Bisphosphonate alternative regimens for the prevention of osteoporotic fragility fractures: BLAST-OFF, a mixed-methods study.

Background: Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates are available, which can be given intravenously and have been shown to improve long-term adherence. However, the most clinically effective and cost-effective alternative bisphosphonate regimen remains unclear. What is the most cost-effective bisphosphonate in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice. Objectives: 1. Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. 2. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. 3. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities. Methods: The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: • Stage 1A - we elicited patient and healthcare experiences to understand their preferences of bisphosphonates for the treatment of osteoporosis. This was undertaken by performing a systematic review and framework synthesis of qualitative studies, followed by semistructured qualitative interviews with participants. • Stage 1B - we updated and expanded the existing Health Technology Assessment systematic review and clinical and cost-effectiveness model, incorporating a more comprehensive review of treatment efficacy, safety, side effects, compliance and long-term persistence. • Stage 2 - we identified and ranked further research questions that need to be answered about the effectiveness and acceptability of bisphosphonates. Results: Patients and healthcare professionals identified a number of challenges in adhering to bisphosphonate medication, balancing the potential for long-term risk reduction against the work involved in adhering to oral alendronate. Intravenous zoledronate treatment was generally more acceptable, with such regimens perceived to be more straightforward to engage in, although a portion of patients taking alendronate were satisfied with their current treatment. Intravenous zoledronate was found to be the most effective, with higher adherence rates compared to the other bisphosphonates, for reducing the risk of fragility fracture. However, oral bisphosphonates are more cost-effective than intravenous zoledronate due to the high cost of zoledronate administration in hospital. The importance of including patients and healthcare professionals when setting research priorities is recognised. Important areas for research were related to patient factors influencing treatment selection and effectiveness, how to optimise long-term care and the cost-effectiveness of delivering zoledronate in an alternative, non-hospital setting. Conclusions: Intravenous zoledronate treatment was generally more acceptable to patients and found to be the most effective bisphosphonate and with greater adherence; however, the cost-effectiveness relative to oral alendronate is limited by its higher zoledronate hospital administration costs. Future work: Further research is needed to support people to make decisions influencing treatment selection, effectiveness and optimal long-term care, together with the clinical and cost-effectiveness of intravenous zoledronate administered in a non-hospital (community) setting. Limitations: Lack of clarity and limitations in the many studies included in the systematic review may have under-interpreted some of the findings relating to effects of bisphosphonates. Trial registration: This trial is registered as ISRCTN10491361. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127550) and is published in full in Health Technology Assessment; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.

Bisphosphonates are drug treatments commonly used to treat osteoporosis. Alendronate is the most used and is taken by mouth, weekly at a specific time of the week, which can be challenging. Less than one in four people continue this treatment beyond 2 years. Alternative bisphosphonates are available, which vary in frequency and how they are administered. The most acceptable and best value-for-money regimen is unclear. Our aim was to determine how effective alternative bisphosphonates are compared to alendronate at preventing fractures and whether reduction in fracture risk was achieved at a reasonable financial cost, but acceptable to patients. The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: Stage 1A: a review of the published evidence on patients' and doctors' views, experiences and preferences regarding different bisphosphonate treatment regimens, followed by interviews with patients and healthcare professionals. Stage 1B: an update of an existing study on how effective bisphosphonates are in preventing fragility fractures caused by osteoporosis and whether they are good value for money. Stage 2: identification of questions that need to be answered about the effectiveness and acceptability of bisphosphonate treatments. Taking bisphosphonate medication often involves quite a lot of effort by patients, particularly when taking alendronate tablets. A yearly infusion of zoledronate treatment was more acceptable, easier to engage with and the most effective treatment compared to alendronate. However, the cost of administering zoledronate in hospital made alendronate better value for money. Bisphosphonates are effective in reducing the risk of fracture, but 'continuing with treatment', particularly alendronate tablets, remains a challenge. A yearly infusion of zoledronate offers an acceptable and effective treatment, but further research is needed to support patients and healthcare professionals in making decisions about the various treatments, benefits and cost savings of administering zoledronate outside of hospital and in the community.

Long-Term Effect of Weight Regain Following Behavioral Weight Management Programs on Cardiometabolic Disease Incidence and Risk: Systematic Review and Meta-Analysis.

BACKGROUND: Behavioral weight management programs (BWMPs) enhance weight loss in the short term, but longer term cardiometabolic effects are uncertain as weight is commonly regained. We assessed the impact of weight regain after BWMPs on cardiovascular risk factors, diabetes, and cardiovascular disease. METHODS: Trial registries, 11 databases, and forward-citation searching (latest search, December 19) were used to identify articles published in English, from any geographical region. Randomized trials of BWMPs in adults with overweight/obesity reporting cardiometabolic outcomes at ≥12 months at and after program end were included. Differences between more intensive interventions and comparator groups were synthesized using mixed-effects, meta-regression, and time-to-event models to assess the impact of weight regain on cardiovascular disease incidence and risk. RESULTS: One hundred twenty-four trials reporting on ≥1 cardiometabolic outcomes with a median follow-up of 28 (range, 11-360) months after program end were included. Median baseline participant body mass index was 33 kg/m2; median age was 51 years. Eight and 15 study arms (7889 and 4202 participants, respectively) examined the incidence of cardiovascular disease and type 2 diabetes, respectively, with imprecise evidence of a lower incidence for at least 5 years. Weight regain in BWMPs relative to comparators reduced these differences. One and 5 years after program end, total cholesterol/HDL (high-density lipoprotein) ratio was 1.5 points lower at both times (82 studies; 19 003 participants), systolic blood pressure was 1.5 mm mercury and 0.4 mm lower (84 studies; 30 836 participants), and HbA1c (%) 0.38 lower at both times (94 studies; 28 083 participants). Of the included studies, 22% were judged at high risk of bias; removing these did not meaningfully change results. CONCLUSIONS: Despite weight regain, BWMPs reduce cardiometabolic risk factors with effects lasting at least 5 years after program end and dwindling with weight regain. Evidence that they reduce the incidence of cardiovascular disease or diabetes is less certain. Few studies followed participants for ≥5 years. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42018105744.

Weight regain after behavioural weight management programmes and its impact on quality of life and cost effectiveness: Evidence synthesis and health economic analyses.

AIMS: We used data from a recent systematic review to investigate weight regain after behavioural weight management programmes (BWMPs, sometimes referred to as lifestyle modification programmes) and its impact on quality-of-life and cost-effectiveness. MATERIALS AND METHODS: Trial registries, databases and forward-citation searching (latest search December 2019) were used to identify randomized trials of BWMPs in adults with overweight/obesity reporting outcomes at ≥12 months, and after programme end. Two independent reviewers screened records. One reviewer extracted data and a second checked them. The differences between intervention and control groups were synthesized using mixed-effect, meta-regression and time-to-event models. We examined associations between weight difference and difference in quality-of-life. Cost-effectiveness was estimated from a health sector perspective. RESULTS: In total, 155 trials (n > 150 000) contributed to analyses. The longest follow-up was 23 years post-programme. At programme end, intervention groups achieved -2.8 kg (95%CI -3.2 to -2.4) greater weight loss than controls. Weight regain after programme end was 0.12-0.32 kg/year greater in intervention relative to control groups, with a between-group difference evident for at least 5 years. Quality-of-life increased in intervention groups relative to control at programme end and thereafter returned to control as the difference in weight between groups diminished. BWMPs with this initial weight loss and subsequent regain would be cost-effective if delivered for under £560 (£8.80-£3900) per person. CONCLUSIONS: Modest rates of weight regain, with persistent benefits for several years, should encourage health care practitioners and policymakers to offer obesity treatments that cost less than our suggested thresholds as a cost-effective intervention to improve long-term weight management. REGISTRATION: The review is registered on PROSPERO, CRD42018105744.

The Acute VertEbRal AugmentaTion (AVERT) study: protocol for a randomised controlled, feasibility trial of spinal medial branch nerve block in hospitalised older patients with vertebral fragility fractures.

INTRODUCTION: Vertebral fragility fractures (VFFs) are the most common type of osteoporotic fracture found in older people, resulting in increasing morbidity and excess mortality. These fractures can cause significant pain, requiring admission to hospital. Vertebroplasty (VP) is effective in reducing pain and allowing early mobilisation in hospitalised patients. However, it may be associated with complications such as cement leakage, infection, bleeding at the injection site and fracture of adjacent vertebrae. It is also costly and not readily accessible in many UK hospitals.A recent retrospective study reported that spinal medial branch nerve block (MBNB), typically used to treat facet arthropathy, had similar efficacy in terms of pain relief compared with VP for the treatment of painful VFF. However, to date, no study has prospectively compared MBNB to VP. We therefore propose a prospective feasibility randomised controlled trial (RCT) to compare the role of MBNB to VP, in hospitalised older patients. METHOD: A parallel, two-arm RCT with participants allocated on a 1:1 ratio to either standard care-VP or MBNB in hospitalised patients aged over 70 with acute osteoporotic vertebral fractures. Follow-up will be at weeks 1, 4 and 8 post intervention. The primary objective is to determine the feasibility and design of a future trial, including specific outcomes of recruitment, adherence to randomisation and safety. Embedded within the trial will be a health economic evaluation to understand resource utilisation and implications of the intervention and a qualitative study of the experiences and insights of trial participants and clinicians. Secondary outcomes will include pain scores, analgesia requirements, resource use and quality of life data. ETHICS AND DISSEMINATION: Ethical approval was granted by the Yorkshire & the Humber Research Ethics Committee (reference 21/YH/0065). AVERT (Acute VertEbRal AugmentaTion) has received approval by the Health Research Authority (reference IRAS 293210) and is sponsored by Nottingham University Hospitals NHS Trust (reference 21HC001). Recruitment is ongoing. Results will be presented at relevant conferences and submitted to appropriate journals for publication on completion. TRIAL REGISTRATION NUMBER: ISRCTN18334053.