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Fracture liaison services
With established clinical and economic benefits from secondary fracture prevention, the focus is on implementing effective and efficient healthcare models such as Fracture Liaison Services (FLSs). This chapter reviews several critical aspects for successful implementation of FLSs: (a) the conceptual models for FLS with evidence for effectiveness; (b) the steps for implementation, encompassing national policy, coalitions and local level activities; (c) benchmarking at the organisational and patient level and signposting to supporting resources from the International Osteoporosis Foundation.
Current approaches to secondary prevention after hip fracture in England and Wales - an analysis of trends between 2016 and 2020 using the National Hip Fracture Database (NHFD).
UNLABELLED: Hip fractures are strong risk factors for further fractures. However, using the National Hip Fracture Database, we observed that in England and Wales, 64% of patients admitted on oral bisphosphonates were discharged on the same and injectable drug use varies from 0-67% and 0.2%-83.6% were deemed "inappropriate" for bone protection. This variability requires further investigation. INTRODUCTION: A key aim for the National Hip Fracture Database (NHFD) is to encourage secondary fracture prevention of the 75,000 patients who break their hip annually in the UK, through bone health assessment and appropriate provision of anti-osteoporosis medication (AOM). We set out to describe trends in anti-osteoporosis medication prescription and examine the types of oral and injectable AOMs being prescribed both before and after a hip fracture. METHODS: We used data freely available from the NHFD www.nhfd.co.uk to analyse trends in oral and injectable AOM prescription across a quarter of a million patients presenting between 2016 and 2020, and more detailed information on the individual type of AOM prescribed for 63,705 patients from 171 hospitals in England and Wales who presented in 2020. RESULTS: Most patients (88.3%) are not taking any AOM when they present with a hip fracture. Half of all patients (50.8%) were prescribed AOM treatment by the time of discharge, but the proportion deemed 'inappropriate for AOM' varied hugely (0.2-83.6%) in different hospitals. Nearly two-thirds (64.2%) of those previously taking an oral bisphosphonate were simply discharged on the same type of medication. The total number of patients discharged on oral medication fell by over a quarter in these five years. The number discharged on injectables increased by nearly three-quarters to 14.2% over the same period, but remains hugely variable across the country, with rates ranging from 0-67% across different units. CONCLUSION: A recent hip fracture is a strong risk factor for future fractures. The huge variability in approaches, and in particular the use of injectables, in different trauma units across England and Wales requires further investigation.
Diagnostic journey for individuals with fibrous dysplasia / McCune albright syndrome (FD/MAS).
BACKGROUND: Reducing delayed diagnosis is a significant healthcare priority for individuals with rare diseases. Fibrous Dysplasia/ McCune Albright Syndrome (FD/MAS) is a rare bone disease caused by somatic activation mutations of NASA. FD/MAS has a broad clinical phenotype reflecting variable involvement of bone, endocrine and other tissues, distribution and severity. The variable phenotype is likely to prolong the diagnostic journey for patients further. AIM: To describe the time from symptom onset to final diagnosis in individuals living with FDMAS. METHODS: We used the UK-based RUDY research database ( www.rudystudy.org ), where patients self-report their diagnosis of FD/MAS. Participants are invited to complete the diagnostic journey based on the EPIRARE criteria. RESULTS: 51 individuals diagnosed with FD/MAS were included in this analysis. Among them, 70% were female, and the median age was 51.0 years (IQR 34.5-57.5]. 12 (35%) individuals reported McCune Albright Syndrome, 11 (21.6%) craniofacial and 11(21.6%) for each of poly- and mono-ostotic FD and 6 (11.8%) did not know their type of FD/MAS. Pain was the commonest first symptom (58.8%), and 47.1% received another diagnosis before the diagnosis of FD/MAS. The median time to final diagnosis from the first symptom was two years with a wide IQR (1,18) and range (0-59 years). Only 12 (23.5%) of individuals were diagnosed within 12 months of their first symptoms. The type of FD/MAS was not associated with the reported time to diagnosis. Significant independent predictors of longer time to final diagnosis included older current age, younger age at first symptom and diagnosis after 2010. CONCLUSION: Individuals with FDMAS have a variable time to diagnosis that can span decades. This study highlights the need for further research on how to improve diagnostic pathways within Orthopaedic and Ear, Nose and Throat (ENT)/Maxillofacial services. Our data provides a baseline to assess the impact of novel NHS diagnostic networks on reducing the diagnostic odyssey.
Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.
OBJECTIVE: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. DESIGN: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. DATA SOURCES: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. RESULTS: The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; β=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. CONCLUSIONS: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128391.
Call to action: a five nations consensus on the use of intravenous zoledronate after hip fracture.
Currently in the UK and Ireland, after a hip fracture most patients do not receive bone protection medication to reduce the risk of refracture. Yet randomised controlled trial data specifically examining patients with hip fracture have shown that intravenous zoledronate reduces refracture risk by a third. Despite this evidence, use of intravenous zoledronate is highly variable following a hip fracture; many hospitals are providing this treatment, whilst most are currently not. A range of clinical uncertainties, doubts over the evidence base and practical concerns are cited as reasons. This paper discusses these concerns and provides guidance from expert consensus, aiming to assist orthogeriatricians, pharmacists and health services managers establish local protocols to deliver this highly clinically and cost-effective treatment to patients before they leave hospital, in order to reduce costly re-fractures in this frail population.
Fracture Risk Assessment and How to Implement a Fracture Liaison Service
The human, healthcare and financial costs of fragility fracture are considerable and at present there is an apparent need to address the growing gap between those who require treatment and those who actually receive it. Fracture Liaison Services (FLS) have been established to address this gap through the identification, treatment and monitoring of those sustaining fragility fractures with the aim of preventing secondary fractures. In this chapter, we present data from studies which support the instigation of FLS as clinically- and cost-effective initiatives. We provide a step-by-step approach to implementation and benchmarking and provide advice regarding the development of an FLS in a low-resource setting.
How to Implement a Fracture Liaison Service
The case for Fracture Liaison Service (FLS) for the prevention of secondary fractures is clear. With an ageing population, the burden of osteoporosis is set to increase. Despite evidence for the clinical effectiveness of secondary fracture prevention, translation in the real world setting remains disappointing: worldwide, eighty per cent of fragility fracture patients are neither assessed nor treated for osteoporosis or falls risk, with the aim of reducing future fracture incidence. If implemented, a wide variety of service models are used to deliver effective secondary fracture prevention. To support and promote the use of effective models of care across the globe, the International Osteoporosis Foundation (IOF) launched the Capture the Fracture® (CTF) programme in 2013. This expert-led and evidence-based programme aims to reduce secondary fractures by facilitating the implementation of FLS on a global level. A primary resource developed by CTF is the Best Practice Framework (BPF), which sets standards for FLS, serves as a benchmark for existing FLS and serves as a guidance tool for developing FLS. In an effort to engage the global medical community, CTF offers a Best Practice Recognition programme where FLS can submit their service to IOF for evaluation against the BPF for a gold, silver or bronze star in recognition of achievements. The FLS is then included in the showcase of best practice and plotted on the CTF Map of Best Practice that displays participating FLS and their respective achievement level. To influence change, the map can be used as a visual representation of FLS available worldwide, their achievements, as well as the areas for opportunity and development in secondary fracture prevention.
Exploring the burden, prevalence and associated factors of chronic musculoskeletal pain in migrants from North Africa and Middle East living in Europe: a scoping review
Background: Immigrants are exposed to numerous risk factors that may contribute to the development of chronic musculoskeletal pain. Recent political and environmental crises in North Africa and the Middle East have led to an increase in immigration to Europe that has challenged the healthcare system and especially the management of chronic conditions. Objective: The aims of this scoping review are to investigate the burden, prevalence, and associated factors of chronic musculoskeletal pain in immigrants from North Africa and the Middle East in Europe during the last decade. The intentions of the review are to inform healthcare policymakers, to identify gaps in the literature, and aid the planning of future research. Design: Online databases Medline, Embase, PubMed and Web of Science were used to identify epidemiological studies published from2012–2022 examining chronic pain in populations from North Africa and the Middle East with a migration background residing in Europe. Results: In total eleven studies were identified conducted in Norway (n = 3), Denmark (n = 3), Germany (n = 1), Austria (n = 1), Sweden (n = 1), and Switzerland (n = 1). Among the identified studies, eight studies were cross-sectional (n = 8), two were prospective cohort studies (n = 2) and one was a retrospective cohort study (n = 1). Data suggested that chronic pain is more prevalent, more widespread, and more severe in people with than without a migration background. Furthermore, immigrants who have resided in the destination country for a longer period experience a higher prevalence of chronic pain compared to those in the early phases of migration. The following factors were found to be associated with chronic pain in this population: female gender, lower education, financial hardship, being underweight or obese, time in transit during migration, experience of trauma, immigration status, anxiety, depression, and post-traumatic stress disorder. Conclusion: Several gaps in the literature were identified. Research is limited in terms of quantity and quality, does not reflect actual immigration trends, and does not account for immigration factors. Prospective cohort studies with long follow-ups would aid in improving prevention and management of chronic pain in populations with a migration background. In particular, they should reflect actual immigration trajectories, account for immigration factors, and have valid comparison groups in the countries of origin, transit and destination.
Gonadal androgens are associated with decreased type I interferon production by plasmacytoid dendritic cells and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents.
mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serum-free testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity.
Patient-reported symptoms and diagnostic journey in Multiple Myeloma.
INTRODUCTION: Late presentation of multiple myeloma (MM) heightens the risk of complication risks, including end-organ damage. This study aimed to: 1) detail the diagnostic journey of MM patients, encompassing symptoms, initial diagnoses, and healthcare professionals met; 2) establish the median duration from symptom onset to MM diagnosis; and 3) examine factors linked to timely MM diagnosis within 12 weeks. METHODS: A total of 300 adults self-reporting MM were analysed from the Rare and Undiagnosed Diseases cohort Study (RUDY). The RUDY study is a web-based platform, where participants provide dynamic consent and self-report their MM diagnosis and information about their diagnostic journey. This includes the estimated date of initial potential first symptoms, descriptions of these symptoms, the healthcare professionals they consulted, and other diagnoses received before the MM diagnosis. Descriptive statistics, combinatorial analyses and logistic regression analyses were used to describe and examine the diagnostic journey of individuals with MM. RESULTS: Overall, 52% of the participants reported other diagnoses before MM diagnosis, with musculoskeletal disorders (47.8%), such as osteoporosis, costochondritis, or muscle strains, being the most common. The most prevalent initial reported symptom was back pain/vertebral fractures (47%), followed by chest/shoulder pain, including rib pain and fractures (20%), and fatigue/tiredness (19.7%). 40% of participants were diagnosed by direct referral from primary care to haematology without seeing other healthcare professionals whilst 60% consulted additional specialists before diagnosis. The median time from symptom onset to MM diagnosis was 4 months (IQR 2-10 months, range 0-172). Seeing an Allied Healthcare Professional such as a physiotherapist, chiropractor or an osteopath (OR = 0.25, 95% CI [0.12, 0.47], p <0.001), experiencing infection symptoms (OR = 0.32, 95% CI [0.13, 0.76], p = 0.013), and having chest or shoulder pain (OR = 0.45, 95% CI [0.23, 0.86], p = 0.020) were associated with a lower likelihood of being diagnosed with MM within 12 weeks. Older age (OR = 1.04, 95% CI [1.02, 1.07], p = 0.001) was associated with a higher likelihood of diagnosis within 12 weeks. DISCUSSION: Developing resources for allied health professionals may improve early recognition of MM.
Anticipated effects of burosumab treatment on long-term clinical sequelae in XLH: expert perspectives.
X-linked hypophosphatemia (XLH) is a rare, progressive, genetic disease with multisystem impact that typically begins to manifest in early childhood. Two treatment options exist: oral phosphate in combination with active vitamin D ("conventional therapy") and a fully human monoclonal anti-FGF23 antibody, burosumab. The clinical benefit of conventional therapy in adults is limited, and poor tolerance and complications are common. Burosumab was first approved as a treatment for XLH in 2018 and its disease-modifying benefits in clinical trials in children suggest burosumab treatment could also alter the disease course in adults. Without long-term clinical data on multiple XLH-related sequelae available, the results of an elicitation exercise are reported, in which eight global experts in XLH posited how long-term treatment with burosumab is anticipated to impact the life course of clinical sequelae in adults with XLH. Based on their clinical experiences, the available evidence and their disease understanding, the experts agreed that some long-term benefits of using burosumab are likely in adults with XLH even if they have a misaligned skeleton from childhood. Burosumab treatment is anticipated to reduce the incidence of fractures and halt the progression of clinical sequelae associated with conventional therapy. While the trajectories for established dental abscesses are not expected to improve with burosumab treatment, dental abscess development may be prevented. Starting treatment with burosumab in childhood to increase the likelihood of an aligned skeleton and continuation into and throughout adulthood to maintain euphosphatemia may optimize patient outcomes, although future real-world investigation is required to support this hypothesis.