Patient-reported outcomes measures of X-linked hypophosphataemia participants: findings from a prospective cohort study in the UK

Background X-linked hypophosphataemia (XLH) is a rare genetic condition passed on through the X chromosome which causes multiple symptoms including weakened teeth, bones, and muscles. Due to the rarity of the condition, little is known about the health outcomes as reported by people with the disease. The objectives of this study were threefold: to characterise key patient reported outcome measures (PROMs) in adults with XLH, to identify clusters of symptom-severity groups based on PROMs, and to analyse the longitudinal progression of available PROMs. Methods Data from 48 participants from the Rare and Undiagnosed Diseases cohort Study (RUDY) was used to analyse both cross-sectional and longitudinal patient-reported outcomes. We analysed data for health-related quality of life (HRQL): EuroQol 5 dimensions-5 levels (EQ-5D-5L), Short-form 36 (SF-36) Physical Component Score (PCS), and SF-36 Mental Component Score (MCS), sleep: Pittsburgh sleep quality index (PSQI) and Epworth Sleepiness scale (ESS), fatigue: Fatigue Severity Scale (FSS) and Functional assessment of chronic illness therapy-fatigue (FACIT-F), pain: Short form McGill pain questionnaire version 2 (SF-MPQ-2) and PainDETECT, and mental well-being: Hospital anxiety and depression scale (HADS) anxiety and depression. Summary statistics, tests of mean differences, mixed-effects models, and cluster analysis were used to describe and examine the various health dimensions of individuals with XLH. Results Overall mean scores were EQ-5D-5L = 0.65, SF-36-PCS = 32.7, and SF-36-MCS = 48.4 for HRQL, ESS = 5.9 and PSQI = 8.9 for sleep, FSS = 32.8 and FACIT-F = 104.4 for fatigue, SF-MPQ-2 = 1.9 for pain, and HADS-depression = 4.7 and HADS-anxiety = 6.2 for mental well-being. 7% reported neuropathic pain (PainDETECT). Whilst many adults with XLH reported good outcomes, extreme or severe problems were reported across all outcomes. Cluster analysis identified that adults with XLH could be divided into two distinct groups, one reporting worse (35.3%) and the other better outcomes (64.7%) (less pain, fatigue, depression, and higher levels of sleep). Longitudinal analysis showed that FACIT-F and HADS-anxiety scores worsened slightly over two years with statistically significant (p  Conclusion Although about two thirds of adult participants of the RUDY cohort with XLH report good health outcomes, for a considerable third much worse outcomes are reported. More research is needed to examine why some experience good and others poor health outcomes and the characteristics which identify them

Social inequality and fractures—secular trends in the Danish population:a case-control study

Summary 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.</p

Patient-reported symptoms and diagnostic journey in Multiple Myeloma

IntroductionLate 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. MethodsA 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.ResultsOverall, 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 &lt;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.DiscussionDeveloping resources for allied health professionals may improve early recognition of MM

a potential solution to some of the challenges of modern biomedical 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

Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease:a propensity-score matched cohort study

BackgroundBisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects.ObjectivesThe aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time.DesignThis was a new-user cohort study design with propensity score matching.Setting and data sourcesData were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1–3 and from the Danish Odense University Hospital Databases for work package 4.ParticipantsPatients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of &lt; 45 ml/minute/1.73 m2 were eligible. A second estimated glomerular filtration rate value of &lt; 45 ml/minute/1.73 m2 within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1–3. Patients with &lt; 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1–4.Interventions/exposureBisphosphonate use, identified from primary care prescriptions (for work packages 1–3) or pharmacy dispensations (for work package 4), was the main exposure.Main outcome measuresWork package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change.ResultsBisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users.LimitationsConfounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively.ConclusionsBisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness.Future workRandomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data

Comparative anti-fracture effectiveness of different oral anti-osteoporosis therapies based on "real-world" data: a meta-analysis of propensity-matched cohort findings from the UK Clinical Practice Research Database and the Catalan SIDIAP Database.

PURPOSE: This paper aims to compare the clinical effectiveness of oral anti-osteoporosis drugs based on the observed risk of fracture while on treatment in primary care actual practice. MATERIALS AND METHODS: We investigated two primary care records databases covering UK National Health Service (Clinical Practice Research Datalink, CPRD) and Catalan healthcare (Information System for Research in Primary Care, SIDIAP) patients during 1995-2014 and 2006-2014, respectivey. Treatment-naive incident users of anti-osteoporosis drugs were included and followed until treatment cessation, switching, death, transfer out, or study completion. We considered hip fracture while on treatment as main outcome and major osteoporotic fractures (hip, clinical spine, wrist, and proximal humerus) as secondary outcome. Users of alendronate (reference group) were compared to those of (1) OBP, (2) strontium ranelate (SR), and (3) selective estrogen receptor modulators (SERMs), after matching on baseline characteristics using propensity scores. Multiple imputation was used to handle missing data on confounders and competing risk modelling for the calculation of relative risk according to therapy. Country-specific data were analyzed separately and meta-analyzed. RESULTS: A total of 163,950 UK and 145,236 Catalan patients were identified. Hip (sub-hazard ratio [SHR] [95% CI] 1.04 [0.77-1.40]) and major osteoporotic (SHR [95% CI] 1 [0.78-1.27]) fracture risks were similar among OBP compared to alendronate users. Both hip (SHR [95% CI] 1.26 [1.14-1.39]) and major osteoporotic (SHR [95% CI] 1.06 [1.02-1.12]) fracture risk were higher in SR compared to alendronate users. SERM users had a reduced hip (SHR [95% CI] 0.75 [0.60-0.94]) and major osteoporotic (SHR [95% CI] 0.77 [0.72-0.83]) fracture risk compared to alendronate users. CONCLUSION: We found a 26% excess hip fracture risk among SR compared to matched alendronate users, in line with placebo-controlled RCT findings. Conversely, in a lower risk population, SERM users had a 25% reduced hip fracture risk compared to alendronate users. Head-to-head RCTs are needed to confirm these findings

Patient-reported experience of clinical care of osteogenesis imperfecta (OI) during the COVID-19 pandemic

Background: Research on the effects of the COVID-19 pandemic on people with rare diseases is limited. Few studies compare healthcare throughout the progression of the ongoing pandemic. Aims: To assess the impact of the pandemic on individuals with osteogenesis imperfecta across two consecutive years, understand what challenges were encountered, and analyse the experience of remote consultation. Methods: An initial survey was distributed following the first lockdown in August 2020, and a second survey in April 2021. The surveys explored four themes- effects on therapy, alternatives to consultation, effect on mental health, and perceived risks of COVID-19. Results: In the 2020 survey, of the 110 respondents, 69 (63%) had at least one appointment delayed due to the lockdown, compared with 89 of the 124 respondents (72%) in 2021. Of the 110 respondents in 2020, 57 (52%) had a remote consultation, increasing to 92 of 124 (74%) in the follow-up survey. In the 2020 survey 63 of 91 respondents (69%) expressed anxiety due to lockdown, compared with 76 of 124 (61%) in 2021. The percentage of total respondents expressing a preference for remote consultation was 48% in 2020, increasing to 71% in 2021. Conclusions: The pandemic has had widespread effects on the mental and physical health of those with OI. These effects, alongside appointment delays, have increased as the pandemic progresses. Encouragingly, the increasing preference for remote consultation may indicate that this could be a viable long-lasting alternative to face-to-face appointments, especially for patients who previously traveled vast distances for specialist care

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

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial

Background: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH).   Methods: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks’ gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records.   Results: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode.   Conclusions: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD