Search

We describe the physical function in adults with osteogenesis imperfecta (OI) and explored clinical and non-clinical factors related to its impairment. Our data showed that physical dysfunction is a common feature of adults with OI, varying by OI severity, and mediated by the presence and quality of pain and fatigue symptoms., Introduction: There is a paucity of data describing physical function in adults with osteogenesis imperfecta (OI). We investigated the effects of OI and its severity on physical function and explored the relationship between physical function and number of fractures and symptomatology., Methods: Adults with OI of different types were recruited from the RUDY study, an ongoing UK-based prospective cohort study. Participants completed demographic and clinical questions and questionnaires. These assessed physical function (SF-36), mobility (EQ-5D-5L and NEADL), fatigue (FACIT-F), and pain (SF-MQ-2). Scores were compared using parametric or non-parametric statistical analyses, whereas correlations between outcomes were examined using univariate and multivariate regression analysis., Results: Seventy-eight adults with OI aged 43.5 ± 14.5 years were enrolled (type I, 32; type III, 11; type IV, 10; unknown type, 26). Physical function (PCS, SF-36) was significantly lower in all participants than normative values (p < 0.001) and in type III than type I (p = 0.008). Mobility was significantly different across the types (EQ-5D-EL, p = 0.007; NEADL, p < 0.001), with type III having more severe problems, followed by types IV, unknown, and I. Physical function was associated with OI type (r = 0.26; p = 0.021), presence and quality of pain (r = - 0.57; p < 0.0001), and fatigue (r = - 0.51; p < 0.0001). Multivariate analysis revealed that physical function correlated independently with age, OI type, fatigue, and non-neuropathic pain., Conclusions: Individuals with OI display a marked deterioration in physical function during adulthood. This impairment varies in severity according to the OI phenotype and is associated with the presence of non-neuropathic pain and fatigue.

Controlling the excessive fracture burden in patients with chronic kidney disease (CKD) Stages G4-G5D remains an impressive challenge. The reasons are 2-fold. First, the pathophysiology of bone fragility in patients with CKD G4-G5D is complex and multifaceted, comprising a mixture of age-related (primary male/postmenopausal), drug-induced and CKD-related bone abnormalities. Second, our current armamentarium of osteoporosis medications has not been developed for, or adequately studied in patients with CKD G4-G5D, partly related to difficulties in diagnosing osteoporosis in this specific setting and fear of complications. Doubts about the optimal diagnostic and therapeutic approach fuel inertia in daily clinical practice. The scope of the present consensus paper is to review and update the assessment and diagnosis of osteoporosis in patients with CKD G4-G5D and to discuss the therapeutic interventions available and the manner in which these can be used to develop management strategies for the prevention of fragility fracture. As such, it aims to stimulate a cohesive approach to the management of osteoporosis in patients with CKD G4-G5D to replace current variations in care and treatment nihilism., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

In a global survey of fracture liaison services, most reported that DXA access met needs. However, adherence to basic DXA quality and reporting procedures was confirmed by only around 50% of institutions and many required education for operators/interpreters. Overall, there is significant variability in the access to, and quality of, DXA services worldwide., Introduction: While the use of dual-energy X-ray absorptiometry (DXA) has been widely adopted worldwide for the assessment of bone mineral density, the quality of DXA facilities is unknown. To address this, a global survey of fracture liaison services (FLS) was conducted by the International Society for Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) to assess the quality of their DXA facilities., Methods: A questionnaire for the accessibility and quality of DXA services was co-created by representatives of the ISCD and the IOF and made available to institutions who participated in the Capture the Fracture Best Practice Framework. From a list of 331 contacted invitees, 124 FLS centres responded; analyses were based on 121 centres with suitable data., Results: Over 70% of institutions reported that, for over 90% of the time, DXA access met service needs, and the scanning/reporting quality was perceived as excellent. However, 25% of DXA facilities reported not being accredited by a professional/governmental organization, and adherence to some basic DXA quality assurance and reporting procedures was confirmed by < 50% of services. Importantly, in excess of 50% of institutions stated that they desired ongoing education in osteoporosis and DXA for operators and interpreters., Conclusion: There is significant variability in the access to and quality of DXA services for established FLS worldwide. Despite two decades of training initiatives in osteoporosis densitometry, many centres are falling short of the standards of the IOF-ISCD Osteoporosis Essentials criteria.

Objective: High bone mass (HBM) is associated with an increased prevalence of radiographic knee OA (kOA), characterized by osteophytosis. We aimed to determine if progression of radiographic kOA, and its sub-phenotypes, is increased in HBM and whether observed changes are clinically relevant., Design: A cohort with and without HBM (L1 and/or total hip bone mineral density Z-score≥+3.2) had knee radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Medial/lateral tibial/femoral osteophyte and medial/lateral joint space narrowing (JSN) grades were summed and Δosteophytes, ΔJSN derived. Pain, function and stiffness were quantified using the WOMAC questionnaire. Associations between HBM status and sub-phenotype progression were determined using multivariable linear/poisson regression, adjusting for age, sex, height, baseline sub-phenotype grade, menopause, education and total body fat mass (TBFM). Generalized estimating equations accounted for individual-level clustering., Results: 169 individuals had repeated radiographs, providing 330 knee images; 63% had HBM, 73% were female, mean (SD) age was 58 (12) years. Whilst HBM was not clearly associated with overall Kellgren-Lawrence measured progression (RR = 1.55 [0.56.4.32]), HBM was positively associated with both Δosteophytes and ΔJSN individually (adjusted mean differences between individuals with and without HBM 0.45 [0.01.0.89] and 0.15 [0.01.0.29], respectively). HBM individuals had higher WOMAC knee pain scores (β = 7.42 [1.17.13.66]), largely explained by adjustment for osteophyte score (58% attenuated) rather than JSN (30% attenuated) or TBFM (16% attenuated). The same pattern was observed for symptomatic stiffness and functional limitation., Conclusions: HBM is associated with osteophyte progression, which appears to contribute to increased reported pain, stiffness and functional loss., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

This paper demonstrates a large post-fracture anti-osteoporosis treatment gap in the period 2005 to 2015. The gap was stable in Denmark at around 88-90%, increased in Catalonia from 80 to 88%, and started to increase in the UK towards the end of our study. Improved post-fracture care is needed., Introduction: Patients experiencing a fragility fracture are at high risk of subsequent fractures, particularly within the first 2 years after the fracture. Previous studies have demonstrated that only a small proportion of fracture patients initiate therapy with an anti-osteoporotic medication (AOM), despite the proven fracture risk reduction of such therapies. The aim of this paper is to evaluate the changes in this post-fracture treatment gap across three different countries from 2005 to 2015., Methods: This analysis, which is part of a multinational cohort study, included men and women, aged 50 years or older, sustaining a first incident fragility fracture. Using routinely collected patient data from three administrative health databases covering Catalonia, Denmark, and the United Kingdom, we estimated the treatment gap as the proportion of patients not treated with AOM within 1 year of their first incident fracture., Results: A total of 648,369 fracture patients were included. Mean age 70.2-78.9 years; 22.2-31.7% were men. In Denmark, the treatment gap was stable at approximately 88-90% throughout the 2005 to 2015 time period. In Catalonia, the treatment gap increased from 80 to 88%. In the UK, an initially decreasing treatment gap-though never smaller than 63%-was replaced by an increasing gap towards the end of our study. The gap was more pronounced in men than in women., Conclusion: Despite repeated calls for improved secondary fracture prevention, an unacceptably large treatment gap remains, with time trends indicating that the problem may be getting worse in recent years.

Objectives: Fibromyalgia is a complex, debilitating, multifactorial condition that can be difficult to manage. Recommended treatments are usually delivered in outpatient settings; evidence suggests that significant inpatient care occurs. We describe the scale and cost of inpatient care with a primary diagnostic code of fibromyalgia within the English National Health Service., Methods: We conducted a cohort-level observational study of all patients admitted to hospital due to a diagnosis of fibromyalgia, between 1 April 2014 and 31 March 2018 inclusive, in the National Health Service in England. We used data from Hospital Episode Statistics Admitted Patient Care to study: the age and sex of patients admitted, number and costs of admissions, length of stay, procedures undertaken, class and type of admission, and distribution of admissions across clinical commissioning groups., Results: A total of 24 295 inpatient admissions, costing £20 220 576, occurred during the 4-year study period. Most patients were women (89%) with peak age of admission of between 45 and 55 years. Most admissions were elective (92%). A number of invasive therapeutic procedures took place, including a continuous i.v. infusion (35%). There was marked geographical variation in the prevalence and cost of inpatient fibromyalgia care delivered across the country, even after accounting for clinical commissioning group size., Conclusions: Many patients are admitted for treatment of their fibromyalgia and given invasive procedures for which there is weak evidence, with significant variation in practice and cost across the country. This highlights the need to identify areas of resource use that can be rationalized and diverted to provide more effective, evidence-based treatment., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The International Osteoporosis Foundation (IOF) Capture the Fracture® Campaign with the Fragility Fracture Network (FFN) and National Osteoporosis Foundation (NOF) has developed eleven patient-level key performance indicators (KPIs) for fracture liaison services (FLSs) to guide quality improvement., Introduction: Fracture Liaison Services (FLSs) are recommended worldwide to reduce fracture risk after a sentinel fracture. Given not every FLS is automatically effective, the IOF Capture the Fracture working group has developed and implemented the Best Practice Framework to assess the organisational components of an FLS. We have now developed a complimentary KPI set that extends this assessment of performance to the patient level., Methods: The Capture the Fracture working group in collaboration with the Fragility Fracture Network Secondary Fragility Fracture Special Interest Group and National Osteoporosis Foundation adapted existing metrics from the UK-based Fracture Liaison Service Database Audit to develop a patient-level KPI set for FLSs., Results: Eleven KPIs were selected. The proportion of patients: with non-spinal fractures; with spine fractures (detected clinically and radiologically); assessed for fracture risk within 12 weeks of sentinel fracture; having DXA assessment within 12 weeks of sentinel fracture; having falls risk assessment; recommended anti-osteoporosis medication; commenced of strength and balance exercise intervention within 16 weeks of sentinel fracture; monitored within 16 weeks of sentinel fracture; started anti-osteoporosis medication within 16 weeks of sentinel fracture; prescribed anti-osteoporosis medication 52 weeks after sentinel fracture. The final KPI measures data completeness for each of the other KPIs. For these indicators, levels of achievement were set at the < 50%, 50-80% and > 80% levels except for treatment recommendation where a level of 50% was used., Conclusion: This KPI set compliments the existing Best Practice Framework to support FLSs to examine their own performance using patient-level data. By using this KPI set for local quality improvement cycles, FLSs will be able to efficiently realise the full potential of secondary fracture prevention and improved clinical outcomes for their local populations.

This study aimed to determine if having an overweight or obese range body mass index (BMI) at time of beginning school is associated with increased fracture incidence in childhood. A dynamic cohort was created from children presenting for routine preschool primary care screening, collected in the Information System for Research in Primary Care (SIDIAP) platform in Catalonia, Spain. Data were collected from 296 primary care centers representing 74% of the regional pediatric population. A total of 466,997 children (48.6% female) with a validated weight and height measurement within routine health care screening at age 4 years (±6 months) between 2006 and 2013 were included, and followed up to the age of 15, migration out of region, death, or until December 31, 2016. BMI was calculated at age 4 years and classified using WHO growth tables, and fractures were identified using previously validated ICD10 codes in electronic primary care records, divided by anatomical location. Actuarial lifetables were used to calculate cumulative incidence. Cox regression was used to investigate the association of BMI category and fracture risk with adjustment for socioeconomic status, age, sex, and nationality. Median follow-up was 4.90 years (interquartile range [IQR] 2.50 to 7.61). Cumulative incidence of any fracture during childhood was 9.20% (95% confidence interval [CI] 3.79% to 14.61%) for underweight, 10.06% (9.82% to 10.29%) for normal weight, 11.28% (10.22% to 12.35%) for overweight children, and 13.05% (10.69% to 15.41%) for children with obesity. Compared with children of normal range weight, having an overweight and obese range BMI was associated with an excess risk of lower limb fracture (adjusted hazard ratio [HR] = 1.42 [1.26 to 1.59]; 1.74 [1.46 to 2.06], respectively) and upper limb fracture (adjusted HR = 1.10 [1.03 to 1.17]; 1.19 [1.07 to 1.31]). Overall, preschool children with an overweight or obese range BMI had increased incidence of upper and lower limb fractures in childhood compared with contemporaries of normal weight. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research., (© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)

Bisphosphonates are contraindicated in moderate-to-severe chronic kidney disease patients. However, they are used to prevent fragility fractures in patients with impaired kidney function, despite a lack of evidence on their effects on bone density in these patients. We demonstrated that Alendronate had a positive effect on bone in these patients., Purpose: This study aimed to assess the association between alendronate use and bone mineral density (BMD) change in subjects with moderate-severe chronic kidney disease (CKD)., Methods: We created a cohort of CKD stage 3B-5 patients by linking all DXA-based measurements in the Funen area, Denmark, to biochemistry, national health registries and filled prescriptions. Exposure was dispensation of alendronate and the outcome was annualized percentage change in BMD at the femoral neck, total hip and lumbar spine. Individuals were followed from first BMD to the latest of subsequent DXA measurements. Alendronate non-users were identified using incidence density sampling and matched groups were created using propensity scores. Linear regression was used to estimate average differences in the annualized BMD., Results: Use of alendronate was rare in this group of patients: propensity score matching (PSM) resulted in 71 alendronate users and 142 non-users with stage 3B-5 CKD (as in the 1 year before DXA). Whilst alendronate users gained an average 1.07% femoral neck BMD per year, non-users lost an average of 1.59% per annum. The PSM mean differences in annualized BMD were + 2.65% (1.32%, 3.99%), + 3.01% (1.74%, 4.28%) and + 2.12% (0.98%, 3.25%) at the femoral neck, total hip and spine BMD, respectively, all in favour of alendronate users., Conclusion: In a real-world cohort of women with stage 3B-5 CKD, use of alendronate appears associated with a significant improvement of 2-3% per year in the femoral neck, total hip and spine BMD. More data are needed on the anti-fracture effectiveness and safety of bisphosphonate therapy in moderate-severe CKD.

Background: Osteogenesis imperfecta, fibrous dysplasia/McCune-Albright syndrome and X-linked hypophosphatemia are three rare musculoskeletal diseases characterised by bone deformities, frequent fractures and pain. Little high-quality research exists on appropriate treatment and long-term management of these conditions in adults. This is further worsened by limited research funding in rare diseases and a general mismatch between the existing research priorities and those of the patients. This partnership adopted the James Lind Alliance approach to identify the top 10 research priorities for rare musculoskeletal diseases in adults through joint patient, carer and healthcare professional collaboration., Results: The initial survey for question collection recruited 198 respondents, submitting a total of 988 questions. 77% of the respondents were patients with a rare musculoskeletal disease. Following out-of-scope question exclusion, repeating query grouping and scientific literature check for answers, 39 questions on treatment and long-term management remained. In the second public survey, 220 respondents, of whom 85% were patients with a rare musculoskeletal disease, their carers, relatives or friends, prioritised these uncertainties, which allowed selection of the top 25. In the last stage, patients, carers and healthcare professionals gathered for a priority setting workshop to reach a consensus on the final top 10 research priorities. These focus on the uncertainties surrounding appropriate treatment and holistic long-term disease management, highlighting several aspects indirect to abnormal bone metabolism, such as extra-skeletal symptoms, psychological care of both patients and their families and disease course through ageing., Conclusions: This James Lind Alliance priority setting partnership is the first to investigate rare bone diseases. The priorities identified here were developed jointly by patients, carers and healthcare professionals. We encourage researchers, funding bodies and other stakeholders to use these priorities in guiding future research for those affected by rare musculoskeletal disorders.

Oral bisphosphonates (oBPs) have been associated with reduced fractures and mortality. However, their risks and benefits are unclear in patients with moderate-severe CKD. This study examined the association between oBPs and all-cause mortality in G3B-5D CKD. This is a population-based cohort study including all subjects with an estimated glomerular filtration rate (eGFR) <45/mL/min/1.73 m 2 (G3B: eGFR <45/mL/min/1.73 m 2 G4: eGFR 15-29/mL/min/1.73 m 2 G5: eGFR <15/mL/min/1.73 m 2 G5D: hemodialysis) aged 40+ years from the UK Clinical Practice Research Datalink (CPRD) and the Catalan Information System for Research in Primary Care (SIDIAP). Previous and current users of other anti-osteoporosis drugs were excluded. oBP use was modeled as a time-varying exposure to avoid immortal time bias. Treatment episodes in oBP users were created by concatenating prescriptions until patients switched or stopped therapy or were censored or died. A washout period of 180 days was added to (date of last prescription +180 days). Propensity scores (PSs) were calculated using prespecified predictors of mortality including age, gender, baseline eGFR, socioeconomic status, comorbidities, previous fracture, co-medications, and number of hospital admissions in the previous year. Cox models were used for PS adjustment before and after PS trimming (the first and last quintiles). In the CPRD, of 19,351 oBP users and 210,954 non-oBP users, 5234 (27%) and 85,105 (40%) deaths were recorded over 45,690 and 915,867 person-years of follow-up, respectively. oBP users had 8% lower mortality risk compared to non-oBP users (hazard ratio [HR] 0.92; 95% CI, 0.89 to 0.95). Following PS trimming, this became nonsignificant (HR 0.98; 95% CI, 0.94 to 1.04). In the SIDIAP, of 4146 oBP users and 86,127 non-oBP users, 1330 (32%) and 36,513 (42%) died, respectively. oBPs were not associated with mortality in PS adjustment and trimming (HR 1.04; 95% CI, 0.99 to 1.1 and HR 0.95; 95% CI, 0.89 to 1.01). In this observational, patient-based cohort study, oBPs were not associated with increased mortality among patients with moderate-severe CKD. However, further studies are needed on other effects of oBPs in CKD patients. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five countries of the European Union plus Sweden (EU6). In 2017, new fragility fractures in the EU6 are estimated at 2.7 million with an associated annual cost of €37.5 billion and a loss of 1.0 million quality-adjusted life years., Introduction: Osteoporosis is characterized by reduced bone mass and strength, which increases the risk of fragility fractures, which in turn, represent the main consequence of the disease. This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five EU countries and Sweden (designated the EU6)., Methods: A series of metrics describing the burden and management of fragility fractures were defined by a scientific steering committee. A working group performed the data collection and analysis. Data were collected from current literature, available retrospective data and public sources. Different methods were applied (e.g. standard statistics and health economic modelling), where appropriate, to perform the analysis for each metric., Results: Total fragility fractures in the EU6 are estimated to increase from 2.7 million in 2017 to 3.3 million in 2030; a 23% increase. The resulting annual fracture-related costs (€37.5 billion in 2017) are expected to increase by 27%. An estimated 1.0 million quality-adjusted life years (QALYs) were lost in 2017 due to fragility fractures. The current disability-adjusted life years (DALYs) per 1000 individuals age 50 years or more were estimated at 21 years, which is higher than the estimates for stroke or chronic obstructive pulmonary disease. The treatment gap (percentage of eligible individuals not receiving treatment with osteoporosis drugs) in the EU6 is estimated to be 73% for women and 63% for men; an increase of 17% since 2010. If all patients who fracture in the EU6 were enrolled into fracture liaison services, at least 19,000 fractures every year might be avoided., Conclusions: Fracture-related burden is expected to increase over the coming decades. Given the substantial treatment gap and proven cost-effectiveness of fracture prevention schemes such as fracture liaison services, urgent action is needed to ensure that all individuals at high risk of fragility fracture are appropriately assessed and treated.

Background: X-linked hypophosphatemia (XLH) is a rare multisystemic disease with a prominent musculoskeletal phenotype. We aim here to improve understanding of the prevalence of XLH across the life course and of overall survival among people with XLH., Methods: This was a population-based cohort study using a large primary care database in the United Kingdom (UK) from 1995 to 2016. XLH cases were matched by age, gender, and practice to up to 4 controls. Trends in prevalence over the study period were estimated (stratified by age) and survival among cases was compared with that of controls., Findings: From 522 potential cases, 122 (23.4%) were scored as at least possible XLH, while 62 (11.9%) were classified as highly likely or likely (conservative definition). In main analyses, prevalence (95% CI) increased from 3.1 (1.5-6.7) per million in 1995-1999 to 14.0 (10.8-18.1) per million in 2012-2016. Corresponding estimates using the conservative definition were 3.0 (1.4-6.5) to 8.1 (5.8-11.4). Nine (7.4%) of the possible cases died during follow-up, at median age of 64 years. Fourteen (2.9%) of the controls died at median age of 72.5 years. Mortality was significantly increased in those with possible XLH compared with controls (hazard ratio [HR] 2.93; 95% CI, 1.24-6.91). Likewise, among those with likely or highly likely XLH (HR 6.65; 1.44-30.72)., Conclusions: We provide conservative estimates of the prevalence of XLH in children and adults within the UK. There was an unexpected increase in mortality in later life, which may have implications for other fibroblast growth factor 23-related disorders., (© Endocrine Society 2019.)

The trial compared three physiotherapy approaches: manual or exercise therapy compared with a single session of physiotherapy education (SSPT) for people with osteoporotic vertebral fracture(s). At 1 year, there were no statistically significant differences between the groups meaning there is inadequate evidence to support manual or exercise therapy., Introduction: To evaluate the clinical and cost-effectiveness of different physiotherapy approaches for people with osteoporotic vertebral fracture(s) (OVF)., Methods: >Prospective, multicentre, adaptive, three-arm randomised controlled trial. Six hundred fifteen adults with back pain, osteoporosis, and at least 1 OVF participated., Interventions: 7 individual physiotherapy sessions over 12 weeks focused on either manual therapy or home exercise compared with a single session of physiotherapy education (SSPT). The co-primary outcomes were quality of life and back muscle endurance measured by the QUALEFFO-41 and timed loaded standing (TLS) test at 12 months., Results: At 12 months, there were no statistically significant differences between groups. Mean QUALEFFO-41: - 1.3 (exercise), - 0.15 (manual), and - 1.2 (SSPT), a mean difference of - 0.2 (95% CI, - 3.2 to 1.6) for exercise and 1.3 (95% CI, - 1.8 to 2.9) for manual therapy. Mean TLS: 9.8 s (exercise), 13.6 s (manual), and 4.2 s (SSPT), a mean increase of 5.8 s (95% CI, - 4.8 to 20.5) for exercise and 9.7 s (95% CI, 0.1 to 24.9) for manual therapy. Exercise provided more quality-adjusted life years than SSPT but was more expensive. At 4 months, significant changes above SSPT occurred in endurance and balance in manual therapy, and in endurance for those ≤ 70 years, in balance, mobility, and walking in exercise., Conclusions: Adherence was problematic. Benefits at 4 months did not persist and at 12 months, we found no significant differences between treatments. There is inadequate evidence a short physiotherapy intervention of either manual therapy or home exercise provides long-term benefits, but arguably short-term benefits are valuable., Trial Registration: ISRCTN 49117867.

Purpose of Review: This review sought to describe quality improvement initiatives in fragility fracture care and prevention., Recent Findings: A major care gap persists throughout the world in the secondary prevention of fragility fractures. Systematic reviews have confirmed that the Fracture Liaison Service (FLS) model of care is associated with significant improvements in rates of bone mineral density testing, initiation of osteoporosis treatment and adherence with treatment for individuals who sustain fragility fractures. Further, these improvements in the processes of care resulted in significant reductions in refracture risk and lower post-fracture mortality. The primary challenge facing health systems now is to ensure that best practice is delivered effectively in the local healthcare setting. Publication of clinical standards for FLS at the organisational and patient level in combination with the establishment of national registries has provided a mechanism for FLS to benchmark and improve their performance. Major efforts are ongoing at the global, regional and national level to improve the acute care, rehabilitation and secondary prevention for individuals who sustain fragility fractures. Active participation in these initiatives has the potential to eliminate current care gaps in the coming decade.

Objective: Rheumatoid factor (RF) testing is used in primary care in the diagnosis of rheumatoid arthritis (RA); however a positive RF may occur without RA. Incorrect use of RF testing may lead to increased costs and delayed diagnoses. The aim was to assess the performance of RF as a test for RA and to estimate the costs associated with its use in a primary care setting., Material and Methods: A retrospective cohort study using the Information System for the Development of Research in Primary Care database (contains primary care records and laboratory results of >80% of the Catalonian population, Spain). Participants were patients ≥18 years with ≥1 RF test performed between 01/01/2006 and 31/12/2011, without a pre-existing diagnosis of RA. Outcome measures were an incident diagnosis of RA within 1 year of testing, and the cost of testing per case of RA., Results: 495,434/4,796,498 (10.3%) patients were tested at least once. 107,362 (21.7%) of those tested were sero-positive of which 2768 (2.6%) were diagnosed with RA within 1 year as were 1141/388,072 (0.3%) sero-negative participants. The sensitivity of RF was 70.8% (95% CI 69.4-72.2), specificity 78.7% (78.6-78.8), and positive and negative predictive values 2.6% (2.5-2.7) and 99.7% (99.6-99.7) respectively. Approximately €3,963,472 was spent, with a cost of €1432 per true positive case., Conclusions: Although 10% of patients were tested for RF, most did not have RA. Limiting testing to patients with a higher pre-test probability would significantly reduce the cost of testing., (Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Interactions between multiple myeloma (MM) and bone marrow (BM) are well documented to support tumour growth, yet the cellular mechanisms underlying pain in MM are poorly understood. We have used in vivo murine models of MM to show significant induction of nerve growth factor (NGF) by the tumour-bearing bone microenvironment, alongside other known pain-related characteristics such as spinal glial cell activation and reduced locomotion. NGF was not expressed by MM cells, yet bone stromal cells such as osteoblasts expressed and upregulated NGF when cultured with MM cells, or MM-related factors such as TNF-α. Adiponectin is a known MM-suppressive BM-derived factor, and we show that TNF-α-mediated NGF induction is suppressed by adiponectin-directed therapeutics such as AdipoRON and L-4F, as well as NF-κB signalling inhibitor BMS-345541. Our study reveals a further mechanism by which cellular interactions within the tumour-bone microenvironment contribute to disease, by promoting pain-related properties, and suggests a novel direction for analgesic development.

Background: A total of 25,000 people in the UK have osteoporotic vertebral fracture (OVF). Evidence suggests that physiotherapy may have an important treatment role., Objective: The objective was to investigate the clinical effectiveness and cost-effectiveness of two different physiotherapy programmes for people with OVF compared with a single physiotherapy session., Design: This was a prospective, adaptive, multicentre, assessor-blinded randomised controlled trial (RCT) with nested qualitative and health economic studies., Setting: This trial was based in 21 NHS physiotherapy departments., Participants: The participants were people with symptomatic OVF., Interventions: Seven sessions of either manual outpatient physiotherapy or exercise outpatient physiotherapy compared with the best practice of a 1-hour single session of physiotherapy (SSPT)., Main Outcome Measures: Outcomes were measured at 4 and 12 months. The primary outcomes were quality of life and muscle endurance, which were measured by the disease-specific QUALEFFO-41 (Quality of Life Questionnaire of the European Foundation for Osteoporosis - 41 items) and timed loaded standing (TLS) test, respectively. Secondary outcomes were (1) thoracic kyphosis angle, (2) balance, evaluated via the functional reach test (FRT), and (3) physical function, assessed via the Short Physical Performance Battery (SPPB), 6-minute walk test (6MWT), Physical Activity Scale for the Elderly, a health resource use and falls diary, and the EuroQol-5 Dimensions, five-level version., Results: A total of 615 participants were enrolled, with 216, 203 and 196 randomised by a computer-generated program to exercise therapy, manual therapy and a SSPT, respectively. Baseline data were available for 613 participants, 531 (86.6%) of whom were women; the mean age of these participants was 72.14 years (standard deviation 9.09 years). Primary outcome data were obtained for 69% of participants (429/615) at 12 months: 175 in the exercise therapy arm, 181 in the manual therapy arm and 173 in the SSPT arm. Interim analysis met the criteria for all arms to remain in the study. For the primary outcomes at 12 months, there were no significant benefits over SSPT of exercise [QUALEFFO-41, difference -0.23 points, 95% confidence interval (CI) -3.20 to 1.59 points; p  = 1.000; and TLS test, difference 5.77 seconds, 95% CI -4.85 to 20.46 seconds; p  = 0.437] or of manual therapy (QUALEFFO-41, difference 1.35 points, 95% CI -1.76 to 2.93 points; p  = 0.744; TLS test, difference 9.69 seconds (95% CI 0.09 to 24.86 seconds; p  = 0.335). At 4 months, there were significant gains for both manual therapy and exercise therapy over SSPT in the TLS test in participants aged < 70 years. Exercise therapy was superior to a SSPT at 4 months in the SPPB, FRT and 6MWT and manual therapy was superior to a SSPT at 4 months in the TLS test and FRT. Neither manual therapy nor exercise therapy was cost-effective relative to a SSPT using the threshold of £20,000 per quality-adjusted life-year. There were no treatment-related serious adverse events., Conclusions: This is the largest RCT to date assessing physiotherapy in participants with OVFs. At 1 year, neither treatment intervention conferred more benefit than a single 1-hour physiotherapy advice session. The focus of future work should be on the intensity and duration of interventions to determine if changes to these would demonstrate more sustained effects., Trial Registration: Current Controlled Trials ISRCTN49117867., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 44. See the NIHR Journals Library website for further project information., Competing Interests: Sarah E Lamb reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme during the conduct of the study and was a member of the following boards: HTA Additional Capacity Funding Board (2012–15), HTA Clinical Trials Board (2010–15), HTA End of Life Care and Add on Studies (2015), HTA Funding Boards Policy Group (previously Commissioning Strategy Group) (2010–15), HTA Maternal, Neonatal and Child Health Methods Group (2013–15), HTA Post-board funding teleconference (Prioritisation Group members to attend) (2010–15), HTA Primary Care Themed Call board (2013–14), HTA Prioritisation Group (2010–15) and NIHR Clinical Trials Unit Standing Advisory Committee (2012–16). Muhammad K Javaid reports personal fees from Optasia Medical Ltd (Cheadle, UK) and Zebra Medical Vision, Inc. (Shefayim, Israel) outside the submitted work. Cyrus Cooper reports personal fees from Alliance for Better Health (Troy, NY, USA), Amgen Inc. (Thousand Oaks, CA, USA), Eli Lilly and Company (Indianapolis, IN, USA), GlaxoSmithKline plc (Middlesex, UK), Medtronic (Watford, UK), Merck & Co. Inc. (Kenilworth, NJ, USA), Novartis Pharmaceuticals UK Ltd (Frimley, UK), Pfizer Inc. (New York, NY, USA), F. Hoffman-La Roche Ltd (Basel, Switzerland), Servier Laboratories Limited (Stoke Poges, UK), Takeda UK Ltd (Wooburn Green, UK) and UCB Pharma (Brussels, Belgium).

Multiple myeloma, the second most frequent blood cancer, and its precursor, monoclonal gammopathy of uncertain significance, are associated with an increased risk of fragility fractures. However, current guidelines fail to offer explicit indications for healthcare professionals in terms of testing and thresholds for onward referral. The purpose of this review is to present the association of these conditions and metabolic bone disease and to highlight the importance of considering a diagnosis of monoclonal gammopathy of uncertain significance and myeloma in the context of a secondary fracture prevention assessment and of a multidisciplinary approach in managing these patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Fibrous Dysplasia / McCune Albright syndrome (FD/MAS) represents a wide spectrum of diseases due to somatic gain-of-function mutations of the GNAS gene. The mutation leads to overactivity in the target tissues and to a wide phenotype of clinical features that vary in severity and age of onset. The rarity of the disease and its variable presentation to multiple specialities often leads to misdiagnosis and inappropriate variability in investigations and treatments. To address this, our international consortium of clinicians, researchers, and patients' advocates has developed pragmatic clinical guidelines for best clinical practice for the definition, diagnosis, staging, treatment and monitoring for FD/MAS to empower patients and support clinical teams in both general and specialised healthcare settings. With the lack of strong evidence to inform care, the guidelines were developed based on review of published literature, long-standing extensive experience of authors, input from other healthcare professionals involved in the care of FD/MAS patients and feedback from patients and patient groups across the globe. This has led to the formulation of a set of statements to inform healthcare professionals, patients, their families, carers and patient groups of the best practice of care. It is anticipated the implementation of these recommendations will lead to improvement in the care of patients with FD/MAS internationally.

Background: Multiple myeloma (MM) is associated with high healthcare resource utilisation and increasing hospitalisation rates. The aim of this study was to characterise the hospital use by patients with MM in the English National Health Service (NHS)., Methods: Routinely-collected aggregate data about all NHS-funded hospital admissions of patients with MM were analysed. Data were obtained from the English Hospital Episodes Statistics on admissions between 1 April 2014 and 31 March 2018., Results: A total of 754,345 admissions were reported over four years, equivalent to a mean of 188,586 admissions per year. Of the 41,845 patients admitted during this period, 42% were women and 58% men. From the total admissions, 90% were elective and 10% unplanned. Mean annual estimated costs over the period were £46 million for elective and £56 million for unplanned admissions. The number of elective admissions increased by 4.5% with costs increasing 1.5% per year; for unplanned admissions, these figures were 4.1% and 9.0%, respectively., Conclusions: MM is associated with a significant number of hospital admissions and NHS costs. The majority of the hospital admissions are elective, but the highest burden in terms of costs relates to unplanned admissions, with numbers increasing over time.

Objective: The neural mechanisms of pain in knee osteoarthritis (OA) are not fully understood, and some patients have neuropathic-like pain associated with central sensitization. To address this, we undertook the present study in order to identify central sensitization using neuroimaging and PainDETECT and to relate it to postarthroplasty outcome., Methods: Patients awaiting arthroplasty underwent quantitative sensory testing, psychological assessment, and functional magnetic resonance imaging (fMRI). Neuroimaging (fMRI) was conducted during punctate stimulation (n = 24) and cold stimulation (n = 20) to the affected knee. The postoperative outcome was measured using the Oxford Knee Score, patient-reported moderate-to-severe long-term pain postarthroplasty, and a range of pain-related questionnaires., Results: Patients with neuropathic-like pain presurgery (identified using PainDETECT; n = 14) reported significantly higher pain in response to punctate stimuli and cold stimuli near the affected joint (P < 0.05). Neural activity in these patients, compared to those without neuropathic-like pain, was significantly lower in the rostral anterior cingulate cortex (P < 0.05) and higher in the rostral ventromedial medulla (RVM) during punctate stimulation (P < 0.05), with significant functional connectivity between these two areas (r = 0.49, P = 0.018). Preoperative neuropathic-like pain and higher neural activity in the RVM were associated with moderate-to-severe long-term pain after arthroplasty (P = 0.0356)., Conclusion: The psychophysical and neuroimaging data suggest that a subset of OA patients have centrally mediated pain sensitization. This was likely due to supraspinally mediated reductions in inhibition and increases in facilitation of nociceptive signaling, and was associated with a worse outcome following arthroplasty. The neurobiologic confirmation of central sensitization in patients with features of neuropathic pain, identified using PainDETECT, provides further support for the investigation of such bedside measures for patient stratification, to better predict postsurgical outcomes., (© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

An evidence-based clinical guideline for the diagnosis and management of Paget's disease of bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget's Association (UK). A systematic review of diagnostic tests and pharmacological and nonpharmacological treatment options was conducted that sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made, but there was insufficient evidence to address eight of the questions posed. The following recommendations were identified as the most important: 1) Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of metabolically active disease in patients with PDB. 2) Serum total alkaline phosphatase (ALP) is recommended as a first-line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB. 3) Bisphosphonates are recommended for the treatment of bone pain associated with PDB. Zoledronic acid is recommended as the bisphosphonate most likely to give a favorable pain response. 4) Treatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalizing total ALP in PDB. 5) Total hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical approach over another. The guideline was endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society. The GDG noted that there had been a lack of research on patient-focused clinical outcomes in PDB and identified several areas where further research was needed. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc., (© 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.)

We have previously demonstrated inverse associations between maternal 25(OH)-vitamin D status and perinatal DNA methylation at the retinoid-X-receptor-alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks' gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at -80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol-supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was -1.98% (95% CI, -3.65 to -0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer-related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc., (© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.)

A cause of hypophosphatemia is phosphate wasting disorders. Knowledge concerning mechanisms involved in phosphate wasting disorders has greatly increased in the last decade by the identification of phosphatonins, among them FGF-23. FGF-23 is a primarily bone derived factor decreasing renal tubular reabsorption of phosphate and the synthesis of calcitriol. Currently, pharmacological treatment of these disorders offers limited efficacy and is potentially associated to gastrointestinal, renal, and parathyroid complications; therefore, efforts have been directed toward newer pharmacological strategies that target the FGF-23 pathway. This review focuses on phosphate metabolism, its main regulators, and phosphate wasting disorders in adults, highlighting the main issues related to diagnosis and current and new potential treatments.

We examined links between markers of social inequality and fracture risk in the Danish population, demonstrating that high income and being married are associated with a significantly lower risk., Introduction: We explored whether the risk of hip, humerus, and wrist fracture was associated with markers of inequality using data from Danish health registries., Methods: All patients 50 years or older with a primary hip (ICD10 S720, S721, S722, and S729) humerus (ICD10 S422, S423, S424, S425, S426, and S427), or wrist (ICD10: S52) fracture were identified from 1/1/1995 to 31/12/2011. Fracture patients were matched 1:1 by age, sex, and year of fracture, to a non-fracture control. Markers of inequality were as follows: income (fifths); marital status (married, divorced, widowed, or unmarried); area of residence (remote, rural, intermediate, or urban). Conditional logistic regression was used to investigate associations between these exposures, and risk of fracture, adjusting for covariates (smoking, alcohol, and Charlson co-morbidity). Interactions were fitted between exposure and covariates where appropriate., Results: A total of 189,838 fracture patients (37,500 hip, 45,602 humerus, and 106,736 wrist) and 189,838 controls were included. Mean age was 73.9 years (hip), 67.5 years (humerus), and 65.3 years (wrist). High income (5th quintile) was significantly associated with a lower odds ratio of all three fractures, compared to average income (3rd quintile). Married subjects had a significantly decreased odds ratio across all three fractures. However, no overall secular difference was observed regarding the influence of the markers of inequality., Conclusion: In conclusion, we have demonstrated important, stable associations between social inequality, assessed using income, marital status, and area of residence, and fracture at the population level. These findings can inform approaches to healthcare, and suggest that much thought should be given to novel interventions aimed especially at those living alone, and ideally societal measures to reduce social inequality.

1q24q25 deletions cause a distinctive phenotype including proportionate short stature, microcephaly, brachydactyly, dysmorphic facial features and intellectual disability. We present a mother and son who have a 672 kb microdeletion at 1q24q25. They have the typical skeletal features previously described but do not have any associated intellectual disability. We compare the genes within our patients' deletion to those in the deletions of previously reported cases. This indicates two genes that may be implicated in the intellectual disability usually associated with this deletion syndrome; PIGC and C1orf105. In addition, our cases provide supporting evidence to recent published work suggesting that the skeletal features may be linked to the microRNAs miR199 and miR214, encoded within intron 14 of the Dynamin-3 gene., (© 2018 Wiley Periodicals, Inc.)

To develop and validate a clinical prediction model of patient-reported pain and function after undergoing total knee replacement (TKR). We used data of 1,649 patients from the Knee Arthroplasty Trial who received primary TKR across 34 centres in the UK. The external validation included 595 patients from Southampton University Hospital, and Nuffield Orthopaedic Centre (Oxford). The outcome was the Oxford Knee Score (OKS) 12-month after TKR. Pre-operative predictors including patient characteristics and clinical factors were considered. Bootstrap backward linear regression analysis was used. Low pre-operative OKS, living in poor areas, high body mass index, and patient-reported anxiety or depression were associated with worse outcome. The clinical factors associated with worse outcome were worse pre-operative physical status, presence of other conditions affecting mobility and previous knee arthroscopy. Presence of fixed flexion deformity and an absent or damaged pre-operative anterior cruciate ligament (compared with intact) were associated with better outcome. Discrimination and calibration statistics were satisfactory. External validation predicted 21.1% of the variance of outcome. This is the first clinical prediction model for predicting self-reported pain and function 12 months after TKR to be externally validated. It will help to inform to patients regarding expectations of the outcome after knee replacement surgery.

The venous thromboembolism risk among anti-osteoporotics is unknown. In this primary care study, the risk with other bisphosphonates [1.05 (0.94-1.18) and 0.96 (0.78-1.18)], strontium [0.90 (0.61-1.34) and 1.19 (0.82-1.74)], in the UK and Spain respectively, and denosumab [1.77 (0.25-12.66)] and teriparatide [1.27 (0.59-2.71)] in Spain, did not differ versus alendronate., Introduction: Most of the known adverse drug reactions described for anti-osteoporosis medication (AOM) have been described in studies comparing AOM users to non-users. We aimed to compare the risk of venous thromboembolism (VTE) among incident users of different AOM compared to alendronate (first line therapy)., Methods: Two cohort studies were performed using data from the UK (CPRD) and Spain (BIFAP) primary care records separately. All patients aged ≥ 50 years with at least 1 year of data available and a new prescription or dispensation of AOM (date for therapy initiation) during 2000-2014 (CPRD) or 2001-2013 (BIFAP) were included. Users of raloxifene/bazedoxifene were excluded from both databases. Five exposure cohorts were identified according to first treatment: (1) alendronate, (2) other bisphosphonates, (3) strontium ranelate, (4) denosumab, and (5) teriparatide. Participants were followed from the day after therapy initiation to the earliest of a treated VTE (cases), end of AOM treatment (defined by a refill gap of 180 days), switching to an alternative AOM, drop-out, death, or end of study period. Incidence rates of VTE were estimated by cohort. Adjusted hazard ratios (HR 95%CI) were estimated according to drug used., Results: Overall, 2035/159,209 (1.28%) in CPRD and 401/83,334 (0.48%) in BIFAP had VTE. Compared to alendronate, adjusted HR of VTE were 1.05 (0.94-1.18) and 0.96 (0.78-1.18) for other bisphosphonates, and 0.90 (0.61-1.34) and 1.19 (0.82-1.74) for strontium in CPRD and BIFAP, respectively; 1.77 (0.25-12.66) for denosumab and 1.27 (0.59-2.71) for teriparatide in BIFAP., Conclusions: VTE risk during AO therapy did not differ by AOM drug use. Our data does not support an increased risk of VTE associated with strontium ranelate use in the community.

To develop consensus on improving the management of patients, we convened an international workshop involving patients, clinicians, and researchers. Key findings included the diagnostic delay and variability in subsequent management with agreement to develop an international natural history study. We now invite other stakeholders to join the partnership., Purpose: The aim of this study was develop a consensus on how to improve the management of patients with fibrous dysplasia and prioritize areas for research METHODS: An international workshop was held over 3 days involving patients, clinicians, and researchers. Each day had a combination of formal presentations and facilitated discussions that focused on clinical pathways and research., Results: The patient workshop day highlighted the variability of patients' experience in getting a diagnosis, the knowledge of general clinical staff, and understanding long-term outcomes. The research workshop prioritized collaborations that improved understanding of the contemporary natural history of fibrous dysplasia/McCune-Albright syndrome (FD/MAS). The clinical workshop outlined the key issues around diagnostics, assessment of severity, treatment and monitoring of patients., Conclusions: In spite of advances in understanding the genetic and molecular underpinnings of fibrous dysplasia/McCune-Albright syndrome, clinical management remains a challenge. From the workshop, a consensus was reached to create an international, multi-stakeholder partnership to advance research and clinical care in FD/MAS. We invite other stakeholders to join the partnership.

Patients with osteoporotic vertebral fractures are at increased risk of hip fracture. In a cohort of hip fracture patients, many had previous imaging studies showing incidental vertebral fractures. Fifty-four percent of fractures were not reported by the radiologist, highlighting a missed opportunity for diagnosing and treating osteoporosis, thereby preventing further fractures., Purpose: Patients with osteoporotic vertebral fragility fractures (VFFs) are at increased risk of future fractures, including hip fractures. Treating osteoporosis in these patients has the potential to reduce the risk of subsequent hip fractures, which are associated with high morbidity, mortality and cost. In this retrospective cohort study, we investigated the reporting and follow-up of VFFs evident on imaging by radiologists at the John Radcliffe Hospital, Oxford., Materials and Methods: Data from the local Fracture Liaison Service was used to case-find all incident hip fractures from 2013 presenting to the trust. We then identified patients who had also undergone a radiological procedure that included the thoracic and/or lumbar spine in the previous 6 years. All identified radiological images were re-examined for the presence of VFFs using the Genant semi-quantitative method., Results: Seven hundred and thirty-two patients over the age of 50 with a hip fracture in 2013 were identified. One hundred and fifty-seven patients had previously undergone a radiological procedure involving the spine, and VFFs were identified in 65/157 (41%). Of these, only 30/65 (46%) were reported by a radiologist when the fracture was first visible. 32/35 (91%) of unreported VFFs were from imaging reported by non-musculoskeletal radiologists. Only 16/65 (25%) of patients with a VFF were documented as being on bone-specific therapy at the time of hip fracture., Conclusions: Our study highlights the under-reporting of osteoporotic vertebral fractures, particularly by non-musculoskeletal radiologists. Better systems for reporting and referring osteoporotic VFFs are necessary to increase the number of patients receiving appropriate osteoporosis treatment.

Purpose This study was conducted in order to systematically review the costs of hip fractures globally and identify drivers of differences in costs. Methods A systematic review was conducted to identify studies reporting patient level fragility hip fracture costs between 1990 and 2015. We extracted data on the participants and costs from these studies. Cost data concerning the index hospitalisation were pooled, and a meta-regression was used to examine its potential drivers. We also pooled data on the first-year costs following hip fracture and considered healthcare, social care as well as other cost categories if reported by studies. Results One hundred and thirteen studies reported costs of hip fracture based on patient level data. Patients developing complications as well as patients enrolled in intervention arms of comparative studies were found to have significantly higher costs compared to the controls. The pooled estimate of the cost for the index hospitalisation was $10,075. Health and social care costs at 12 months were $43,669 with inpatient costs being their major driver. Meta-regression analysis identified age, gender and geographic region as being significantly associated with the differences in costs for the index hospitalisation. Conclusion Hip fracture poses a significant economic burden and variation exists in their costs across different regions. We found that there was a considerable variation across studies in terms of study design, methodology, follow-up period, costs considered and results reported that highlights the need for more standardisation in this area of research.

Objective: Positive associations between radiographic osteoarthritis (OA) and areal bone mineral density (BMD) have been demonstrated and appear strongest when bony features of OA are considered. To date, these associations have not been assessed using HRpQCT., Design: A total of 318 participants (170 men and 148 women), aged 72.1-81.4 years from a non-selected cohort, underwent HRpQCT of the distal radius and tibia along with hip radiography. Differences in bone microarchitecture were assessed between those with and without osteophytes, sclerosis or joint space narrowing (JSN) in either hip., Results: Men with osteophytes alone had significantly higher radial trabecular volumetric BMD (Tb.vBMD) and radial and tibial trabecular thickness (Tb.Th). Men with both sclerosis and osteophytes had significantly higher cortical volumetric BMD (Ct.vBMD) and cortical thickness (Ct.Th) at the distal tibia than those with osteophytes alone (P < 0.05). These relationships were maintained after adjustment for age and Body Mass Index (BMI), and were not replicated in women. Bone microarchitecture did not differ significantly in those with JSN from those without it in men or women., Conclusions: Our findings suggest higher Tb.vBMD and Tb.Th in men with osteophytosis but higher tibial Ct.vBMD and Ct.Th in men with hip joint sclerosis. These results do however require replication in other cohorts., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

The primary objective is the description of bone mineral density (BMD) and body composition in newly licensed jockeys. One in three male, flat jockeys has a very low bone mineral density. Further research is needed to assess the short-term risk of fractures and long-term health implications of these findings., Introduction: Describe bone mineral density (BMD) and body composition in entry-level male and female, flat and jump jockeys in Great Britain., Methods: Data was collected on jockeys applying for a professional jockey license between 2013 and 2015. Areal BMD at the spine, femoral neck (FN), total hip and body composition were assessed by dual-energy X-ray absorptiometry (DXA) scan. We examined differences between BMD and body composition by gender and race type (flat or jump). Volumetric bone mineral apparent density (BMAD) of the spine and FN was also calculated to account for group differences in bone size., Results: Seventy-nine male flat jockeys (age 18.5 ± 1.9, BMI 19.0 ± 1.4), 69 male jump (age 20.7 ± 2.0, BMI 20.6 ± 1.3) and 37 female flat jockeys (age 19.3 ± 2.0, BMI 20.8 ± 1.7) took part in this study. Spine BMD Z-scores ≤-2 for male flat, male jump and female flat jockeys were 29, 13 and 2.7%, respectively. Spine BMD was lower in male than female flat jockeys (p<0.001). All BMD scores were lower in male flat compared to male jump jockeys (p<0.001). Body fat percent (BF %) was lower in male flat jockeys compared to male jump and female flat jockeys (p<0.05). Lean mass index (LMI) was lower in male flat compared to male jump jockeys (p<0.001)., Conclusions: Male flat jockeys had a significantly lower BMD, LMI and BF% compared to jump jockeys and female flat jockeys. Male flat jockeys had lower spine BMD scores than females. Individual bone maturation may influence these findings. Further investigation into the relevance of low BMD and altered body composition on jockey health is required.

Context: Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation., Objective: To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation., Design: Within-randomization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation., Setting: Hospital antenatal clinics., Participants: In total, 682 women of white ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), and rs2282679 (GC) were genotyped., Interventions: 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery., Main Outcome Measure: 25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [β represents the change in 25(OH)D per additional common allele]., Results: Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [β = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (β = -5.2 nmol/L; 95% CI, -8.2 to -2.2 nmol/L; P = 0.001) and rs2282679 (GC) (β = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas rs12785878 and rs6013897 (CYP24A1) were not., Conclusions: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity., (Copyright © 2017 Endocrine Society)

Objectives: To assess the prevalences across Europe of radiological indices of degenerative inter-vertebral disc disease (DDD); and to quantify their associations with, age, sex, physical anthropometry, areal BMD (aBMD) and change in aBMD with time., Methods: In the population-based European Prospective Osteoporosis Study, 27 age-stratified samples of men and women from across the continent aged 50+ years had standardized lateral radiographs of the lumbar and thoracic spine to evaluate the severity of DDD, using the Kellgren-Lawrence (KL) scale. Measurements of anterior, mid-body and posterior vertebral heights on all assessed vertebrae from T4 to L4 were used to generate indices of end-plate curvature., Results: Images from 10 132 participants (56% female, mean age 63.9 years) passed quality checks. Overall, 47% of men and women had DDD grade 3 or more in the lumbar spine and 36% in both thoracic and lumbar spine. Risk ratios for DDD grades 3 and 4, adjusted for age and anthropometric determinants, varied across a three-fold range between centres, yet prevalences were highly correlated in men and women. DDD was associated with flattened, non-ovoid inter-vertebral disc spaces. KL grade 4 and loss of inter-vertebral disc space were associated with higher spine aBMD., Conclusion: KL grades 3 and 4 are often used clinically to categorize radiological DDD. Highly variable European prevalences of radiologically defined DDD grades 3+ along with the large effects of age may have growing and geographically unequal health and economic impacts as the population ages. These data encourage further studies of potential genetic and environmental causes., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Patients have extensive experience of their disease that can enhance the design and execution of research leading to significant innovations and efficiencies in the research process. The research community on the whole have been slow to adopt practices that enable patients to become active partners in research. Digital technologies are providing the means to do this more easily and so are increasingly being used to interact with patients and involve them in the design and execution of research. The RUDY (Rare UK Diseases of bone, joints and blood vessels) study's pioneering approach applies a custom-developed electronic platform where patients can contribute information over time about their disease experience, lifestyle and clinical history. This is combined with a state-of-the-art Dynamic Consent model and a commitment to patient-driven research, to further our understanding of rare diseases. This paper describes the RUDY study and the benefits that have been gained from adopting this partnership approach to research.

Background: Osteoarthritis (OA) is a progressively degenerative joint disease influenced by structural and metabolic factors. There is growing evidence that subchondral bone is involved in both symptomatic and structural progression in OA. The Wnt pathway has been implicated in the progression of OA but the expression and function of the Wnt inhibitors, Dikkopf (DKK-1) and sclerostin (SOST), are unclear., Methods: We examined the regional distribution of DKK-1 and SOST in subchondral bone of the femoral head using resection specimens following arthroplasty in patients presenting with end-stage OA. Cylindrical cores for immunohistochemistry were taken through midpoint of full thickness cartilage defect, partial cartilage defect, through base of osteophyte and through macroscopically normal cartilage., Results: Subchondral bone was thickest in cores taken from regions with full cartilage defect and thinnest in cores taken from osteophyte regions. In subchondral bone, expression of both DKK-1 and SOST was observed exclusively in osteocytes. Expression was highest in subchondral bone in cores taken from regions with partial but not full thickness cartilage defects. DKK-1 but not SOST was expressed by chondrocytes in cores with macroscopically normal cartilage., Conclusion: The current study describes the regional cellular distribution of SOST and DKK-1 in hip OA. Expression was highest in the osteocytes in bone underlying partial thickness cartilage defects. It is however not clear if this is a cause or a consequence of alterations in the overlying cartilage. However, it is suggestive of an active remodeling process which might be targeted by disease-modifying agents.

Fracture liaison services are recommended as a model of best practice for organizing patient care and secondary fracture prevention for hip fracture patients, although variation exists in how such services are structured. There is considerable uncertainty as to which model is most cost-effective and should therefore be mandated. This study evaluated the cost- effectiveness of orthogeriatric (OG)- and nurse-led fracture liaison service (FLS) models of post-hip fracture care compared with usual care. Analyses were conducted from a health care and personal social services payer perspective, using a Markov model to estimate the lifetime impact of the models of care. The base-case population consisted of men and women aged 83 years with a hip fracture. The risk and costs of hip and non-hip fractures were derived from large primary and hospital care data sets in the UK. Utilities were informed by a meta-regression of 32 studies. In the base-case analysis, the orthogeriatric-led service was the most effective and cost-effective model of care at a threshold of £30,000 per quality-adjusted life years gained (QALY). For women aged 83 years, the OG-led service was the most cost-effective at £22,709/QALY. If only health care costs are considered, OG-led service was cost-effective at £12,860/QALY and £14,525/QALY for women and men aged 83 years, respectively. Irrespective of how patients were stratified in terms of their age, sex, and Charlson comorbidity score at index hip fracture, our results suggest that introducing an orthogeriatrician-led or a nurse-led FLS is cost-effective when compared with usual care. Although considerable uncertainty remains concerning which of the models of care should be preferred, introducing an orthogeriatrician-led service seems to be the most cost-effective service to pursue. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Background: Innovations in technology have contributed to rapid changes in the way that modern biomedical research is carried out. Researchers are increasingly required to endorse adaptive and flexible approaches to accommodate these innovations and comply with ethical, legal and regulatory requirements. This paper explores how Dynamic Consent may provide solutions to address challenges encountered when researchers invite individuals to participate in research and follow them up over time in a continuously changing environment., Methods: An interdisciplinary workshop jointly organised by the University of Oxford and the COST Action CHIP ME gathered clinicians, researchers, ethicists, lawyers, research participants and patient representatives to discuss experiences of using Dynamic Consent, and how such use may facilitate the conduct of specific research tasks. The data collected during the workshop were analysed using a content analysis approach., Results: Dynamic Consent can provide practical, sustainable and future-proof solutions to challenges related to participant recruitment, the attainment of informed consent, participant retention and consent management, and may bring economic efficiencies., Conclusions: Dynamic Consent offers opportunities for ongoing communication between researchers and research participants that can positively impact research. Dynamic Consent supports inter-sector, cross-border approaches and large scale data-sharing. Whilst it is relatively easy to set up and maintain, its implementation will require that researchers re-consider their relationship with research participants and adopt new procedures.

Fragility fractures of the hip have a major impact on the lives of patients and their families. This study highlights significant geographical variation in secondary fracture prevention with even the highest performing regions failing the majority of patients despite robust evidence supporting the benefits of diagnosis and treatment., Introduction: The purpose of the study is to describe the geographic variation in anti-osteoporosis drug therapy prescriptions before and after a hip fracture during 1999-2013 in the UK., Methods: We used primary care data (Clinical Practice Research Datalink) to identify patients with a hip fracture and primary care prescriptions of any anti-osteoporosis drugs prior to the index hip fracture and up to 5 years after. Geographic variations in prescribing before and after availability of generic oral bisphosphonates were analysed. Multivariable logistic regression models were adjusted for gender, age and body mass index (BMI)., Results: Thirteen thousand sixty-nine patients (76 % female) diagnosed with a hip fracture during 1999-2013 were identified. Eleven per cent had any anti-osteoporosis drug prescription in the 6 months prior to the index hip fracture. In the 0-4 months following a hip fracture, 5 % of patients were prescribed anti-osteoporosis drugs in 1999, increasing to 51 % in 2011 and then decreasing to 39 % in 2013. The independent predictors (OR (95 % CI)) of treatment initiation included gender (male 0.42 (0.36-0.49)), BMI (0.98 per kg/m 2 increase (0.97-1.00)) and geographic region (1.29 (0.89-1.87) North East vs. 0.56 (0.43-0.73) South Central region). Geographic differences in prescribing persisted over the 5-year follow-up. If all patients were treated at the rate of the highest performing region, then nationally, an additional 3214 hip fracture patients would be initiated on therapy every year., Conclusions: Significant geographic differences exist in prescribing of anti-osteoporosis drugs after hip fracture despite adjustment for potential confounders. Further work examining differences in health care provision may inform strategies to improve secondary fracture prevention after hip fracture., Competing Interests: AS, SH and AD have no competing financial interests relevant to the submitted work. DPA, JL, CC, MKJ and AJ received grants from NIHR HS&DR during the conduct of the study. Outside the submitted work, MKJ reports personal fees from Lilly UK, Amgen, Sevier, Merck, Medtronic, Internis, Consilient Health, Stirling Anglia, Mereo Biopharma and Optasia. He serves on the Scientific Committee of the National Osteoporosis Society and International Osteoporosis Foundation; DPA received grants from Bioiberica S.A. and Amgen Spain S.A.; CC received personal fees from Servier, Amgen, Eli Lilly, Merck, Medtronic and Novartis. AJ has received consultancy, lecture fees and honoraria from Servier, UK Renal Registry, Oxford Craniofacial Unit, IDIAP Jordi Gol, Freshfields Bruckhaus Deringer, has held advisory board positions (which involved receipt of fees) from Anthera Pharmaceuticals, INC., and received research sponsorship from ROCHE.

Context: Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response., Objective: We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol., Design: Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy., Setting: Hospital antenatal clinics., Participants: A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks., Interventions: 1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery., Main Outcome Measure: 25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison)., Results: 25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (β = -0.81 [95% confidence interval -1.39, -0.22]), lower compliance with study medication (%) (β = -0.28 [-0.072, -0.48]), lower early pregnancy 25(OH)D (nmol/L) (β = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (β = -10.5 [-6.4, -14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation., Conclusions: Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.