Does bone mineral density improve the predictive accuracy of fracture risk assessment?: a prospective cohort study in Northern Denmark

Objective: To evaluate the added predictive accuracy of bone mineral density (BMD) to fracture risk assessment.Design Prospective cohort study using data between 01 January 2010 and 31 December 2012. Setting: North Denmark Osteoporosis Clinic of referred patients presenting with at least one fracture risk factor to the referring doctor.Participants Patients aged 40–90 years; had BMD T-score recorded at the hip and not taking osteoporotic preventing drugs for more than 1 year prior to baseline. Main outcome measures: Incident diagnoses of osteoporotic fractures (hip, spine, forearm, humerus and pelvis) were identified using the National Patient Registry of Denmark during 01 January 2012–01 January 2014. Cox regression was used to develop a fracture model based on predictors in the Fracture Risk Assessment Tool (FRAX®), with and without, binary and continuous BMD. Change in Harrell’s C-Index and Reclassification tables were used to describe the added statistical value of BMD. Results: Adjusting for predictors included in FRAX®, patients with osteoporosis (T-score ≤−2.5) had 75% higher hazard of a fracture compared with patients with higher BMD (HR: 1.75 (95% CI 1.28 to 2.38)). Forty per cent lower hazard was found per unit increase in continuous BMD T-score (HR: 0.60 (95% CI 0.52 to 0.69)).Accuracy improved marginally, and Harrell’s C-Index increased by 1.2% when adding continuous BMD (0.76 to 0.77). Reclassification tables showed continuous BMD shifted 529 patients into different risk categories; 292 of these were reclassified correctly (57%; 95% CI 55% to 64%). Adding binary BMD however no improvement: Harrell’s C-Index decreased by 0.6%. Conclusions: Continuous BMD marginally improves fracture risk assessment. Importantly, this was only found when using continuous BMD measurement for osteoporosis. It is suggested that future focus should be on evaluation of this risk factor using routinely collected data and on the development of more clinically relevant methodology to assess the added value of a new risk factor

Mind the (treatment) gap: a global perspective on current and future strategies for prevention of fragility fractures

This narrative review considers the key challenges facing healthcare professionals and policymakers responsible for providing care to populations in relation to bone health. These challenges broadly fall into four distinct themes: (1) case finding and management of individuals at high risk of fracture, (2) public awareness of osteoporosis and fragility fractures, (3) reimbursement and health system policy and (4) epidemiology of fracture in the developing world. Findings from cohort studies, randomised controlled trials, systematic reviews and meta-analyses, in addition to current clinical guidelines, position papers and national and international audits, are summarised, with the intention of providing a prioritised approach to delivery of optimal bone health for all. Systematic approaches to case-finding individuals who are at high risk of sustaining fragility fractures are described. These include strategies and models of care intended to improve case finding for individuals who have sustained fragility fractures, those undergoing treatment with medicines which have an adverse effect on bone health and people who have diseases, whereby bone loss and, consequently, fragility fractures are a common comorbidity. Approaches to deliver primary fracture prevention in a clinically effective and cost-effective manner are also explored. Public awareness of osteoporosis is low worldwide. If older people are to be more pro-active in the management of their bone health, that needs to change. Effective disease awareness campaigns have been implemented in some countries but need to be undertaken in many more. A major need exists to improve awareness of the risk that osteoporosis poses to individuals who have initiated treatment, with the intention of improving adherence in the long term. A multisector effort is also required to support patients and their clinicians to have meaningful discussions concerning the risk-benefit ratio of osteoporosis treatment. With regard to prioritisation of fragility fracture prevention in national policy, there is much to be done. In the developing world, robust epidemiological estimates of fracture incidence are required to inform policy development. As the aging of the baby boomer generation is upon us, this review provides a comprehensive analysis of how bone health can be improved worldwide for all

Exploring bone mineral density changes in total knee arthroplasty revisions and the impact of conal implants

Introduction The link between low bone mineral density (BMD) leading to greater fracture risk is well established in the literature; what is not fully understood is the impact of total knee revisions (rTKR) and cone implantation on BMD. This is important due to the increasing fracture risk associated with reductions in BMD. This feasibility study investigated a new type of Stryker cone for rTKR patients, and its impact on BMD utilising different imaging technologies and providing recommendations to be implemented for a full follow up trial. Method A systematic review was conducted to investigate total knee replacement (TKR) and rTKR on BMD results to establish known reported BMD changes after surgery, and to highlight the knee regions investigated. A bovine study was then conducted in order to test the different setup imaging technologies and possible analysis of the cones. Additionally, a novel piece of 3D SHAPER hip software was utilised to investigate bone changes in the hip across three groups (TKR, rTKR, and controls) which could then be compared to the main BMD changes or used as an alternative to the other imaging options. The main study involved recruiting 37 participants all undergoing rTKR to either a cone or non cone group, with all participants undergoing a series of scans via: CT scans (only at six months), DXA and x ray at intervals of pre op, six weeks, three, six and 12 months. Additionally, all participants completed questionnaires on mental health, lower extremity functionality, and quality of life. In addition to BMD investigation, hip and knee alignment was also explored at pre and post op intervals, as well as pixel density changes, both utilising long leg x ray imaging. Results Systematic review results reported 2,431 papers, of which 27 studies were included, across all the studies BMD losses appeared greatest at 12 months. The bovine study helped develop the imaging and analysis required for the main study. The 3D SHAPER ability to be applied to hip DXA imaging showed promise; which was reflected in the control, rTKR and TKR data. The development of different imaging technologies have potential in moving forward into a full trial. Recommendations would include: utilising DXA imaging as the main modality, given its gold standard for BMD changes and its consistency when using a standardised positioning protocol and ROI placement. Long leg x- 3 ray imaging to be used to investigate alignment and pixel density changes, as this imaging is convenient as part of routine follow-up care, although the inclusion of a step wedge within all long leg images would be required to allow pixel density standardisation for investigating in-growth. Finally, the CT imaging could not determine ingrowth in this feasibility study, and therefore should not be utilised in the full study. For the main feasibility study results, 35 participants attended pre--op, 26 attended six weeks and three months, at six months 25 attended, and 22 at 12 months. Results show rTKR is associated with lower BMD in the tibial and femoral stems, and in the medial tibial condyle, and associated with increases beyond the tibial and femoral stems, in both groups. The main difference is in lateral tibial condyle where there are associated increases in BMD in the cone group, and losses reported in the non--cone group. The questionnaire results show a favourable impact for rTKR, with reductions in depression, anxiety, and increases in functionality post--surgery, with the cone group reporting greater changes, although not statistically significant between groups. Alignment analysis shows little difference between

Hyperparathyroidism and parathyroidectomy in patients on renal replacement therapy

Background. Secondary hyperparathyroidism (sHPT) is characterized by over function of the parathyroid glands and disturbances in mineral metabolism as a result of renal failure. It is common among patients with end-stage renal disease (ESRD) and it often persists after successful renal transplantation. sHPT is associated with osteoporosis and cardiovascular morbidity and mortality. There are two main ways to treat this condition, either by medical therapy or surgical removal of the parathyroid glands, parathyroidectomy (PTX). Another complication in patients with ESRD is New-Onset Diabetes After Transplantation (NODAT). Immunosuppressive medications and personal risk factors for diabetes mellitus have been associated with the condition. We aimed to study the effect of PTX on the risk of death, cardio-/cerebrovascular events (CVE), and hip fractures. We also studied the incidence of NODAT at our department and whether there is an association between NODAT and sHPT.Methods. A nested index-referent study was performed within the Swedish Renal Registry (SRR). Patients on maintenance dialysis or with renal transplant at the time of PTX were included. The PTX patients were randomly matched for age, sex and underlying renal disease with up to five referent patients who had not undergone PTX. To calculate survival time and hazard ratios (HR), indexes and referents were assigned the calendar date (d) of the PTX of the index patient. The risk of death, CVE, and fractures after PTX were calculated using crude and adjusted Cox proportional hazards regressions. Data were extracted from patient charts to calculate the incidence of NODAT, and logistic regressions were performed to analyze potential risk factors for NODAT including sHPT.Results. There were 20 056 patients in the SRR between 1991 and 2009. Of these, 579 (423 on dialysis and 156 with a renal transplant at d) incident patients with PTX were matched with 1234/736 non-PTX patients. The adjusted relative risk of death was a HR of 0.80 [95% confidence interval (CI) 0.65–0.99] for dialysis patients who had undergone PTX compared with matched patients who had not. Corresponding result for the patients with a renal allograft at d was a HR of 1.10 (95% CI 0.71–1.70). The results for CVE:s were a HR of 1.24 (95% CI 1.03–1.49) for dialysis patients with PTX compared to non-PTX dialysis patients and a HR of 0.53 (95% CI 0.34–0.84) for transplanted patients. The HR for hip fractures in PTX patients was 0.40 (95% CI 0.18–0.88) compared to non-PTX patients. We found a first-year post-transplant incidence of NODAT of 15%, and an odds ratio (OR) of 4.25 (95% CI 1.13-15.92) for the association between PTH levels above twice the normal range and NODAT.Conclusions. PTX was associated with improved survival in patients on maintenance dialysis. However, there was no survival advantage after PTX in patients with a functioning renal allograft. PTX was associated with a higher risk of CVE after PTX for patients on maintenance dialysis. This was in contrast to some previous studies. However, the risk was lower for patients with a functioning renal allograft at the time of PTX. Parathyroidectomy was associated with a reduced risk of hip fractures in women with sHPT. The first-year cumulative incidence of NODAT was 15% at our department between the years 2000 and 2011. We showed an association between elevated levels of PTH and NODAT in transplanted patient

Pharmacoepidemiology and health economics of adherence to pharmaceutical fracture prevention

Background: Osteoporosis is a disease characterized by weak bone, affecting hundreds of millions of people worldwide, predominantly postmenopausal women. The main clinical consequence of the disease is bone fractures and the lifetime risk of any fracture has been estimated at ~55% in Norwegian women. Hip and vertebral fractures are the two most serious fracture types, associated with substantial pain, disability, and even death. Even though there is consensus that patients at high risk of fracture should be treated, there is still a troubling treatment gap that shows few signs of closing. Only 6.6% of untreated patients receive treatment after their first fracture and there are ~225,000 untreated individuals with a bone mineral density indicative of osteoporosis in Sweden. An equally noteworthy aspect of undertreatment is poor adherence (compliance and persistence) to treatment, i.e. how patients and physicians adhere to dosing instructions and treatment regimens. Many patients stop filling prescriptions at pharmacies prematurely (refill non-persistence) and this is a cause for concern with respect to effective fracture prevention. There are also reports that dispensings at pharmacies are too few and far between to provide adequate drug exposure (measured as refill compliance). Oral alendronate, a bisphosphonate, constitutes ~80% of all osteoporosis treatments and is generally recommended for 3-5 years. Treating osteoporosis have in most industrialized countries been estimated to be cost-effective (compared with no treatment) but this depends on several factors, such as the risk of the patient population, drug costs, treatment effectiveness, and the treatment alternatives being compared. Treatment adherence is often not factored into such cost-effectiveness analyses. Objectives: This thesis aims at addressing pharmacoepidemiologic and health economic aspects of poor compliance and persistence to osteoporosis treatment by both establishing the extent of the problem and consequences for fracture risk in a Swedish setting, as well as investigating how it can be incorporated into the health economic framework to inform reimbursement decisions and regional priorities for recommended prescription standards. The topics of health-economic value or treatment persistence are by no means specific to the Swedish setting. Therefore, even though the included publications are based on Swedish data, the background and findings are also often put in an international context, or entirely without reference to geography. Methods & papers: Three of the articles used Swedish register data on pharmacy dispensings, diagnosis codes, and mortality. Repeat dispensings at pharmacies by 57,000 individuals were used to estimate refill persistence and refill compliance as an approximation of true drug exposure. Paper I investigated the proportion of patients starting an osteoporosis treatment that stopped their treatment prematurely at different time points, as well as the implications on the risk of fracture in groups stratified by refill persistence. Paper II addressed how automatic generic substitution (for off-patent medication) influence persistence to treatment of oral bisphosphonates. A natural experiment was devised for the years 2006-2009 where an off-patent medication was compared to an on-patent medication to isolate the effect of generic substitution. The effect on persistence for patients getting their first medication refill substituted at the pharmacy was also investigated. Paper III, amended with a new analysis in a larger dataset, investigated the residual effect after treatment with bisphosphonates on fracture risk and explored whether a healthy adherer effect (i.e. that patients with an inherently lower fracture risk stay longer on treatment) confounds the association between refill persistence and residual anti-fracture effect. Paper IV proposes a health economic simulation model framework for incorporating adherence and studying the important drivers of cost-effectiveness in this context. Main conclusions: • Refill persistence to typical oral osteoporosis medication estimated from pharmacy dispensing in Sweden is poor, with ~50% stopping treatment within 12 months. Prescription refill gaps among persistent patients appears to be a margnial problem, with 96% of patients having access to >80% of intended doses. • Poor refill persistence to osteoporosis treatments is associated with an increased fracture risk in an exposure-dependant manner. • Automatic generic substitution of alendronate tablets at pharmacies was likely causing reduced treatment persistence to treatment during 2006- 2009. Patients who had their alendronate product substituted at the first prescription refill had 25% higher risk of stopping their treatment. This topic should be revisited in more recent data and for other therapeutic areas. • It is likely that treatments shorter than 6 months with oral bishposphonates has little effect on fracture risk. • Oral bisphophonates taken for at least 12 months may confer a residual effect of 20-35% on the risk of any fracture for up to 5 years after stopping treatment. It is not clear if and how such a residual effect wanes with time after stopping treatment. The health economic implications of residual effect can be considerable, depending on the context. • There is a statistically significant inverse relationship between time on bisphosphonate treatment and post-treatment fracture risk. This finding supports an assumption that the magnitude of a residual effect depends on the preceding time on treatment with bisphophonates in health-economic evaluations. • Incorporating treatment adherence into a health economic evaluation in osteoporosis can have a substantial impact, but is context specific. The choice of accounting for or disregarding adherence to treatment may have an impact on both treatment recommendations, priorities, reimbursement, and prices of treatments for osteoporosis. Poor persistence to osteoporosis treatments causes increased morbidity and mortality. Improving persistence to osteoporosis treatments would confer substantial health benefit for both patients and society. The clinical and health-economic consequences of persistence to osteoporosis treatments should not be disregarded when setting priorities and drug prices

A review of the effectiveness of lower limb orthoses used in cerebral palsy

To produce this review, a systematic literature search was conducted for relevant articles published in the period between the date of the previous ISPO consensus conference report on cerebral palsy (1994) and April 2008. The search terms were 'cerebral and pals* (palsy, palsies), 'hemiplegia', 'diplegia', 'orthos*' (orthoses, orthosis) orthot* (orthotic, orthotics), brace or AFO