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Response to: 'Correspondence on 'Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study'' by Zheng We thank Dr Zheng for his comments on our recently published article in the Annals of the Rheumatic Diseases entitled 'Concom-itant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study'. 1 2 Our main goal in this study was to bring more clinical insight into the simultaneous use of these two common medications in patients with rheumatoid arthritis (RA), that is, oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), using data from a large primary care database and pharmacoepidemiological methodologies. Our results showed that there was an interaction in the risk of osteoporotic (OP) fractures with concomitant use of oral GCs and PPIs in patients with RA. Based on the adjusted hazard ratios and according to the formula proposed by Rothman et al, 3 the relative excess risk due to interaction (RERI) was: 1.60-1.23 − 1.22 + 1 = 0.15. We now have also calculated the CIs and the statistical significance of this index using the method proposed by Hosmer and Lemeshow. 4 5 The lower and upper limits of the 95% CI of the RERI were −0.16 and 0.45, respectively, and the p value was 0.36. This means, although we observed a 15% more risk of OP fracture with concomitant use of oral GCs and PPIs in addition to the single use of each drug versus non-use of both, this additive interaction was not statistically significant. As we discussed in our paper, there is currently no proven biological mechanism for an action of PPIs on bone or falling, 6 while the effects of GCs on bone and the musculoskeletal system are quite established. Our secondary analyses (ie, lower fracture risk with long-term or higher daily doses of PPIs compared with short-term or lower daily doses) did not support the few proposed potential mechanisms, such as hypochlorhydria and calcium malabsorption, or an increased fall risk due to malab-sorption of magnesium or vitamin B 12. This is important to consider when interpreting a potential additive interaction between oral GCs and PPIs on fracture risk. Without this basic knowledge, it would be extremely difficult to confer any conclusions on a plausible synergistic action of these two drugs, since it would sound more as a methodological reasoning rather than a clinical explanation.

Summary: Oral glucocorticoids may increase major osteoporotic fracture risk (MOF) in myasthenia gravis patients. To assess this risk, we performed a case–control study including all Danish patients with a MOF between 1995 and 2011. We also pooled our data with data from another study. We found no increased risk. Osteoporosis prevention remains advisable. Purpose/introduction: The prolonged use of high doses of oral glucocorticoids (GCs), a common treatment in patients with myasthenia gravis (MG), may increase major osteoporotic fracture (MOF) risk. Previous epidemiological studies did not exclusively focus on patients with MG or had relatively few GC-exposed MG patients. Aims were to evaluate the risk of MOF in MG patients using oral GCs in a large study population and to perform a pooled analysis with data from previous work. Methods: A population-based case–control study (1995–2011) was conducted using the Danish National Health Service. Cases had sustained a MOF, and controls had not. All were aged ≥ 18 years. Multivariate conditional logistic regression estimated odds ratios (ORs) among MG patients using oral GCs versus non-users. Adjustments were made for comorbidities and comedications. In the pooled analysis, results were pooled by the use of generic inverse variance methods, assuming a random-effects model. Results: We identified 376,858 cases and 376,858 controls. MOF risk was not elevated in MG patients currently using oral GCs compared to MG patients not on oral GCs (ORadj.: 1.26 (95% CI 0.68–2.33)). The use of the highest cumulative dose of oral GCs (≥ 7 g) did not show an increased risk of MOF among MG patients (ORadj.: 2.00 (95% CI 0.90–4.44)). Our pooled analysis also showed no association between oral GC use and MOF risk. Conclusion: This study showed that oral GC use in patients with MG was not associated with increased risk of MOF in our case–control study and pooled analysis. Osteoporosis prevention in MG patients based on clinical guidelines remains advisable.

Cognitive decline and osteoporosis often coexist and some evidence suggests a causal link. However, there are no data on the longitudinal relationship between cognitive decline, bone loss and fracture risk, independent of aging. This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline (>= 3 points) on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged >= 65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Association between cognitive decline and (i) bone loss was estimated using mixed-effects models; and (ii) fracture risk was estimated using adjusted Cox models. Over 95% of participants had normal cognition at baseline (MMSE >= 24). The annual % change in MMSE was similar for both genders (women -0.33, interquartile range [IQR] -0.70 to +0.00; and men -0.34, IQR: -0.99 to 0.01). After multivariable adjustment, cognitive decline was associated with bone loss in women (6.5%; 95% confidence interval [CI], 3.2% to 9.9% for each percent decline in MMSE from baseline) but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly (multivariable hazard ratio [HR], 1.61; 95% CI, 1.11 to 2.34). There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women. Further studies are needed to determine mechanisms that link these common conditions. (c) 2021 American Society for Bone and Mineral Research (ASBMR). The Canadian Multicentre Osteoporosis Study was funded by the Canadian Institutes of Health Research (CIHR); Merck Frosst Canada Ltd.; Eli Lilly Canada Inc.; Novartis Pharmaceuticals Inc.; The Alliance: sanofi-aventis & Procter and Gamble Pharmaceuticals Canada Inc.; Servier Canada Inc.; Amgen Canada Inc.; The Dairy Farmers of Canada; and The Arthritis Society. This work was supported by the National Health Medical Research Council Australia Projects 1070187, 1008219, and 1073430. Other funding bodies were an Osteoporosis Australia-Amgen grant; the Bupa Health Foundation (formerly MBF Foundation); the Mrs Gibson and Ernst Heine Family Foundation; and untied grants from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Servier, and Novartis

Background: The COVID-19 outbreak has put an unprecedented strain on Emergency Departments (EDs) and other critical care resources. Early detection of patients that are at high risk of clinical deterioration and require intensive monitoring, is key in ED evaluation and disposition. A rapid and easy risk-stratification tool could aid clinicians in early decision making. The Shock Index (SI: heart rate/systolic blood pressure) proved useful in detecting hemodynamic instability in sepsis and myocardial infarction patients. In this study we aim to determine whether SI is discriminative for ICU admission and in-hospital mortality in COVID-19 patients.Methods: Retrospective, observational, single-center study. All patients >= 18 years old who were hospitalized with COVID-19 (defined as: positive result on reverse transcription polymerase chain reaction (PCR) test) between March 1, 2020 and December 31, 2020 were included for analysis. Data were collected from electronic medical patient records and stored in a protected database. ED shock index was calculated and analyzed for its discriminative value on in-hospital mortality and ICU admission by a ROC curve analysis.Results: In total, 411 patients were included. Of all patients 249 (61%) were male. ICU admission was observed in 92 patients (22%). Of these, 37 patients (40%) died in the ICU. Total in-hospital mortality was 28% (114 patients). For in-hospital mortality the optimal cut-off SI >= 0.86 was not discriminative (AUC 0.49 (95% CI: 0.43-0.56)), with a sensitivity of 12.3% and specificity of 93.6%. For ICU admission the optimal cut-off SI >= 0.57 was also not discriminative (AUC 0.56 (95% CI: 0.49-0.62)), with a sensitivity of 78.3% and a specificity of 34.2%.Conclusion: In this cohort of patients hospitalized with COVID-19, SI measured at ED presentation was not discriminative for ICU admission and was not useful for early identification of patients at risk of clinical deterioration. (C) 2021 Elsevier Inc. All rights reserved.

Risperidone and aripiprazole, commonly used antipsychotics in children with autism spectrum disorder (ASD), have previously been associated with elevated fracture risk in other populations. The aim of this study was to evaluate and compare the risk of fracture among children with ASD using risperidone or aripiprazole. This was a retrospective, propensity-score matched cohort study, set between January 2013 and December 2018. We used the MarketScan Medicaid insurance data, which covers multiple states of the United States. We included ASD children aged 2-18 years, who were new users of aripiprazole or risperidone and with no prior history of antipsychotic use or fractures. The main exposure was the continued use of aripiprazole or risperidone. The incidence rates of any fracture during follow-up were evaluated, and the risk between aripiprazole and risperidone was compared via Cox-proportional hazard models. Results were stratified by age, sex, duration of exposure and fracture site. In total, 3312 patients (78% male; mean [SD] age 11.0 [3.7] years) were identified for each cohort. Over the full duration of follow-up, fracture incidence rates per 1000 patient-years were 23.2 for risperidone and 38.4 for aripiprazole (hazard ratio and 95% confidence interval: 0.60 [0.44-0.83]). Risks were similar between cohorts throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. Extremity fractures drove most of the increased risk, with the biggest differences in lower leg and ankle fractures. Differences widened for children aged 10 years or younger (HR [95% CI]: 0.47 [0.30-0.74]). In conclusion, compared to aripiprazole, risperidone was associated with 40% lower risk of fracture. Further analysis on the mechanism and long-term bone health of antipsychotic-treated children with ASD is warranted.Lay summary We compared the risk of bone fractures among 6624 children with autism spectrum disorder (ASD), half of whom used risperidone and half of whom used aripiprazole. Taking other factors into account, risks were similar between the two groups throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. The biggest differences were in lower leg and ankle fractures. Overall, compared with aripiprazole, risperidone was associated with 40% lower risk of fracture.

Introduction: People with diabetes could have an increased risk of falls as they show more complications, morbidity and use of medication compared to the general population. This study aimed to estimate the risk of falls and to identify risk factors associated with falls in people with diabetes. The second aim was to estimate fall-related injuries, such as lesions and fractures, including their anatomic localization in people with diabetes compared with the general population. Methods: From the Danish National Patient Register, we identified people with Type 1 Diabetes (T1D) (n=12,975) Type 2 Diabetes (T2D) (n=407,009). The cohort was divided into two groups, with respective control groups matched on age and sex (1:1). All episodes of people hospitalized with a first fall from 1996 to 2017 were analyzed using a Cox proportional-hazards model. Risk factors such as age, sex, diabetic complications, a history of alcohol abuse and the use of medication were included in an adjusted analysis. The incidence rate, incidence rate difference and incidence rate ratio (IRR) of falls and the anatomic localization of fall-related injuries as lesions and fractures were identified. Results and Discussion: The cumulative incidence, of falls requiring hospital treatment, was 13.3% in T1D, 11.9% in T2D. In the adjusted analysis, T1D and T2D were associated with a higher risk of falls [T1D, Hazard Ratio (HR): 1.33 (95% CI: 1.25 - 1.43), T2D, HR: 1.19 (95% CI:1.16 - 1.22), respectively]. Women [group 1, HR 1.21 (CI:95%:1.13 - 1.29), group 2, HR 1.61 (CI:95%:1.58-1.64)], aged >65 years [groups 1, HR 1.52 (CI:95%:1.39 - 1.61), group 2, HR 1.32 (CI:95%:1.58-1.64)], use of selective serotonin receptor inhibitors (SSRI) [group 1, HR 1.35 (CI:95%:1.1.30 - 1.40), group 2, HR 1.32 (CI:95%:1.27-1.38)], opioids [group 1, HR 1.15 (CI:95%:1.12 - 1.19), group 2, HR 1.09 (CI:95%:1.05-1.12)] and a history of alcohol abuse [group 1, HR 1.77 (CI:95%:1.17 - 2.15), group 2, HR 1.88 (CI:95%:1.65-2.15)] were significantly associated with an increased risk of falls in both groups. The IRR of fall-related injuries as hip, radius, humerus and skull/facial fractures were higher in people with T2D than controls [IRR 1.02 (CI:95%:1.01-1.04), IRR 1.39 (CI:95%: 1.18-1.61), IRR 1.24 (CI:95%: 1.12-1.37) and IRR 1.15 (CI:95%:1.07-1.24)]. People with T1D had a higher IRR of hip fractures than controls [IRR: 1.11 (CI:95%:1.02 – 1.23)]. Conclusion: People with diabetes have an increased risk of first fall and a higher incidence of fall- related injuries, including fractures. Advanced aging and sex are non-modifiable risk factors, whereas diabetes, the use of SSRIs and opioids and alcohol abuse could be potentially modifiable risk factors for falls. Gaining information on risk factors for falls could guide the management of diabetes treatment, i.e., choice of drugs, which enables us to improve treatment, particularly in people with a high risk of falls and fractures associated with high mortality.

Obtaining high-resolution scans of bones and joints for clinical applications is challenging. HR-pQCT is considered the best technology to acquire high-resolution images of the peripheral skeleton in vivo, but a breakthrough for widespread clinical applications is still lacking. Recently, we showed on trapezia that CBCT is a promising alternative providing a larger FOV at a shorter scanning time. The goals of this study were to evaluate the accuracy of CBCT in quantifying trabecular bone microstructural and predicted mechanical parameters of the distal radius, the most often investigated skeletal site with HR-pQCT, and to compare it with HR-pQCT. Nineteen radii were scanned with four scanners: (1) HR-pQCT (XtremeCT, Scanco Medical AG, @ (voxel size) 82 μm), (2) HR-pQCT (XtremeCT-II, Scanco, @60.7 μm), (3) CBCT (NewTom 5G, Cefla, @75 μm) reconstructed and segmented using in-house developed software and (4) microCT (VivaCT40, Scanco, @19 μm-gold standard). The following parameters were evaluated: predicted stiffness, strength, bone volume fraction (BV/TV) and trabecular thickness (Tb.Th), separation (Tb.Sp) and number (Tb.N). The overall accuracy of CBCT with in-house optimized algorithms in quantifying bone microstructural parameters was comparable (R2 = 0.79) to XtremeCT (R2 = 0.76) and slightly worse than XtremeCT-II (R2 = 0.86) which were both processed with the standard manufacturer's technique. CBCT had higher accuracy for BV/TV and Tb.Th but lower for Tb.Sp and Tb.N compared to XtremeCT. Regarding the mechanical parameters, all scanners had high accuracy (R2 [Formula: see text] 0.96). While HR-pQCT is optimized for research, the fast scanning time and good accuracy renders CBCT a promising technique for high-resolution clinical scanning. ispartof: Calcified Tissue International vol:108 issue:3 pages:314-323 ispartof: location:United States status: published

Background Considering the heavy economic burden of osteoporotic fractures, the limits of healthcare resources, and the recent availability of new anti-osteoporosis drugs, there is continuing interest in economic evaluation studies of osteoporosis management strategies. Objectives This study aims to (1) systematically review recent economic evaluations of drugs for osteoporosis and (2) to apply an osteoporosis-specific guideline to critically appraise them. Methods A literature search was undertaken using PubMed, EMBASE, National Health Service Economic Evaluation database, and the Cost-Effectiveness Analysis Registry to identify original articles containing economic evaluations of anti-osteoporosis drugs, published between 1 July, 2013 and 31 December, 2019. A recent European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases-International Osteoporosis Foundation (ESCEO-IOF) guideline for the conduct and reporting of economic evaluations in osteoporosis was used to assess the quality of included articles. Results The database search retrieved 3860 records, of which 27 studies fulfilled the inclusion criteria. These studies were conducted in 15 countries; 12 active drugs were assessed, including various traditional pharmacological treatments such as bisphosphonates, raloxifene, strontium ranelate, denosumab, and teriparatide, and new agents such as abaloparatide, romosozumab, and gastro-resistant risedronate. Eight out of 12 studies that compared traditional oral bisphosphonates to other active interventions (denosumab, zoledronic acid, gastro-resistant risedronate, and teriparatide) suggested that the other active agents were generally cost-effective or dominant. Additionally, the cost-effectiveness of sequential therapy has recently been assessed and indications are that it can lead to extra health benefits (larger gains in quality-adjusted life-year). The key drivers of cost effectiveness included baseline fracture risk, drug effect on the risk of fractures, drug cost, and medication adherence/persistence. The current average score for quality assessment was 17 out of 25 (range 2–15); room for improvement was observed for most studies, which could potentially be explained by the fact that most studies were published prior to the osteoporosis-specific guideline. Greater adherence to guideline recommendations was expected for future studies. The quality of reporting was also suboptimal, especially with regard to treatment side effects, treatment effect after discontinuation, and medication adherence. Conclusions This updated review provides an overview of recently published cost-effectiveness analyses. In comparison with a previous review, recent economic evaluations of anti-osteoporosis drugs were conducted in more countries and included more active drugs and sequential therapy as interventions/comparators. The updated economic evidence could help decision makers prioritize health interventions and the unmet/unreported quality issues indicated by the osteoporosis-specific guideline could be useful in improving the transparency, quality, and comparability of future economic evaluations in osteoporosis. Electronic supplementary material The online version of this article (10.1007/s40273-020-00965-9) contains supplementary material, which is available to authorized users.

AIMS: A diabetic foot ulcer (DFU) is a severe condition associated with morbidity and mortality. Population-based studies are rare and limited by access to reliable data. Without this data, efforts in primary prevention cannot be evaluated. Therefore, we examined the incidence and changes over time for the first DFU in people with diabetes. We also examined hospitalization and all-cause mortality and their changes over time.METHODS: From the UK primary care CPRD GOLD database (2007-2017), we identified 129,624 people with diabetes by a prescription for insulin or a non-insulin anti-diabetic drug. DFUs were identified using Read codes and expressed as incidence rates (IRs). Changes over time were described using Poisson and logistic regression and expressed as incidence rate ratios (IRRs) and odds ratios (ORs) respectively.RESULTS: The mean IR of first registered DFUs was 2.5 [95% CI: 2.1-2.9] per 1000 person-years for people with type 2 diabetes and 1.6 [1.3-1.9] per 1000 person-years for people with type 1. The IRs declined for people with type 2 diabetes (IRR per year: 0.97 [0.96-0.99]), while no changes were observed for people with type 1 diabetes (IRR per year: 0.96 [0.89-1.04]). Average hospitalization and 1-year mortality risk for people with type 2 diabetes were 8.2% [SD: 4.7] and 11.7% [SD: 2.2] respectively. Both declined over time (OR: 0.89 [0.84, 0.94] and 0.94 [0.89, 0.99]).CONCLUSION: The decline in all IRs, hospitalizations and mortality in people with type 2 diabetes suggests that prevention and care of the first DFU has improved for this group in primary care in the UK.

Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged >= 60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7-15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with aT-score of -1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, facilitating informed decision making about risk and thus treatment for individuals with different risk profiles. (c) 2020 American Society for Bone and Mineral Research.

Celiac disease (CD) is a known risk factor for osteoporosis and fractures. The prevalence of CD in patients with a recent fracture is unknown. We therefore systematically screened patients at a fracture liaison service (FLS) to study the prevalence of CD. Patients with a recent fracture aged ≥ 50 years were invited to VieCuri Medical Center’s FLS. In FLS attendees, bone mineral density (BMD) and laboratory evaluation for metabolic bone disorders and serological screening for CD was systematically evaluated. If serologic testing for CD was positive, duodenal biopsies were performed to confirm the diagnosis CD. Data were collected in 1042 consecutive FLS attendees. Median age was 66 years (Interquartile range (IQR) 15), 27.6% had a major and 6.9% a hip fracture, 26.4% had osteoporosis and 50.8% osteopenia. Prevalent vertebral fractures were found in 29.1%. CD was already diagnosed in two patients (0.19%), one still had a positive serology. Three other patients (0.29%) had a positive serology for CD (one with gastro-intestinal complaints). In two of them, CD was confirmed by duodenal histology (0.19%) and one refused further evaluation. The prevalence of biopsy-proven CD was therefore 0.38% (4/1042) of which 0.19% (2/1042) was newly diagnosed. The prevalence of CD in patients with a recent fracture at the FLS was 0.38% and within the range of reported prevalences in the Western-European population (0.33–1.5%). Newly diagnosed CD was only found in 0.19%. Therefore, standard screening for CD in FLS patients is not recommended.

Aims Besides conventional radiographs, the use of MRI, CT, and bone scintigraphy is frequent in the diagnosis of a fracture of the scaphoid. However, which techniques give the best results remain unknown. The investigation of a new imaging technique initially requires an analysis of its precision. The primary aim of this study was to investigate the interobserver agreement of high-resolution peripheral quantitative CT (HR-pQCT) in the diagnosis of a scaphoid fracture. A secondary aim was to investigate the interobserver agreement for the presence of other fractures and for the classification of scaphoid fracture. Methods Two radiologists and two orthopaedic trauma surgeons evaluated HR-pQCT scans of 31 patients with a clinically-suspected scaphoid fracture. The observers were asked to determine the presence of a scaphoid or other fracture and to classify the scaphoid fracture based on the Herbert classification system. Fleiss kappa statistics were used to calculate the interobserver agreement for the diagnosis of a fracture. Intraclass correlation coefficients (ICCs) were used to assess the agreement for the classification of scaphoid fracture. Results A total of nine (29%) scaphoid fractures and 12 (39%) other fractures were diagnosed in 20 patients (65%) using HR-pQCT across the four observers. The interobserver agreement was 91% for the identification of a scaphoid fracture (95% confidence interval (CI) 0.76 to 1.00) and 80% for other fractures (95% CI 0.72 to 0.87). The mean ICC for the classification of a scaphoid fracture in the seven patients diagnosed with scaphoid fracture by all four observers was 73% (95% CI 0.42 to 0.94). Conclusion We conclude that the diagnosis of scaphoid and other fractures is reliable when using HR-pQCT in patients with a clinically-suspected fracture. Cite this article: Bone Joint J 2020;102-B(4):478–484.

Background: Joint space assessment for rheumatoid arthritis (RA) by ordinal conventional radiographic scales is susceptible to floor and ceiling effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides superior resolution, and may detect earlier changes. The goal of this work was to compare existing 3D methods to calculate joint space width (JSW) metrics in human metacarpophalangeal (MCP) joints with HR-pQCT and reach consensus for future studies. Using the consensus method, we established reproducibility with repositioning as well as feasibility for use in second-generation HR-pQCT scanners.Methods: Three published JSW methods were compared using datasets from individuals with RA from three research centers. A SPECTRA consensus method was developed to take advantage of strengths of the individual methods. Using the SPECTRA method, reproducibility after repositioning was tested and agreement between scanner generations was also established.Results: When comparing existing JSW methods, excellent agreement was shown for JSW minimum and mean (ICC 0.987-0.996) but not maximum and volume (ICC 0.000-0.897). Differences were identified as variations in volume definitions and algorithmic differences that generated high sensitivity to boundary conditions. The SPECTRA consensus method reduced this sensitivity, demonstrating good scan-rescan reliability (ICC >0.911) except for minimum JSW (ICC 0.656). There was strong agreement between results from first- and second-generation HR-pQCT (ICC >0.833).Conclusions: The SPECTRA consensus method combines unique strengths of three independently-developed algorithms and leverages underlying software updates to provide a mature analysis to measure 3D JSW. This method is robust with respect to repositioning and scanner generations, suggesting its suitability for detecting change.

IntroductionPatients with osteoporosis may suffer from a fracture after minimal trauma. Osteoporotic vertebral compression fractures (OVCFs) are among the most common fractures, often leading to substantial pain. There is a need for evidence-based conservative treatment to aid in the management of OVCFs. The objective of this randomised controlled trial (RCT) is to evaluate the effectiveness and cost-effectiveness of dynamic bracing in addition to standard care for improving quality of life (QoL) in patients suffering from an OVCF.Methods and analysisNinety-eight postmenopausal women from two academic and four community hospitals with a recent symptomatic thoracolumbar OVCF will be randomised into either the standard care or dynamic bracing group. In the dynamic bracing group, the Spinova Osteo orthosis will be used in addition to standard care. Standard care comprises pain control with analgesics, physical therapy and osteoporosis medication. The primary outcome parameter is QoL 1 year after inclusion, as measured by the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO-41). Secondary outcome parameters are pain, pain medication used, functional disability, sagittal spinal alignment, recurrence rate of OVCFs and physical activity in daily life. A trial-based economic evaluation consisting of both cost-effectiveness analysis and cost-utility analysis will be performed based on empirical data obtained in the RCT. A process evaluation will assess the feasibility of dynamic bracing. All outcomes will be assessed at baseline, 6 weeks, 3 months, 6 months, 9 months and 12 months.Ethics and disseminationEthical approval has been granted by the Medical Ethics Committee, University Hospital Maastricht and Maastricht University (METC azM/UM) (NL74552.068.20/METC 20-055). Patients will be included only after verification of eligibility and obtaining written informed consent. Results will be disseminated via the Dutch National Osteoporosis Patient Society and via publications and conferences.Trial registration numberNL8746.

Purpose Inhibition of dipeptidyl peptidase (DPP-)4 could reduce coronavirus disease 2019 (COVID-19) severity by reducing inflammation and enhancing tissue repair beyond glucose lowering. We aimed to assess this in a prospective cohort study. Methods We studied in 565 patients with type 2 diabetes in the CovidPredict Clinical Course Cohort whether use of a DPP-4 inhibitor prior to hospital admission due to COVID-19 was associated with improved clinical outcomes. Using crude analyses and propensity score matching (on age, sex and BMI), 28 patients using a DPP-4 inhibitor were identified and compared to non-users. Results No differences were found in the primary outcome mortality (matched-analysis = odds-ratio: 0,94 [95% confidence interval: 0,69 – 1,28], p-value: 0,689) or any of the secondary outcomes (ICU admission, invasive ventilation, thrombotic events or infectious complications). Additional analyses comparing users of DPP-4 inhibitors with subgroups of non-users (subgroup 1: users of metformin and sulphonylurea; subgroup 2: users of any insulin combination), allowing to correct for diabetes severity, did not yield different results. Conclusions We conclude that outpatient use of a DPP-4 inhibitor does not affect the clinical outcomes of patients with type 2 diabetes who are hospitalized because of COVID-19 infection.

Scaphoid fractures are difficult to diagnose with current imaging modalities. It is unknown whether the shape of the scaphoid bone, assessed by statistical shape modeling, can be used to differentiate between fractured and non-fractured bones. Therefore, the aim of this study was to investigate whether the presence of a scaphoid fracture is associated with shape modes of a statistical shape model (SSM). Forty-one high-resolution peripheral quantitative computed tomography (HR-pQCT) scans were available from patients with a clinically suspected scaphoid fracture of whom 15 patients had a scaphoid fracture. The scans showed no motion artefacts affecting bone shape. The scaphoid bones were semi-automatically contoured, and the contours were converted to triangular meshes. The meshes were registered, followed by principal component analysis to determine mean shape and shape modes describing shape variance. The first five out of the forty shape modes cumulatively explained 87.8% of the shape variance. Logistic regression analysis was used to study the association between shape modes and fracture presence. The regression models were used to classify the 41 scaphoid bones as fractured or non-fractured using a cut-off value that maximized the sum of sensitivity and specificity. The classification of the models was compared with fracture diagnosis on HR-pQCT. A regression model with four shape modes had an area under the ROC-curve of 72.3% and correctly classified 75.6% of the scaphoid bones (fractured: 60.0%, non-fractured: 84.6%). To conclude, fracture presence in patients with a clinically suspected scaphoid fracture appears to be associated with the shape of the scaphoid bone.

High-resolution peripheral quantitative computed tomography (HR-pQCT) devices can scan extremities at bone microstructural level in vivo and are used mainly in research of bone diseases. Two HR-pQCT scanners are commercially available to date: XtremeCT (first generation) and XtremeCT-II (second generation) from Scanco Medical AG (Switzerland). Recently, we have proposed an adaptive local thresholding (AT) technique and showed that it can improve quantification accuracy of bone microstructural parameters, with visually less sharp cone-beam CT (CBCT) images providing a similar accuracy than XtremeCT. The aim of this study was to evaluate whether the AT segmentation technique could enhance the accuracy of HR-pQCT in quantifying bone microstructural images and to assess whether the agreement between XtremeCT and XtremeCT-II could be improved. Nineteen radii were scanned with three scanners from Scanco Medical AG: (1) XtremeCT at 82 μm, (2) XtremeCT-II at 60.7 μm and (3) the small animal microCT scanner VivaCT40 at 19 μm voxel size. The scans were segmented applying two different methods, once following the manufacturer standard technique (ST), and once by means of AT. Three-dimensional (3D) morphological analysis was performed on the trabecular volume of the segmented images using the manufacturer's standard software to calculate bone volume fraction (BV/TV), trabecular thickness (Tb.Th), separation (Tb.Sp) and number (Tb.N). The average accuracy of XtremeCT improved from R2 = 0.76 (ST) to 0.85 (AT) and reached the same level of accuracy as XtremeCT-II with ST (R2 = 0.86). The largest improvements were obtained for BV/TV and Tb.Th. For XtremeCT-II, mean accuracy improved slightly from R2 = 0.86 (ST) to 0.89 (AT). For both segmentations and both scanners, the standard section was quantified slightly more accurate than the subchondral section. The agreement between the scanners was enhanced from R2 = 0.89 (ST) to 0.98 (AT). In conclusion, AT can enhance the accuracy of XtremeCT to quantify distal radius bone microstructural parameters close to XtremeCT-II level and increases the agreement between the two HR-pQCT scanners. High-resolution peripheral quantitative computed tomography, segmentation, bone microstructural parameters. ispartof: BONE vol:154 ispartof: location:United States status: published

Background Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. Methods In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. Results The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support–free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

Background Given the health and economic burden of fractures related to osteoporosis, suboptimal adherence to medication and the increasing importance of shared-decision making, the Improvement of osteoporosis Care Organized by Nurses (ICON) study was designed to evaluate the effectiveness, cost-effectiveness and feasibility of a multi-component adherence intervention (MCAI) for patients with an indication for treatment with anti–osteoporosis medication, following assessment at the Fracture Liaison Service after a recent fracture. The MCAI involves two consultations at the FLS. During the first consultation, a decision aid is will be used to involve patients in the decision of whether to start anti-osteoporosis medication. During the follow-up visit, the nurse inquires about, and stimulates, medication adherence using motivational interviewing techniques. Methods A quasi-experimental trial to evaluate the (cost-) effectiveness and feasibility of an MCAI, consisting of a decision aid (DA) at the first visit, combined with nurse-led adherence support using motivational interviewing during the follow-up visit, in comparison with care as usual, in improving adherence to oral anti-osteoporosis medication for patients with a recent fracture two Dutch FLS. Medication persistence, defined as the proportion of patients who are persistent at one year assuming a refill gap Discussion We expect that the ICON-study will show that the MCAI is a (cost-)effective intervention for improving persistence with anti-osteoporosis medication and that it is feasible for implementation at the FLS. Trial registration This trial has been registered in the Netherlands Trial Registry, part of the Dutch Cochrane Centre (Trial NL7236 (NTR7435)). Version 1.0; 26-11-2020.

ObjectiveTo study the SARS-CoV-2 infection rate among hospital healthcare workers after the first wave of the COVID-19 pandemic, and provide more knowledge in the understanding of the relationship between infection, symptomatology and source of infection.DesignA cross-sectional study in healthcare workers.SettingNorthern Limburg, the Netherlands.ParticipantsAll employees of VieCuri Medical Center (n=3300) were invited to enrol in current study. In total 2507 healthcare workers participated.InterventionBetween 22 June 2020 and 3 July 2020, participants provided venous blood samples voluntarily, which were tested for SARS-CoV-2 antibodies with the Wantai SARS-CoV-2 Ig total ELISA test. Work characteristics, exposure risks and prior symptoms consistent with COVID-19 were gathered through a survey.Main outcome measureProportion of healthcare workers with positive SARS-CoV-2 serology.ResultsThe overall seroprevalence was 21.1% (n=530/2507). Healthcare workers between 17 and 30 years were more likely to have SARS-CoV-2 antibodies compared with participants >30 years. The probability of having SARS-CoV-2 antibodies was comparable for healthcare workers with and without direct patient (OR 1.42, 95% CI 0.86 to 2.34) and COVID-19 patient contact (OR 1.62, 95% CI 0.80 to 3.33). On the contrary, exposure to COVID-19 positive coworkers (OR 1.83, 95% CI 1.15 to 2.93) and household members (OR 6.09, 95% CI 2.23 to 16.64) was associated with seropositivity. Of those healthcare workers with SARS-CoV-2 antibodies, 16% (n=85/530) had not experienced any prior COVID-19-related symptoms. Only fever and anosmia were associated with seropositivity (OR 1.90, 95% CI 1.42 to 2.55 and OR 10.51, 95% CI 7.86 to 14.07).ConclusionsHealthcare workers caring for hospitalised COVID-19 patients were not at an increased risk of infection, most likely as a result of taking standard infection control measures into consideration. These data show that compliance with infection control measures is essential to control secondary transmission and constrain the spread of the virus.

Introduction. To reduce the risk of nosocomial transmission, suspected COVID-19 patients entering the Emergency Department (ED) were assigned to a high-risk (ED) or low-risk (acute medical unit, AMU) area based on symptoms, travel and contact history. The objective of this study was to evaluate the performance of our pre-triage screening method and to analyse the characteristics of initially undetected COVID-19 patients. Methods. This was a retrospective, observational, single centre study. Patients ≥ 18 years visiting the AMU-ED between 17 March and 17 April 2020 were included. Primary outcome was the (correct) number of COVID-19 patients assigned to the AMU or ED. Results. In total, 1287 patients visited the AMU-ED: 525 (40.8%) AMU, 762 (59.2%) ED. Within the ED group, 304 (64.3%) of 473 tested patients were COVID-19 positive, compared to 13 (46.4%) of 28 tested patients in the AMU group. Our pre-triage screening accuracy was 63.7%. Of the 13 COVID-19 patients who were initially assigned to the AMU, all patients were ≥65 years of age and the majority presented with gastro-intestinal or non-specific symptoms. Conclusion. Older COVID-19 patients presenting with non-specific symptoms were more likely to remain undetected. ED screening protocols should therefore also include non-specific symptoms, particularly in older patients.

ObjectiveDevelop and validate models that predict mortality of patients diagnosed with COVID-19 admitted to the hospital.DesignRetrospective cohort study.SettingA multicentre cohort across 10 Dutch hospitals including patients from 27 February to 8 June 2020.ParticipantsSARS-CoV-2 positive patients (age ≥18) admitted to the hospital.Main outcome measures21-day all-cause mortality evaluated by the area under the receiver operator curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value. The predictive value of age was explored by comparison with age-based rules used in practice and by excluding age from the analysis.Results2273 patients were included, of whom 516 had died or discharged to palliative care within 21 days after admission. Five feature sets, including premorbid, clinical presentation and laboratory and radiology values, were derived from 80 features. Additionally, an Analysis of Variance (ANOVA)-based data-driven feature selection selected the 10 features with the highest F values: age, number of home medications, urea nitrogen, lactate dehydrogenase, albumin, oxygen saturation (%), oxygen saturation is measured on room air, oxygen saturation is measured on oxygen therapy, blood gas pH and history of chronic cardiac disease. A linear logistic regression and non-linear tree-based gradient boosting algorithm fitted the data with an AUC of 0.81 (95% CI 0.77 to 0.85) and 0.82 (0.79 to 0.85), respectively, using the 10 selected features. Both models outperformed age-based decision rules used in practice (AUC of 0.69, 0.65 to 0.74 for age >70). Furthermore, performance remained stable when excluding age as predictor (AUC of 0.78, 0.75 to 0.81).ConclusionBoth models showed good performance and had better test characteristics than age-based decision rules, using 10 admission features readily available in Dutch hospitals. The models hold promise to aid decision-making during a hospital bed shortage.

Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39-0.96] and 1.35 [95% CI 0.86-2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%-84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients. (c) 2019 American Society for Bone and Mineral Research.

Several guidelines recommend a bone and fall-related osteoporosis risk assessment in all patients with fracture and age 50 years. In practice, however, there is no consensus whether screening 85 years is useful.To evaluate the subsequent fracture risk in all patient 85 years, comparing the two populations of Fracture Liaison Service (FLS) attenders and non-attenders.All patients 85 years that presented at the FLS with a non-vertebral fracture were included in the study during a 5-year period (September 2004 and December 2009). Excluded were pathologic fractures, death 30 days, or patients on osteoporosis treatment. in patients that attended the FLS, assessment of bone mineral density and fall-risk factors were screened. In both the attenders and non-attenders groups, mortality and subsequent fracture rates were scored during a follow-up of 2 years.282 patients fulfilled inclusion criteria for screening, of which 160 (57%) patients did not attend the FLS. 122 patients were screened for osteoporosis and fall-related risk of whom 72 were diagnosed with osteoporosis. Subsequent fracture risk in both groups was 19%. Medical treatment was started in 51 patients, of which 15 patients developed a subsequent fracture. Cox-regression analysis indicated a significantly lower mortality rate, but not a diminished subsequent fracture rate in the FLS screened population compared to the non-attenders.The advantage of a FLS in reducing subsequent fracture risk in patients 85 years seems to be limited. In practice a large proportion of these patients are not screened.

Distal radius fractures (DRFs) occur in various complexity patterns among patients differing in age, gender, and bone mineral density (BMD). Our aim was to investigate the association of patient characteristics, BMD, bone microarchitecture, and bone strength with the pattern complexity of DRFs. In this study, 251 patients aged 50-90 years with a radiologically confirmed DRF who attended the Fracture Liaison Service of VieCuri Medical Centre, the Netherlands, between November 2013 and June 2016 were included. In all patients fracture risk factors and underling metabolic disorders were evaluated and BMD measurement with vertebral fractures assessment by dual-energy X-ray absorptiometry was performed. Radiographs of all DRFs were reviewed by two independent investigators to assess fracture pattern complexity according to the AO/OTA classification in extra-articular (A), partially articular (B), and complete articular (C) fractures. For this study, patients with A and C fractures were compared. Seventy-one patients were additionally assessed by high-resolution peripheral quantitative computed tomography. Compared to group A, mean age, the proportion of males, and current smokers were higher in group C, but BMD and prevalent vertebral fractures were not different. In univariate analyses, age, male gender, trabecular area, volumetric BMD (vBMD), and stiffness were associated with type C fractures. In multivariate analyses, only male gender (odds ratio (OR) 8.48 95% confidence interval (CI) 1.75-41.18, p = 0.008]) and age (OR 1.11 [95% CI 1.03-1.19, p = 0.007]) were significantly associated with DRF pattern complexity. In conclusion, our data demonstrate that age and gender, but not body mass index, BMD, bone microarchitecture, or strength were associated with pattern complexity of DRFs.(c) 2019 The Authors. Journal of Orthopaedic Research (R) Published by Wiley Periodicals, Inc. J Orthop Res 37:1690-1697, 2019 This study was supported by the VieCuri MC trust for research and innovation. Bert van Rietbergen is a consultant for Scanco Medical AG. Daniels, AM (reprint author), VieCuri Med Ctr, Dept Surg, Venlo, Netherlands. adaniels@viecuri.nl

Greater kyphosis angles lead to increased loading on vertebral bodies in computational models. However, results about the relationship between severity of kyphosis and incident vertebral fracture (VF) risk have been conflicting. Therefore, the aim of this study was to evaluate associations between 1) prevalent VFs and severity of kyphosis, and 2) severity of kyphosis and incident VF risk in smokers with or without chronic obstructive pulmonary disease (COPD). Former and current smokers with or without COPD were included. CT scans were made at baseline, 1-year, and 3-year follow-up. VFs were evaluated on superposed sagittal CT reconstructions. Kyphosis was measured as the angle between the lines above T-4 and below T-9 or T-12. We included 1239 subjects (mean age 61.3 +/- 8.0 years, 61.1% male, 80.6% with COPD), of whom 253 (20.4%) had a prevalent VF and 294 (23.7%) an incident VF within 3 years. Presence, number, and severity of prevalent VFs were associated with a greater kyphosis angle. The mean increase in kyphosis angle within 3 years was small but significantly greater in subjects with incident VFs compared with those without (2.2 +/- 4.1 versus 1.2 +/- 3.9 degrees, respectively, for T-4 to T-12 angle, p

Background: Xentuzumab (Xen), an IGF-1/-2-neutralizing Ab, binds IGF-1 and IGF-2, inhibits their growth-promoting signaling, and suppresses AKT activation by everolimus (Ev). This Phase 1b/2 trial evaluates Xen in combination with Ev and exemestane (Ex) in HR+/HER2− LA/mBC. Methods: The two-arm, open-label, randomized Phase 2 part enrolled female patients (pts) with HR+/HER2− LA/mBC not amenable to curative therapy and refractory to nonsteroidal aromatase inhibitors. Pts were randomized (1:1) to: oral Ev (10 mg/d) + Ex (25 mg/d); or Xen (1000 mg/wk iv) + Ev (10 mg/d) + Ex (25 mg/d). Randomization was stratified by visceral metastases (VM; Y vs N). Treatment continued in 28-day cycles until progression, intolerable adverse events (AEs) or other reasons for discontinuation. Primary endpoint was progression-free survival (PFS), with an interim futility analysis incorporated in the study design. Results: Following the results of the interim analysis, the Data Monitoring Committee (DMC) advised early termination of the trial and discontinuation of Xen treatment. Thus, Xen treatment exposure time and time-to-event data for the Xen+Ev+Ex arm are limited. Of the 139 women treated (Xen+Ev+Ex 70; Ev+Ex 69), 77% had VM. Median PFS was not significantly different between arms (Xen+Ev+Ex vs Ev+Ex, 7.3 vs 5.6 months; HR [95% CI] 0.97 [0.57–1.65]; p=0.91). In a pre-specified subgroup of pts without VM, Xen+Ev+Ex showed favorable PFS vs Ev+Ex (HR 0.21 [0.05–0.98]; Pint=0.0141). Pint values Conclusion: In the overall population, PFS did not improve with the addition of Xen to Ev+Ex and the trial was therefore discontinued early. Nevertheless, a favorable signal was observed in the pre-specified subgroup of pts without VM when treated with Xen+Ev+Ex, which warrants additional investigation. The safety profile was comparable between arms. Citation Format: Crown J, Sablin M-P, Cortés J, Bergh J, Im S-A, Lu Y-S, Martínez N, Neven P, Lee KS, Morales S, Pérez-Fidalgo JA, Adamson D, Goncalves A, Prat A, Jerusalem G, Schlieker L, Espadero R-M, Bogenrieder T, Chin-Lun Huang D, Schmid P. Xentuzumab (BI 836845), an insulin-like growth factor (IGF)-neutralizing antibody (Ab), combined with exemestane and everolimus in hormone receptor-positive (HR+) locally advanced/metastatic breast cancer (LA/mBC): Randomized phase 2 results [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-01.

Primary press-fit fixation of femoral knee prostheses is obtained thanks to the inside dimensions of the implant being undersized with respect to the bone cuts created intra-operatively, dictated by a press-fit specified by the implant design. However, during prostheses press-fit implantation, high compressive and shear stresses at the implant-bone interface are generated, which causes permanent bone damage. The extent of this damage is unknown, but it may influence the implant stability and be a contributing factor to aseptic loosening, a main cause of revisions for knee arthroplasty. The aim of this ex-vivo study was to quantify, using high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging and Digital Volume Correlation (DVC), permanent bone deformation due to press-fit femoral knee implantation of a commonly used implant. Six human cadaveric distal femora were resected and imaged with HR-pQCT (60.7 mu m/voxel, isotropic). Femurs were fitted with cementless femoral knee implants (Sigma PFC) and rescanned after implant removal. For each femur, permanent deformation was examined in the anterior, posterior-medial and posterior-lateral condyles for volumes of interest (VOIs) of 10 mm depth. The bone volume fraction (BV/TV) for the VOIs in pre- and post-implantation images was calculated, at increasing depth from the bone surface. DVC was applied on the VOIs pre- and post-implantation, to assess trabecular bone displacements and plastically accumulated strains. The "BV/TVpost/BV/TVpre ratio vs. depth" showed, consistently among the six femurs, three consecutive points of interest at increasing bone depth, indicating: bone removal (ratio 100%) and no changes (ratio = 100%). Accordingly, the trabecular bone displacement computed by DVC suggested bone compaction up to 2.6 +/- 0.8 mm in depth, with peak third principal strains of -162,100 +/- 55,000 mu epsilon (mean absolute error: 1,000-2,000 mu epsilon, SD: 200-500 mu epsilon), well above the yield strain of bone (7,000-10,000 mu epsilon). Combining 3D-imaging, at spatial resolutions obtainable with clinical HR-pQCT, and DVC, determines the extent of plastic deformation and accumulated compressive strains occurring within the bone due to femoral press-fit implantation. The methods and data presented can be used to compare different implants, implant surface coatings and press-fit values. These can also be used to advance and validate computational models by providing information about the bone-implant interface obtained experimentally. Future studies using these methods can assist in determining the influence of bone damage on implant stability and the subsequent osseointegration.

Objectives: Clinical trials have shown that low-dose glucocorticoid therapy in patients with rheumatoid arthritis (RA) reduces bone loss in hands or hip, but the effect on osteoporotic fractures is not yet clear. Therefore, we investigated the use of low-dose oral glucocorticoids and risk of osteoporotic fractures among patients with RA. Methods: This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997-2017. Exposure to oral glucocorticoids was stratified by the most recent prescription in current (1 year) use, and average daily and cumulative doses. Risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis, and ribs) were estimated by time-dependent Cox proportional-hazards models, adjusted for life-style parameters, comorbidities, and comedications. Secondary analyses assessed osteoporotic fracture risk with a combination of average daily and cumulative doses of oral glucocorticoids. Results: Among 15 123 patients with RA (mean age 68.8 years, 68% females), 1640 osteoporotic fractures occurred. Current low-dose oral glucocorticoid therapy (≤7.5 mg prednisolone equivalent/day) in patients with RA was not associated with overall risk of osteoporotic fractures (adjusted hazard ratio 1.14, 95% CI 0.98-1.33) compared with past glucocorticoid use, but was associated with an increased risk of clinical vertebral fracture (adjusted hazard ratio 1.59, 95% CI 1.11-2.29). Results remained unchanged regardless of a short-term or a long-term use of oral glucocorticoids., Rheumatology, 61 (4)

OBJECTIVE: To compare survival of individuals with coronavirus disease 2019 (COVID-19) treated in hospitals that either did or did not routinely treat patients with hydroxychloroquine or chloroquine.METHODS: We analysed data of COVID-19 patients treated in nine hospitals in the Netherlands. Inclusion dates ranged from 27 February to 15 May 2020, when the Dutch national guidelines no longer supported the use of (hydroxy)chloroquine. Seven hospitals routinely treated patients with (hydroxy)chloroquine, two hospitals did not. Primary outcome was 21-day all-cause mortality. We performed a survival analysis using log-rank test and Cox regression with adjustment for age, sex and covariates based on premorbid health, disease severity and the use of steroids for adult respiratory distress syndrome, including dexamethasone.RESULTS: Among 1949 individuals, 21-day mortality was 21.5% in 1596 patients treated in hospitals that routinely prescribed (hydroxy)chloroquine, and 15.0% in 353 patients treated in hospitals that did not. In the adjusted Cox regression models this difference disappeared, with an adjusted hazard ratio of 1.09 (95% CI 0.81-1.47). When stratified by treatment actually received in individual patients, the use of (hydroxy)chloroquine was associated with an increased 21-day mortality (HR 1.58; 95% CI 1.24-2.02) in the full model.CONCLUSIONS: After adjustment for confounders, mortality was not significantly different in hospitals that routinely treated patients with (hydroxy)chloroquine compared with hospitals that did not. We compared outcomes of hospital strategies rather than outcomes of individual patients to reduce the chance of indication bias. This study adds evidence against the use of (hydroxy)chloroquine in hospitalised patients with COVID-19.

Summary: This is a survey study concerning osteoporosis care during the COVID-19 pandemic in the Netherlands. Respondents reported that osteoporosis care stagnated and lower quality of care was provided. This leads to the conclusion that standardization of osteoporosis care delivery in situations of crisis is needed. Purpose: During the initial phase of the COVID-19 pandemic, there was no guidance of professional societies or guidelines on the organization of osteoporosis care in case of such a crisis, and treatment relied on local ad hoc strategies. Experiences from the current pandemic need to be taken into account for the near future, and therefore, a national multidisciplinary survey was carried out in the Netherlands. Methods: A survey of 17 questions concerning the continuation of bone mineral density measurements by Dual Energy X-ray absorptiometry (DXA), outpatient clinic visits, and prescription of medication was sent to physicians, nurses, nurse practitioners, and physician assistants working in the field of osteoporosis. Results: 77 respondents finished the questionnaire, of whom 39 (50.6%) reported a decline in DXA-scanning and 36 (46.8%) no scanning at all during the pandemic. There was an increase in remote consultations for both new and control patient visits (n = 48, 62.3%; n = 62, 81.7% respectively). Lower quality of care regarding fracture prevention was reported by more than half of the respondents (n = 44, 57.1%). Treatment with intravenous bisphosphonates and denosumab was delayed according to 35 (45.4%) and 6 (6.3%) of the respondents, respectively. Conclusion: During the COVID-19 pandemic, osteoporosis care almost completely arrested, especially because of the discontinuation of DXA-scanning and closing of outpatient clinics. More than half of the respondents reported a substantial lower quality of osteoporosis care during the COVID pandemic. To prevent an increase in fracture rates and a decrease in patient motivation, adherence and satisfaction, standardization of osteoporosis care delivery in situations of crisis is needed.

Background: Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2 diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and the underlying mechanism is unclear. Objective: To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism. Methods: A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD (2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least one prescription of a non-insulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea (SU) use. Analyses were adjusted for lifestyle variables, comorbidities, and concomitant drug use. Results: Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the presence of signs of hypovolemia were not associated with an increased risk of LLA. Conclusion: Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences between individual SGLT2-Is are required to rule out a canagliflozin-specific effect..

We read with much interest the two correspondences on our recently published paper by Lin et al and Gong and Zhang in the Annals of the Rheumatic Diseases .1–3 We conducted a retrospective cohort study to evaluate the association between concomitant use of two commonly used medications in patients with rheumatoid arthritis (RA), that is, oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), and risk of osteoporotic (OP) fractures. We used data from one of the largest primary care databases in the world, the Clinical Practice Research Datalink (CPRD). While this database is a rich source, it does have some inherent limitations. The first question of both correspondences addresses one of these limitations of the CPRD, that is, the absence of any direct measure of RA disease activity in the database, such as the Disease Activity Score in 28 joints. The values of C reactive protein (CRP) were also not available for all patients, and if available, not for the whole follow-up period. Therefore, we decided not to include CRP in the analyses, considering our on-treatment study design and importance of having information on covariates during all person-times from patients for the entire follow-up. We were aware of this limitation and mentioned this in the paper. We also reported our strategy to overcome …

Cementless femoral total knee arthroplasty (TKA) components use a press-fit (referred to as interference fit) to achieve initial fixation. A higher interference fit could lead to a superior fixation, but it could also introduce more damage to the bone during implantation. The purpose of the current study was to investigate the effect of interference fit on the micromotions and gap opening/closing at the bone-implant interface. Experimental tests were performed in six pairs of cadaveric femurs implanted with femoral components using a low interference fit of 350 mu m and a high interference fit of 700 mu m. The specimens were subjected to the peak loads of gait and squat, based on the Orthoload dataset. Digital Image Correlation (DIC) was used to measure the micromotions and opening/closing in different regions of interest (ROIs). Two linear mixed-effect statistical models were created with micromotions and gap opening/closing as dependent variables. ROIs, loading conditions, and implant designs as independent variables, and cadaver specimens as random intercepts. The results revealed no significant difference between the two interference fit implants for micromotions (p = 0.837 for gait and p = 0.065 for squat), nor for the gap opening/closing (p = 0.748 for gait and p = 0.561 for squat). In contrast, significant differences were found between loading and most of the ROIs in both dependent variables (p < 0.0001). Additionally, no difference in bone deformation was found between low and high interference fit. Changing interference between either 350 mu m or 700 mu m did not affect the primary stability of a femoral TKA component. There could be an interference fit threshold beyond which fixation does not further improve. A research grant from Aesculap (Aesculap, B. Braun, Tuttlingen, Germany) supported this work. We would like to thank Dr. Thomas Hoogeboom for his help in developing the statistical model, Richard van Swam for the help and support during the experimental tests, Leon Driessen for all the segmentation work with the HR-pQCT scans, Max Bakker for the Matlab support, and Erik de Vries for the surface morphology measurements. We are also thankful to Justine Eerden for her collaboration in this project. Sanchez, E (corresponding author), Orthopaed Res Lab 611,Geert Gmotepl Zuid 30, NL-6525 GA Nijmegen, Netherlands. Esther.SanchezGarza@radboudumc.nl

ObjectiveValidated clinical risk scores are needed to identify patients with COVID-19 at risk of severe disease and to guide triage decision-making during the COVID-19 pandemic. The objective of the current study was to evaluate the performance of early warning scores (EWS) in the ED when identifying patients with COVID-19 who will require intensive care unit (ICU) admission for high-flow-oxygen usage or mechanical ventilation.MethodsPatients with a proven SARS-CoV-2 infection with complete resuscitate orders treated in nine hospitals between 27 February and 30 July 2020 needing hospital admission were included. Primary outcome was the performance of EWS in identifying patients needing ICU admission within 24 hours after ED presentation.ResultsIn total, 1501 patients were included. Median age was 71 (range 19–99) years and 60.3% were male. Of all patients, 86.9% were admitted to the general ward and 13.1% to the ICU within 24 hours after ED admission. ICU patients had lower peripheral oxygen saturation (86.7% vs 93.7, p≤0.001) and had a higher body mass index (29.2 vs 27.9 p=0.043) compared with non-ICU patients. National Early Warning Score 2 (NEWS2) ≥ 6 and q-COVID Score were superior to all other studied clinical risk scores in predicting ICU admission with a fair area under the receiver operating characteristics curve of 0.740 (95% CI 0.696 to 0.783) and 0.760 (95% CI 0.712 to 0.800), respectively. NEWS2 ≥6 and q-COVID Score ≥3 discriminated patients admitted to the ICU with a sensitivity of 78.1% and 75.9%, and specificity of 56.3% and 61.8%, respectively.ConclusionIn this multicentre study, the best performing models to predict ICU admittance were the NEWS2 and the Quick COVID-19 Severity Index Score, with fair diagnostic performance. However, due to the moderate performance, these models cannot be clinically used to adequately predict the need for ICU admission within 24 hours in patients with SARS-CoV-2 infection presenting at the ED.

Objective: The main objective of this cohort study is to determine the prevalence and incidence of morphometric vertebral fractures (VFs) over 7 years follow-up, in institutionalized adults with refractory epilepsy and intellectual disability (ID).Methods: Dual-energy X-ray Absorptiometry (DXA) and Vertebral Fracture Assessment (VFA) were performed in 2009 and 2016. Vertebrae T4-L4 were assessed using quantitative morphometry. Severity of VFs was graded as 1 (mild; 20-25% reduction in height), 2 (moderate; 25-40% reduction) or 3 (severe; >40% reduction) according to the method described by Genant. Prevalent VFs were analyzed at baseline. VFs (grade 1, 2 or 3) present at follow-up, but not at baseline, were considered new VFs. Worsening VFs were defined as VFs with at least one grade deterioration at follow-up, compared to baseline (grade 1 to 2 or 3, or grade 2 to 3). Patients were treated with anti-osteoporosis treatment according to the Dutch guideline.Results: Baseline and follow-up DXA and VFA could be obtained in 141 patients (87 male) aged between 18-79 years old (mean 44.8 +/- 15.7). At baseline, 56 patients had at least one prevalent VF. Patients with a prevalent VF were significantly older than patients without (49.2 +/- 13.7 vs 41.9 +/- 16.4, p Significance: In adults with refractory epilepsy VFA is challenging, due to physical and behavioral aspects, resulting in a substantial proportion of unevaluable vertebrae and scans. Nevertheless, 40% of the patients had a VF at baseline and after 7 years follow-up, 27% had at least one new and/or worsening VF despite adequate anti-osteoporosis treatment.

Obtaining high-resolution scans of bones and joints for clinical applications is challenging. HR-pQCT is considered the best technology to acquire high-resolution images of the peripheral skeleton in vivo, but a breakthrough for widespread clinical applications is still lacking. Recently, we showed on trapezia that CBCT is a promising alternative providing a larger FOV at a shorter scanning time. The goals of this study were to evaluate the accuracy of CBCT in quantifying trabecular bone microstructural and predicted mechanical parameters of the distal radius, the most often investigated skeletal site with HR-pQCT, and to compare it with HR-pQCT. Nineteen radii were scanned with four scanners: (1) HR-pQCT (XtremeCT, Scanco Medical AG, @ (voxel size) 82 μm), (2) HR-pQCT (XtremeCT-II, Scanco, @60.7 μm), (3) CBCT (NewTom 5G, Cefla, @75 μm) reconstructed and segmented using in-house developed software and (4) microCT (VivaCT40, Scanco, @19 μm-gold standard). The following parameters were evaluated: predicted stiffness, strength, bone volume fraction (BV/TV) and trabecular thickness (Tb.Th), separation (Tb.Sp) and number (Tb.N). The overall accuracy of CBCT with in-house optimized algorithms in quantifying bone microstructural parameters was comparable (R

Over the last decades, the use of high-resolution imaging systems to assess bone microstructural parameters has grown immensely. Yet, no standard defining the quantification of these parameters exists. It has been reported that different voxel size and/or segmentation techniques lead to different results. However, the effect of the evaluation software has not been investigated so far. Therefore, the aim of this study was to compare the bone microstructural parameters obtained with two commonly used commercial software packages, namely IPL (Scanco, Switzerland) and CTan (Bruker, Belgium). We hypothesized that even when starting from the same segmented scans, different software packages will report different results. Nineteen trapezia and nineteen distal radii were scanned at two resolutions (20 μm voxel size with microCT and HR-pQCT 60 μm). The scans were segmented using the scanners' default protocol. The segmented images were analyzed twice, once with IPL and once with CTan, to quantify bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), trabecular number (Tb.N) and specific bone surface (BS/BV). Only small differences between IPL and CTan were found for BV/TV. For Tb.Th, Tb.Sp and BS/BV high correlations (R2 ≥ 0.99) were observed between the two software packages, but important relative offsets were observed. For microCT scans, the offsets were relative constant, e.g., around 15% for Tb.Th. However, for the HR-pQCT scans the mean relative offsets ranged over the different bone samples (e.g., for Tb.Th from 14.5% to 19.8%). For Tb.N, poor correlations (0.43 ≤ R2 ≤ 0.81) for all tested cases were observed. We conclude that trabecular bone microstructural parameters obtained with IPL and CTan cannot be directly compared except for BV/TV. For Tb.Th, Tb.Sp and BS/BV, correction factors can be determined, but these depend on both the image voxel size and specific anatomic location. The two software packages did not produce consistent data on Tb.N. The development of a universal standard seems desirable.

In the human femoral neck, the contribution of the cortical and trabecular architecture to mechanical strength is known to depend on the load direction.In this work, we investigate if QCT-derived homogenized voxel finite element (hvFE) simulations of varying hip loading conditions can be used to study the architecture of the femoral neck. The strength of 19 pairs of human femora was measured ex vivo using nonlinear hvFE models derived from high-resolution peripheral QCT scans (voxel size: 30.3 mu m). Standing and side-backwards falling loads were modeled. Quasi-static mechanical tests were performed on 20 bones for comparison. Associations of femur strength with volumetric bone mineral density (vBMD) or microstructural parameters of the femoral neck obtained from high-resolution QCT were compared between mechanical tests and simulations and between standing and falling loads.Proximal femur strength predictions by hvFE models were positively associated with the vBMD of the femoral neck (R-2 > 0.61, p 0.27, p 0.38, p

A Summary A pilot study on the use of P-EU to identify patients without osteoporosis and/or a subclinical vertebral fracture after a recently sustained non-vertebral fracture (NVF).Introduction Screening with portable devices at emergency departments or plaster rooms could be of interest to limit referrals for dual X-ray absorptiometry (DXA) and vertebral fracture assessment (VFA). We calculated the number of negative tests for osteoporosis and/or subclinical vertebral fractures (VFs) using pulse-echo ultrasonometry (P-UE) at different thresholds.Patients and methods In this cross-sectional study, 209 consecutive women of 50-70 years with a recent non-vertebral fracture (NVF) were studied at the Fracture Liaison Service (FLS) of one hospital. All women received DXA/VFA and P-EU (Bindex (R)) assessments. Various P-EU thresholds (based on the density index (DI, g/cm(2))) were analyzed to calculate the best balance between true negative (indeed no osteoporosis and/or subclinical VF) and false negative tests (osteoporosis and/or subclinical VF according to DXA/VFA).Results Eighty-three women had osteoporosis (40%) and 17 women at least one VF (8%). Applying the manufacturer's recommended P-EU threshold (DI 0.844 g/cm(2)) being their proposed cut-off for not having hip osteoporosis resulted in 77 negative tests (37%, 31% true negative and 6% false negative tests). A DI of 0.896 g/cm(2) resulted in 40 negative tests (19.3%) (38 true negative (18.3%) and 2 false negative tests (1.0%)).Conclusion The application of P-EU enables the identification of a substantial proportion of women with recent non-vertebral fractures at the FLS who would not need a DXA/VFA referral because they had no osteoporosis and/or subclinical vertebral fractures. The most conservative P-EU threshold resulted in 18.3% true negative tests verified by DXA/VFA against 1% false negative test results.

Small cortical interruptions may be the first sign of an erosion, and more interruptions can be found in patients with rheumatoid arthritis (RA) compared with healthy subjects. First, we compared the number and size of interruptions in patients with RA with healthy subjects using high-resolution peripheral quantitative CT (HR-pQCT). Second, we investigated the association between structural damage and inflammatory markers on conventional radiography (CR) and MRI with interruptions on HR-pQCT. Third, the added value of HR-pQCT over CR and MRI was investigated. The finger joints of 39 patients with RA and 38 healthy subjects were examined through CR, MRI, and HR-pQCT. CRs were scored using the Sharp/Van der Heijde method. MRI images were analyzed for the presence of erosions, bone marrow edema, and synovitis. HR-pQCT images were analyzed for the number, surface area, and volume of interruptions using a semiautomated algorithm. Descriptives were calculated and associations were tested using generalized estimating equations. Significantly more interruptions and both a larger surface area and the volume of interruptions were detected in the metacarpophalangeal joints of patients with RA compared with healthy subjects (median, 2.0, 1.42 mm2 , and 0.48 mm3 versus 1.0, 0.69 mm2 , and 0.23 mm3 , respectively; all p

Dietary intake has been shown to affect bone health via both proinflammatory and anti- inflammatory mechanisms. Some dietary constituents such as zinc, magnesium and calcium have anti-inflammatory effect and are beneficial for the bone physiology. The aim was to analyze bone mineral density (BMD), bone remodeling markers, serum vitamin D values and overall intake of the dietary minerals (calcium, magnesium, zinc and sodium) with respect to the dietary inflammatory index (DII) score. Women (N = 400) included in this study were divided in subgroups according to the adherence to DII score. Q1 indicated participants having the lowest DII values and highest adherence to anti-inflammatory diet, while Q4 were participants having pro- inflammatory diet. Kruskal–Wallis test was used to analyze the adherence of the bone status parameters to the DII score as well as the adherence of dietary minerals to DII score. Multiple regression analyses was employed to test the relationship between BMD and bone remodeling markers with the DII score and age. P\0.05 was considered as statistically significant. Our results revealed that women whose dietary habits were more in anti- inflammatory quartiles, had significantly higher values of the lumbar spine BMD (P = 0.01), left hip BMD (P\0.01) and bone alkaline phosphatase (P\0.01). They also had significantly higher intakes of dietary calcium, magnesium and zinc, P\0.01, respectively. Multiple regression analyses revealed that age and DII were significantly and inversely correlated to left hip BMD, while deoxypyridinoline was just proportional to age and DII, P\0.01, respectively. Study results suggest that anti-inflammatory diet is associated with high BMD and younger age.

Introduction: Chronic obstructive pulmonary disease (COPD) is characterised by persistent airflow obstruction and respiratory symptoms. While short course systemic GCs are prescribed in patients with acute COPD exacerbations, little is known of the risk of fractures with intermittent exposure to high-dose GC and the effect of proxies of disease severity.Methods: A case-control study was conducted using the Danish National Hospital Discharge Registry (NHDR) between January 1996 to December 2011. Conditional logistics regression models were used to derive adjusted odds ratios (OR) risk of fractures in subjects with COPD stratified by intermittent high-dose, and proxies of disease severity.Result: A total of 635,536 cases and the same number of controls were identified (mean age 67.5 +/- 13.8, 65% female). COPD patients with intermittent use of high average daily dose oral glucocorticoids did not have an increased risk of any, osteoporotic, hip or clinically symptomatic vertebral fracture compared to non-COPD patients (adj. OR 0.65; 95% CI: 0.50-0.86, 0.70; 95% CI: 0.70-0.99, 1.17; 95% CI: 0.59-2.32, 1.98; 95% CI: 0.59-6.65 respectively). We identified an elevated risk of osteoporotic fracture among patients who visited the emergency unit (adj. OR 1.47; 95% CI 1.20-1.79) or were hospitalised in the past year for COPD (adj. OR 1.76; 95% CI 1.66-1.85). Current GC use among COPD patients was associated with an increased risk of osteoporotic, hip and clinically symptomatic vertebral fractures compared to patients without COPD.Conclusion: Intermittent high-dose GCs was not associated with an increased risk of any, osteoporotic, hip or clinically symptomatic vertebral fractures in patients with COPD. Current GC use was however associated with an increased risk of hip and clinically symptomatic vertebral fractures. Therefore, emphasis on prophylactic treatment of fractures may not be essential in patients with COPD receiving intermittent dose of GCs, whereas this should be considered for high-dose long-term users with advanced COPD disease stage, postmenopausal women and men over 40 years. (C) 2018 Elsevier Inc. All rights reserved.