoral neck BMD and all physical function tests as predictors both individually and simultaneously. Receiver operating characteristic (ROC) analyses and Fine and Gray analyses were also performed to investigate associations between physical function and incident fractures. RESULTS: OLS was the only physical function test to be significantly and independently associated with increased risk of any fracture (HR 1.13 [1.04-1.23]), MOF (HR 1.15 [1.04-1.26]) and hip fracture (HR 1.34 [1.11-1.62]). Adjusting for age, BMI, CRFs and femoral neck BMD did not materially alter these associations. ROC analysis for OLS, together with age, BMI, femoral neck BMD and CRFs, yielded area under the curve values of 0.642, 0.647 and 0.732 for any fracture, MOF and hip fracture, respectively. In analyses considering the competing risk of death, OLS was the only physical function test consistently associated with fracture outcomes (subhazard ratio [SHR] 1.10 [1.01-1.19] for any fracture, SHR 1.11 [1.00-1.22] for MOF and SHR 1.25 [1.03-1.50] for hip fracture). Walking speed was only independently associated with the risk of hip fracture in all Cox regression models and in the Fine and Gray analyses. CONCLUSIONS: Among the five physical function tests, OLS was independently associated with all fracture outcomes, even after considering the competing risk of death, indicating that OLS is the most reliable physical function test for predicting fracture risk in older women.

Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician's choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician's choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or 'all' patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician's choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2-ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53-altered patients. In summary, ARPIs outperform taxanes and physician's choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 .

Clinical Trial Protocol for ProBio: An Outcome-adaptive and Randomised Multiarm Biomarker-driven Study in Patients with Metastatic Prostate Cancer.

ProBio is an outcome-adaptive, multiarm, multiple-assignment randomised, biomarker-driven platform trial in men with metastatic castration-resistant prostate cancer. Here we describe the amended clinical protocol, focusing on expansion of the trial to include patients with de novo metastatic hormone-sensitive prostate cancer.

The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis. METHODS: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC. DISCUSSION: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study. CONCLUSIONS: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.

Association Between Cortical Bone Microstructure and Statin Use in Older Women.

Context: Treatment with statins has been associated with increased bone mineral density, but whether this association depends on differences in cortical or trabecular volumetric bone microstructure is unknown. Objective: The aim of this study was to investigate if treatment with statins is associated with bone microstructure and geometry in older women. Design Setting and Participants: Older women were included in a population-based study of 3028 women (mean age ± SD, 77.8 ± 1.6 years) from the greater Gothenburg area in Sweden. Information regarding medical history, medication, and lifestyle factors was obtained from validated questionnaires. Main Outcome: Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography. Results: The 803 women in the cohort who used statins had higher body weight, worse physical function, and more frequent cardiovascular disease and diabetes than nonusers (P < 0.05). Statin users had lower cortical porosity (radius, 2.2 ± 1.9 vs 2.5 ± 2.0%; tibia, 5.2 ± 2.4 vs 5.4 ± 2.5; P = 0.01), higher cortical bone density (radius, 1008 ± 39.1 vs 1001 ± 38.4 mg/cm3; tibia, 919 ± 42.6 vs 914 ± 41.5; P < 0.01), and greater cortical area (radius, 60.5 ± 9.6 vs 58.6 ± 9.7 mm2; tibia, 150.0 ± 23.6 vs 146.7 ± 23.8; P < 0.01) than nonusers after adjustment for a large number of confounders, including age, weight, smoking, other medications, and prevalent diseases. Conclusions: Use of statins was associated with better cortical bone characteristics in older women.

Fall Risk Assessment Predicts Fall-Related Injury, Hip Fracture, and Head Injury in Older Adults.

OBJECTIVES: To 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. DESIGN: Cross sectional observational study. SETTING: Sweden. PARTICIPANTS: Older adults (mean age 82.4 ± 7.8) who had a fall risk assessment using the DFRI at baseline (N = 128,596). MEASUREMENTS: Information 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. RESULTS: During 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). CONCLUSION: Fall 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.

Clinical experience with an automatic threshold tracking algorithm study.

The automatic threshold tracking pacing system algorithm developed by St. Jude Medical, verifies ventricular capture beat by beat by recognizing the evoked response (ER) following each pacemaker stimulus. The present automatic threshold tracking function requires a bipolar ventricular lead with low polarization. The aim of this study was to evaluate a new algorithm developed to use with unipolar leads with different levels of polarization. An external pacemaker with the ability to sense intrinsic R waves and measure ER signals, as well as deliver stimulus, was used. An algorithm for detecting the true ER in a unipolar sensing configuration (tip-case) was developed. Based on the assumption that the true evoked R wave amplitude is independent of the stimulation amplitude, the algorithm calculates and subtracts the polarization present at any pacing stimulus from the measured ER. The resulting signal is analyzed to verify capture. This study comprises 35 patients of which 26 were new implants and 9 had chronic leads. The automatic threshold-tracking algorithm was calibrated for each patient and pacing was performed at different pulse amplitudes and pulse duration. Capture was verified for each paced beat. The recordings were stored for later comparison with the tape-recorded intracardiac heart signals. The new algorithm correctly verified capture or loss of capture for every single analyzed beat at the different pacing outputs in every individual patient. The results from this initial study suggests that the new ER detection principle will allow automatic threshold tracking to be used not only with low polarization bipolar leads but with most leads.