100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Radiographic Cortical Thickness Index Predicts Fragility Fracture in Gaucher Disease.

Background Patients with Gaucher disease (GD) have a high risk of fragility fractures. Routine evaluation of bone involvement in these patients includes radiography and repeated dual-energy x-ray absorptiometry (DXA). However, osteonecrosis and bone fracture may affect the accuracy of DXA. Purpose To assess the utility of DXA and radiographic femoral cortical thickness measurements as predictors of fragility fracture in patients with GD with long-term follow-up (up to 30 years). Materials and Methods Patients with GD age 16 years and older with a detailed medical history, at least one bone image (DXA and/or radiographs), and minimum 2 years follow-up were retrospectively identified using three merged UK-based registries (Gaucherite study, enrollment 2015-2017; Clinical Bone Registry, enrollment 2003-2006; and Mortality Registry, enrollment 1993-2019). Cortical thickness index (CTI) and canal-to-calcar ratio (CCR) were measured by two independent observers, and inter- and intraobserver reliability was calculated. The fracture-predictive value of DXA, CTI, CCR, and cutoff values were calculated using receiver operating characteristic curves. Statistical differences were assessed using univariable and multivariable analysis. Results Bone imaging in 247 patients (123 men, 124 women; baseline median age, 39 years; IQR, 27-50 years) was reviewed. The median follow-up period was 11 years (IQR, 7-19 years; range, 2-30 years). Thirty-five patients had fractures before or at first bone imaging, 23 patients had fractures after first bone imaging, and 189 patients remained fracture-free. Inter- and intraobserver reproducibility for CTI/CCR measurements was substantial (range, 0.96-0.98). In the 212 patients with no baseline fracture, CTI (cutoff, ≤0.50) predicted future fractures with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI: 0.84, 0.99; sensitivity, 92%; specificity, 96%) than DXA T-score at total hip (AUC, 0.78; 95% CI: 0.51, 0.91; sensitivity, 64%; specificity, 93%), femoral neck (AUC, 0.73; 95% CI: 0.50, 0.86; sensitivity, 64%; specificity, 73%), lumbar spine (AUC, 0.69; 95% CI: 0.49, 0.82; sensitivity, 57%; specificity, 63%), and forearm (AUC, 0.78; 95% CI: 0.59, 0.89; sensitivity, 70%; specificity, 70%). Conclusion Radiographic cortical thickness index of 0.50 or less was a reliable independent predictor of fracture risk in Gaucher disease. Clinical trial registration no. NCT03240653 © RSNA, 2022 Supplemental material is available for this article.

3-D joint space mapping at the ankle from weight-bearing CT: reproducibility, repeatability, and challenges for standardisation.

OBJECTIVES: We present a 3-D approach to joint space width (JSW) measurement across the ankle from weight-bearing CT (WBCT) to demonstrate inter-operator reproducibility, test-retest repeatability, and how differences in angulation affect ankle JSW distribution. METHODS: One side from repeat WBCT imaging of both feet and ankles was analysed from 23 individuals as part of their routine clinical care pathway. Joint space mapping was performed at four facets across the talus: talonavicular, talar dome and medial gutter (dome-medial), lateral gutter, and posterior subtalar. Inter-operator reproducibility was calculated for two users, while test-retest repeatability was calculated by comparing the two visits, both presented as Bland-Altman statistics. Statistical parametric mapping determined any significant relationships between talocrural joint space angulation and 3-D JSW distribution. RESULTS: The average ± standard deviation interval between imaging was 74.0 ± 29.6 days. Surface averaged bias ± limits of agreement were similar for reproducibility and repeatability, the latter being: talonavicular 0.01 ± 0.26 mm, dome-medial 0.00 ± 0.28 mm, lateral gutter - 0.02 ± 0.40 mm, and posterior subtalar 0.02 ± 0.34 mm. Results are presented as 3-D distribution maps, with optimum test-retest repeatability reaching a smallest detectable difference of ± 0.15 mm. CONCLUSIONS: Joint space mapping is a robust approach to 3-D quantification of JSW measurement, inter-operator reproducibility, and test-retest repeatability at the ankle, with sensitivity reaching a best value of ± 0.15 mm. Standardised imaging protocols and optimised metal artefact reduction will be needed to further understand the clinical value of these 3-D measures derived from WBCT. CLINICAL RELEVANCE STATEMENT: Weight-bearing computed tomography is an increasingly important tool in the clinical assessment of orthopaedic ankle disorders. This paper establishes the performance of measuring 3-D joint space width using this technology, which is an important surrogate marker for severity of osteoarthritis. KEY POINTS: • Joint space width values and error metrics from across the ankle measured from weight-bearing CT can be presented as 3-D maps that show topographic variation. • The best sensitivity for detecting meaningful change in 3-D joint space width at the ankle was ± 0.15 mm, a value less than the isotropic imaging voxel dimensions. • Standardised imaging protocols and optimised metal artefact reduction will be needed to understand the clinical value of 3-D measures from weight-bearing CT.

Use of the Electronic Health Record During Clinical Encounters: An Experience Survey.

PURPOSE: Use of the electronic health record (EHR) during face-to-face clinical encounters affects communication, and prior research has been inconclusive regarding its effect. This survey study assessed health care practitioner use of EHR-specific communication skills and patient and practitioner experiences and attitudes regarding EHR use during clinical encounters. METHODS: For this US-based study, we distributed previously validated surveys to practitioners and adult patients (aged >18 years) at academic primary care practices from July 1, 2018 through August 31, 2018. The electronic practitioner survey was completed first; a paper survey was administered to patients after appointments. Descriptive statistics were calculated, and the Cochran-Armitage test was used to assess for associations between key variables. RESULTS: The practitioner response was 72.9% (43/59); patient response, 45.2% (452/1,000). Practitioners reported maintaining less eye contact (79.1%), listening less carefully (53.5%), focusing less on patients (65.1%), and visits feeling less personal (62.8%). However, patients reported that practitioners provided sufficient eye contact (96.8%) and listened carefully (97.0%); they disagreed that practitioners focused less on them (86.7%) or that visits felt less personal (87.2%). Patients thought EHR use was positive (91.7%); only one-third of practitioners (37.2%) thought that patients would agree with that statement. Practitioners reported stress, burnout, and a lack of sufficient time for EHR documentation. CONCLUSIONS: A discrepancy existed in this study between patient and practitioner experiences and attitudes about EHR use, which appeared to negatively affect the experience of health care practitioners but not patients. Organizations should adopt formal strategies to improve practitioner experiences with EHR use.

Phosphaturic Mesenchymal Tumor of the Ankle: A Case Report and Review of the Literature.

We report the case of a phosphaturic mesenchymal tumor of the ankle; an extremely rare lesion that causes osteomalacia via paraneoplastic renal phosphate wasting. A 41-year-old man was referred to plastic surgery with a swelling over the anterior ankle, which had been increasing in size for 1 year. Focused ultrasound assessment was inconclusive, but excision biopsy demonstrated features in keeping with a phosphaturic mesenchymal tumor. Evidence of tumor-induced osteomalacia was subsequently identified on review of historical biochemistry. The patient was followed-up for 1 year with normalization of serum phosphate. In this case report, we present a discussion of the differential diagnosis for foot and ankle soft tissue lesions, and a review of the literature regarding the diagnosis and management of these tumors. Accurate identification of any soft tissue lesion on clinical examination alone is extremely challenging and excision biopsy should be considered in cases of diagnostic uncertainty.

Quantitative Three-dimensional Assessment of Knee Joint Space Width from Weight-bearing CT.

Background Imaging of structural disease in osteoarthritis has traditionally relied on MRI and radiography. Joint space mapping (JSM) can be used to quantitatively map joint space width (JSW) in three dimensions from CT images. Purpose To demonstrate the reproducibility, repeatability, and feasibility of JSM of the knee using weight-bearing CT images. Materials and Methods Two convenience samples of weight-bearing CT images of left and right knees with radiographic Kellgren-Lawrence grades (KLGs) less than or equal to 2 were acquired from 2014 to 2018 and were analyzed retrospectively with JSM to deliver three-dimensional JSW maps. For reproducibility, images of three sets of knees were used for novice training, and then the JSM output was compared against an expert's assessment. JSM was also performed on 2-week follow-up images in the second cohort, yielding three-dimensional JSW difference maps for repeatability. Statistical parametric mapping was performed on all knee imaging data (KLG, 0-4) to show the feasibility of a surface-based analysis in three dimensions. Results Reproducibility (in 20 individuals; mean age, 58 years ± 7 [standard deviation]; mean body mass index, 28 kg/m2 ± 6; 14 women) and repeatability (in nine individuals; mean age, 53 years ± 6; mean body mass index, 26 kg/m2 ± 4; seven women) reached their lowest performance at a smallest detectable difference less than ±0.1 mm in the central medial tibiofemoral joint space for individuals without radiographically demonstrated disease. The average root mean square coefficient of variation was less than 5% across all groups. Statistical parametric mapping (33 individuals; mean age, 57 years ± 7; mean body mass index, 27 kg/m2 ± 6; 23 women) showed that the central-to-posterior medial joint space was significantly narrower by 0.5 mm for each incremental increase in the KLG (threshold P < .05). One knee (KLG, 2) demonstrated a baseline versus 24-month change in its three-dimensional JSW distribution that was beyond the smallest detectable difference across the lateral joint space. Conclusion Joint space mapping of the knee using weight-bearing CT images is feasible, demonstrating a relationship between the three-dimensional joint space width distribution and structural joint disease. It is reliably learned by novice users, can be personalized for disease phenotypes, and can be used to achieve a smallest detectable difference that is at least 50% smaller than that reported to be achieved at the highest performance level in radiography. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Roemer in this issue.

Identification of novel pathogenic variants and features in patients with pseudohypoparathyroidism and acrodysostosis, subtypes of the newly classified inactivating PTH/PTHrP signaling disorders.

Albright hereditary osteodystrophy (AHO) is a complex disorder defined by the presence of a short adult stature relative to the height of an unaffected parent and brachydactyly type E, as well as a stocky build, round face, and ectopic calcifications. AHO and pseudohypoparathyroidism (PHP) have been used interchangeably in the past. The term PHP describes end-organ resistance to parathyroid hormone (PTH), occurring with or without the physical features of AHO. Conversely, pseudopseudohypoparathyroidism (PPHP) describes individuals with AHO features in the absence of PTH resistance. PHP and PPHP are etiologically linked and caused by genetic and/or epigenetic alterations in the guanine nucleotide-binding protein alpha-stimulating (Gs α) locus (GNAS) in chromosome 20q13. Another less-recognized group of skeletal dysplasias, termed acrodysostosis, partially overlap with skeletal, endocrine, and neurodevelopmental features of AHO/PHP and can be overlooked in clinical practice, causing confusion in the literature. Acrodysostosis is caused by defects in two genes, PRKAR1A and PDE4D, both encoding important components of the Gs α-cyclic adenosine monophosphate-protein kinase A signaling pathway. We describe the clinical course and genotype of two adult patients with overlapping AHO features who harbored novel pathogenic variants in GNAS (c.2273C > G, p.Pro758Arg, NM_080425.2) and PRKAR1A (c.803C > T, p.Ala268Val, NM_002734.4), respectively. We highlight the value of expert radiological opinion and molecular testing in establishing correct diagnoses and discuss phenotypic features of our patients, including the first description of subcutaneous ossification and spina bifida occulta in PRKAR1A-related acrodysostosis, in the context of the novel inactivating PTH/PTH related peptide signaling disorder classification system.

Health Behaviors and Preventive Healthcare Utilization Among African-American Attendees at a Faith-Based Public Health Conference: Healthy Churches 2020.

Unhealthy eating habits and physical inactivity along with lack of access to quality healthcare contribute to the marked health disparities in chronic diseases among African-Americans. Faith-based public health conferences offer a potential opportunity to improve health literacy and change health behaviors through health promotion within this population, thereby reducing health disparities. This study examined the self-reported health behaviors and preventive healthcare utilization patterns of 77 participants at a predominantly African-American faith-based public health conference, Healthy Churches 2020. A self-administered questionnaire was distributed to a sample of attendees to assess their health behaviors (diet and physical activity), preventive healthcare utilization (annual healthcare provider visits), and health-promoting activities at their places of worship. The results indicate that attendees of a faith-based public health conference have adequate preventive healthcare utilization, but suboptimal healthy behaviors. Our findings support the need for ongoing health-promoting activities with an emphasis on diet and physical activity among this population.

Quantitative 3D analysis of bone in hip osteoarthritis using clinical computed tomography.

OBJECTIVE: To assess the relationship between proximal femoral cortical bone thickness and radiological hip osteoarthritis using quantitative 3D analysis of clinical computed tomography (CT) data. METHODS: Image analysis was performed on clinical CT imaging data from 203 female volunteers with a technique called cortical bone mapping (CBM). Colour thickness maps were created for each proximal femur. Statistical parametric mapping was performed to identify statistically significant differences in cortical bone thickness that corresponded with the severity of radiological hip osteoarthritis. Kellgren and Lawrence (K&L) grade, minimum joint space width (JSW) and a novel CT-based osteophyte score were also blindly assessed from the CT data. RESULTS: For each increase in K&L grade, cortical thickness increased by up to 25 % in distinct areas of the superolateral femoral head-neck junction and superior subchondral bone plate. For increasing severity of CT osteophytes, the increase in cortical thickness was more circumferential, involving a wider portion of the head-neck junction, with up to a 7 % increase in cortical thickness per increment in score. Results were not significant for minimum JSW. CONCLUSIONS: These findings indicate that quantitative 3D analysis of the proximal femur can identify changes in cortical bone thickness relevant to structural hip osteoarthritis. KEY POINTS: • CT is being increasingly used to assess bony involvement in osteoarthritis • CBM provides accurate and reliable quantitative analysis of cortical bone thickness • Cortical bone is thicker at the superior femoral head-neck with worse osteoarthritis • Regions of increased thickness co-locate with impingement and osteophyte formation • Quantitative 3D bone analysis could enable clinical disease prediction and therapy development.

Deep learning-based quantification of osteonecrosis using magnetic resonance images in Gaucher disease.

Gaucher disease is one of the most common lysosomal storage disorders. Osteonecrosis is a principal clinical manifestation of Gaucher disease and often leads to joint collapse and fractures. T1-weighted (T1w) modality in MRI is widely used to monitor bone involvement in Gaucher disease and to diagnose osteonecrosis. However, objective and quantitative methods for characterizing osteonecrosis are still limited. In this work, we present a deep learning-based quantification approach for the segmentation of osteonecrosis and the extraction of characteristic parameters. We first constructed two independent U-net models to segment the osteonecrosis and bone marrow unaffected by osteonecrosis (UBM) in spine and femur respectively, based on T1w images from patients in the UK national Gaucherite study database. We manually delineated parcellation maps including osteonecrosis and UBM from 364 T1w images (176 for spine, 188 for femur) as the training datasets, and the trained models were subsequently applied to all the 917 T1w images in the database. To quantify the segmentation, we calculated morphological parameters including the volume of osteonecrosis, the volume of UBM, and the fraction of total marrow occupied by osteonecrosis. Then, we examined the correlation between calculated features and the bone marrow burden score for marrow infiltration of the corresponding image, and no strong correlation was found. In addition, we analyzed the influence of splenectomy and the interval between the age at first symptom and the age of onset of treatment on the quantitative measurements of osteonecrosis. The results are consistent with previous studies, showing that prior splenectomy is closely associated with the fractional volume of osteonecrosis, and there is a positive relationship between the duration of untreated disease and the quantifications of osteonecrosis. We propose this technique as an efficient and reliable tool for assessing the extent of osteonecrosis in MR images of patients and improving prediction of clinically important adverse events.

Buds of new bone formation within the Femoral Head of Hip Fracture Patients Coincide with Zones of Low Osteocyte Sclerostin.

Romosozumab treatment reduces the rate of hip fractures and increases hip bone density, increasing bone formation by inhibiting sclerostin protein. We studied the normal pattern of bone formation and osteocyte expression in the human proximal femur because it is relevant to both antisclerostin treatment effects and fracture. Having visualized and quantified buds of new bone formation in trabeculae, we hypothesized that they would coincide with areas of (a) higher mechanical stress and (b) low sclerostin expression by osteocytes. In patients with hip fracture, we visualized each bud of active modeling-based formation (forming minimodeling structure [FMiS]) in trabecular cores taken from different parts of the femoral head. Trabecular bone structure was also measured with high-resolution imaging. More buds of new bone formation (by volume) were present in the higher stress superomedial zone (FMiS density, N.FMiS/T.Ar) than lower stress superolateral (p < 0.05), and inferomedial (p < 0.001) regions. There were fewer sclerostin expressing osteocytes close to or within FMiS. FMiS density correlated with greater amount, thickness, number, and connectivity of trabeculae (bone volume BV/TV, r = 0.65, p < 0.0001; bone surface BS/TV, r = 0.47, p < 0.01; trabecular thickness Tb.Th, r = 0.55, p < 0.001; trabecular number Tb.N, r = 0.47, p < 0.01; and connectivity density Conn.D, r = 0.40, p < 0.05) and lower trabecular separation (Tb.Sp, r = -0.56, p < 0.001). These results demonstrate modeling-based bone formation in femoral trabeculae from patients with hip fracture as a potential therapeutic target to enhance bone structure. © 2023 American Society for Bone and Mineral Research (ASBMR).

Teamwork measure relates to provider experience, burnout, and intent to stay.

OBJECTIVES: To develop a brief teamwork measure and determine how teamwork relates to provider experience, burnout, and work intentions. STUDY DESIGN: Survey of clinicians. METHODS: We analyzed data from Optum's 2019 biannual clinician survey, including a validated burnout measure and measures of provider experience and intent to stay. A 6-item measure of team effectiveness (TEAM) focused on efficiency, communication, continuous improvement, and leadership. Construct validity was assessed with content, reliability, and correlation with burnout. Generalized estimating equations with robust SEs determined relationships among TEAM score, provider experience, and intent to stay, controlling for demographics, clustering, and practice factors. RESULTS: Of 1500 physicians and advanced practice clinicians (1387 with complete data; response rate 56%), there were 58% in primary care; 57% were women, and 38% identified as Asian, Black/Hispanic, or another race/ethnicity other than White non-Hispanic. Burnout was present in 30%. The Cronbach α was excellent (0.86), and TEAM correlated with the validated burnout measure (adjusted odds ratio [OR] of lower burnout with high TEAM score, 0.28; 95% CI, 0.19-0.40; P < .0001). Clinicians with TEAM scores of at least 4 were more likely to have positive provider experiences (79% favorable vs 24% with low TEAM score; P < .001), had lower burnout rates (17% vs 44%%; P < .001), and more often intended to stay (93% vs 65%; P < .001). TEAM index score was strongly associated with provider experience (adjusted OR, 11.72; 95% CI, 8.11-16.95; P < .001) and intent to stay (adjusted OR, 7.24; 95% CI, 5.34-9.83; P < .001). CONCLUSIONS: The TEAM index is related to provider experience, burnout, and intent to stay, and it may help organizations optimize clinical work environments.

Outpatient Primary Care Practitioner Access: Gender-Based Preferences.

Background: Primary care practices are evolving under the pressure of modern-day challenges, with some clinics now introducing the choice of new nontraditional care models designed to maximize patients' needs with practitioner efficiency. These changes include team models consisting of advanced practitioners and physicians, as well as new care delivery formats such as virtual care. With a growing number of options for care, it is unclear whether patients' gender affects their visit preferences; therefore, we surveyed patients presenting to an outpatient internal medicine clinic in Arizona to understand how practice variations impact patient satisfaction of their primary care. Methods: Patients seen in an outpatient internal medicine clinic were surveyed. Multivariable models adjusting for age, marital status, education level, and income were used to evaluate gender-based care preferences. Results: Of 796 total participants (446 women, 350 men), women were more likely to prefer continuity of care with the same health care practitioner (90.2% women vs. 85.0% men, p = 0.028) and allied health staff (AHS) (36.3% women vs. 28.0% men, p = 0.0031) over convenience of appointment or quicker response time than men. However, after multivariable analysis, no statistically significant relationships remained. Discussion: Women favored both continuity of care with the same health care provider and AHS over faster access to primary care. A large majority of men had similar preferences for continuity of care. To provide the highest level of care with greatest patient satisfaction, understanding individual preferences for care delivery will be important.

PHOENIX (Picking up Hidden Osteoporosis Effectively during Normal CT Imaging without additional X-rays): protocol for a randomised, multicentre feasibility study.

INTRODUCTION: Two million out of the UK's 5 million routine diagnostic CT scans performed each year incorporate the thoracolumbar spine or pelvic region. Up to one-third reveal undiagnosed osteoporosis or vertebral fractures. We developed an intervention, Picking up Hidden Osteoporosis Effectively during Normal CT Imaging without additional X-rays ('PHOENIX'), to facilitate early detection and management of osteoporosis in people attending hospitals for CT scans. METHODS AND ANALYSIS: A multicentre, randomised, pragmatic feasibility study. From the general CT-attending population, women aged ≥65 years and men aged ≥75 years attending for CT scans are invited to participate, via a novel consent form incorporating Fracture Risk Assessment (FRAX) questions. Those at increased 10-year risk (within the amber or red zones of the UK FRAX graphical outputs for further action) are block randomised (1:1:1) to (1) PHOENIX intervention, (2) active control or (3) usual care. The PHOENIX intervention comprises (i) retrieving the CT scans using the NHS Image Exchange Portal, (ii) Mindways QCT Pro software analysis of CT hip and spine none density with CT vertebral fracture assessment, (iii) sending the participants' general practitioner (GP) a clinical report including diagnosis, necessary investigations and recommended treatment. Baseline CT scans from groups 2 and 3 are assessed with the PHOENIX intervention only at study end. Assuming 25% attrition, the study is powered to find a predicted superior osteoporosis treatment rate with PHOENIX (20%) vs 16% among patients whose GPs were sent the FRAX questionnaire only (active control) and 5% in the usual care group. Five hospitals are participating to determine feasibility. The co-primary feasibility outcome measures are (a) ability to randomise 375 patients within 10 months and (b) retention of 75% of survivors, completing their 1-year bone health outcome questionnaire. Secondary 1-year outcomes include osteoporosis/vertebral fracture identification rates and osteoporosis treatment rates. Stakeholder acceptability and economic aspects are evaluated. ETHICS AND DISSEMINATION: Approved by committee (National Research Ethics Service) East of England (EE) as REF/19/EE/0176. Dissemination will be through the Royal Osteoporosis Society (to patients and public) as well as to clinician peers via national and international bone/rheumatology scientific and clinical meetings. TRIAL REGISTRATION NUMBER: ISRCTN14722819.

Multiparametric 3-D analysis of bone and joint space width at the knee from weight bearing computed tomography.

Objective: Computed tomography (CT) can deliver multiple parameters relevant to osteoarthritis. In this study we demonstrate that a 3-D multiparametric approach at the weight bearing knee with cone beam CT is feasible, can include multiple parameters from across the joint space, and can reveal stronger relationships with disease status in combination. Design: 33 participants with knee weight bearing CT (WBCT) were analysed with joint space mapping and cortical bone mapping to deliver joint space width (JSW), subchondral bone plate thickness, endocortical thickness, and trabecular attenuation at both sides of the joint. All data were co-localised to the same canonical surface. Statistical parametric mapping (SPM) was applied in uni- and multivariate models to demonstrate significant dependence of parameters on Kellgren & Lawrence grade (KLG). Correlation between JSW and bony parameters and 2-week test-retest repeatability were also calculated. Results: SPM revealed that the central-to-posterior medial tibiofemoral joint space was significantly narrowed by up to 0.5 mm with significantly higher tibial trabecular attenuation up to 50 units for each increment in KLG as single features, and in a wider distribution when combined (p<0.05). These were also more strongly correlated with worsening KLG grade category. Test-retest repeatability was subvoxel (0.37 mm) for nearly all thickness parameters. Conclusions: 3-D JSW and tibial trabecular attenuation are repeatable and significantly dependent on radiographic disease severity at the weight bearing knee joint not just alone, but more strongly in combination. A quantitative multiparametric approach with WBCT may have potential for more sensitive investigation of disease progression in osteoarthritis.

Digital health interventions for osteoporosis and post-fragility fracture care.

The growing burden from osteoporosis and fragility fractures highlights a need to improve osteoporosis management across healthcare systems. Sub-optimal management of osteoporosis is an area suitable for digital health interventions. While fracture liaison services (FLSs) are proven to greatly improve care for people with osteoporosis, such services might benefit from technologies that enhance automation. The term 'Digital Health' covers a variety of different tools including clinical decision support systems, electronic medical record tools, patient decision aids, patient apps, education tools, and novel artificial intelligence (AI) algorithms. Within the scope of this review are AI solutions that use algorithms within health system registries to target interventions. Clinician-targeted, patient-targeted, or system-targeted digital health interventions could be used to improve management and prevent fragility fractures. This review was commissioned by The Royal Osteoporosis Society and Bone Research Academy during the production of the 2020 Research Roadmap (https://theros.org.uk), with the intention of identifying gaps where targeted research funding could lead to improved patient health. We explore potential uses of digital technology in the general management of osteoporosis. Evidence suggests that digital technologies can support multidisciplinary teams to provide the best possible patient care based on current evidence and to support patients in self-management. However, robust randomised controlled studies are still needed to assess the effectiveness and cost-effectiveness of these technologies.

UK clinical guideline for the prevention and treatment of osteoporosis.

The National Osteoporosis Guideline Group (NOGG) has revised the UK guideline for the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. Accredited by NICE, this guideline is relevant for all healthcare professionals involved in osteoporosis management. INTRODUCTION: The UK National Osteoporosis Guideline Group (NOGG) first produced a guideline on the prevention and treatment of osteoporosis in 2008, with updates in 2013 and 2017. This paper presents a major update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. METHODS: Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence. RESULTS: Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment and intervention thresholds, management of vertebral fractures, non-pharmacological and pharmacological treatments, including duration and monitoring of anti-resorptive therapy, glucocorticoid-induced osteoporosis, and models of care for fracture prevention. Recommendations are made for training; service leads and commissioners of healthcare; and for review criteria for audit and quality improvement. CONCLUSION: The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals involved in its management. This position paper has been endorsed by the International Osteoporosis Foundation and by the European Society for the Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.

Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density.

Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 µg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a -0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (-4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise.

The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF-family receptor-α2 (GFRα2) and its ligand, neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects.