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)

Summary 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

Anti‐osteoporosis medication dispensing by clinical commissioning groups in England: an ecological study of variability in practice and of the effect of the Covid‐19 pandemic

Purpose: To investigate whether the rate of Anti‐Osteoporosis Medication (AOM) dispensing was related to prevalence of risk factors and hip fracture incidence in the local population. Methods: The Open Prescribing database was used to analyse dispensed AOM at the level of Clinical Commissioning Groups (CCGs) in England. Male Healthy Life Expectancy (MHLE), Female Healthy Life Expectancy (FHLE), the prevalence of smoking and active adults, the incidence of hip fracture and of alcohol related hospital admissions, and local dispensing of a comparator drug (atorvastatin) were considered as predictor variables. Linear and multilinear regression were performed. Using atorvastatin as a comparator, AOM dispensing was compared after the start of the Covid‐19 pandemic with the same quarter the previous year. Results: Rates of AOM per 1000 people aged over 65 years in a CCG area varied between 379.2 and 1129.1, with a mean of 670.3. Population risk factors were individually related to the amount of AOM dispensed in an area. Collectively, local activity levels in adults (p = 0.042) and local hip fracture incidence (p = 0.003) were significantly negatively correlated with rates of AOM dispensed. Rates of alendronate dispensing fell significantly at the start of the Covid‐19 pandemic (p < 0.001), whilst atorvastatin dispensing rates significantly increased (p < 0.001). Conclusion: Lower rates of AOM dispensing were seen in areas with a higher proportion of active adults and higher incidence of hip fracture. Multidisciplinary services should be developed to address this care gap with consideration given to local population risk factors. Community pharmacists are ideally placed to play a vital role in osteoporosis management

Fracture risk in type 2 diabetic patients: A clinical prediction tool based on a large population-based cohort

BACKGROUND: An increased fracture risk has been described as a complication of Type 2 diabetes mellitus (T2DM). Clinical prediction models for general population have a limited predictive accuracy for fractures in T2DM patients. The aim was to develop and validate a clinical prediction tool for the estimation of 5-year hip and major fracture risk in T2DM patients. METHODS AND RESULTS: A cohort of newly diagnosed T2DM patients (n = 51,143, aged 50-85, 57% men) was extracted from the Information System for the Development of Research in Primary Care (SIDIAP) database, containing computerized primary care records for >80% of the population of Catalonia, Spain (>6 million people). Patients were followed up from T2DM diagnosis until the earliest of death, transfer out, fracture, or end of study. Cox proportional hazards regression was used to model the 5-year risk of hip and major fracture. Calibration and discrimination were assessed. Hip and major fracture incidence rates were 1.84 [95%CI 1.64 to 2.05] and 7.12 [95%CI 6.72 to 7.53] per 1,000 person-years, respectively. Both hip and major fracture prediction models included age, sex, previous major fracture, statins use, and calcium/vitamin D supplements; previous ischemic heart disease was also included for hip fracture and stroke for major fracture. Discrimination (0.81 for hip and 0.72 for major fracture) and calibration plots support excellent internal validity. CONCLUSIONS: The proposed prediction models have good discrimination and calibration for the estimation of both hip and major fracture risk in incident T2DM patients. These tools incorporate key T2DM macrovascular complications generally available in primary care electronic medical records, as well as more generic fracture risk predictors. Future work will focus on validation of these models in external cohorts

Models of care for the delivery of secondary fracture prevention after hip fracture:a health service cost, clinical outcomes and cost-effectiveness study within a region of England.

Background Professional bodies have produced comprehensive guidance about the management of hip fracture. They recommend orthogeriatric services focusing on achieving optimal recovery, and fracture liaison services (FLSs) focusing on secondary fracture prevention. Despite such guidelines being in place, there is significant variation in how services are structured and organised between hospitals. Objectives To establish the clinical effectiveness and cost-effectiveness of changes to the delivery of secondary fracture prevention services, and to identify barriers and facilitators to changes. Design A service evaluation to identify each hospital’s current models of care and changes in service delivery. A qualitative study to identify barriers and facilitators to change. Health economics analysis to establish NHS costs and cost-effectiveness. A natural experimental study to determine clinical effectiveness of changes to a hospital’s model of care. Setting Eleven acute hospitals in a region of England. Participants Qualitative study – 43 health professionals working in fracture prevention services in secondary care. Interventions Changes made to secondary fracture prevention services at each hospital between 2003 and 2012. Main outcome measures The primary outcome is secondary hip fracture. Secondary outcomes include mortality, non-hip fragility fracture and the overall rate of hip fracture. Data sources Clinical effectiveness/cost-effectiveness analyses – primary hip fracture patients identified from (1) Hospital Episode Statistics (2003–13, n = 33,152); and (2) Clinical Practice Research Datalink (1999–2013, n = 11,243). Results Service evaluation – there was significant variation in the organisation of secondary fracture prevention services, including staffing levels, type of service model (consultant vs. nurse led) and underlying processes. Qualitative – fracture prevention co-ordinators gave multidisciplinary health professionals capacity to work together, but communication with general practitioners was challenging. The intervention was easily integrated into practice but some participants felt that implementation was undermined by under-resourced services. Making business cases for a service was particularly challenging. Natural experiment – the impact of introducing an orthogeriatrician on 30-day and 1-year mortality was hazard ratio (HR) 0.73 [95% confidence interval (CI) 0.65 to 0.82] and HR 0.81 (95% CI 0.75 to 0.87), respectively. Thirty-day and 1-year mortality were likewise reduced following the introduction or expansion of a FLS: HR 0.80 (95% CI 0.71 to 0.91) and HR 0.84 (95% CI 0.77 to 0.93), respectively. There was no significant impact on time to secondary hip fracture. Health economics – the annual cost in the year of hip fracture was estimated at £10,964 (95% CI £10,767 to £11,161) higher than the previous year. The annual cost associated with all incident hip fractures in the UK among those aged ≥ 50 years (n = 79,243) was estimated at £1215M. At a £30,000 per quality-adjusted life-year threshold, the most cost-effective model was introducing an orthogeriatrician. Conclusion In hip fracture patients, orthogeriatrician and nurse-led FLS models are associated with reductions in mortality rates and are cost-effective, the orthogeriatrician model being the most cost-effective. There was no evidence for a reduction in second hip fracture. Qualitative data suggest that weaknesses lie in treatment adherence/monitoring, a possible reason for the lack of effectiveness on second hip fracture outcome. The effectiveness on non-hip fracture outcomes remains unanswered. Future work Reliable estimates of health state utility values for patients with hip and non-hip fractures are required to reduce uncertainty in health economic models. A clinical trial is needed to assess the clinical effectiveness and cost-effectiveness of a FLS for non-hip fracture patients. Funding The National Institute for Health Research (NIHR) Health Services and Delivery Research programme and the NIHR Musculoskeletal Biomedical Research Unit, University of Oxford

Response to Antenatal Cholecalciferol Supplementation Is Associated With Common Vitamin D-Related Genetic Variants.

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

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

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

Safety of Oral Bisphosphonates in Moderate-to-Severe Chronic Kidney Disease: A Binational Cohort Analysis

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m2 , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR)