Title: The BLAST OFF (Bisphosphonate aLternAtive regimenS for the prevenTion of Osteoporotic Fragility Fractures) Study
Funder: Department of Health and Social Care

Abstract: Background_x000D_ Osteoporosis is a condition where the bones become weak, are described as fragile and can easily break (fracture). When a person has suffered one fragility fracture, the risk of sustaining another is high. Bisphosphonates are medicines prescribed for osteoporosis that reduce the risk of fracture. Alendronate is the bisphosphonate that is most commonly used and has to be taken weekly, at a specific time of day, which can be challenging for some patients to follow (treatment compliance). Less than 1 in 4 people continue this treatment (treatment persistence) beyond 2 years. Alternative bisphosphonates are available, which vary in frequency and how they are administered (Zoledronate, for example is given an as an injection once every year). This approach has shown better compliance and longer-term persistence than weekly Alendronate, although the most acceptable and best value for money regimen remains unclear._x000D_ _x000D_ Aim_x000D_ We aim to determine how effective alternative bisphosphonates are compared to oral Alendronate at preventing fractures and whether reduction in fracture risk is achieved at a reasonable financial cost, but acceptable to patients._x000D_ _x000D_ Design and methods_x000D_ The study will be conducted in two stages, stages 1A and 1B in parallel, followed by stage 2._x000D_ _x000D_ • Stage 1A-we plan to update an existing study on the effectiveness of and value for money provided by bisphosphonates for the prevention of fragility fractures published in 2016 which has informed current national guidelines. As part of this we will also conduct a more comprehensive review of studies which have assessed treatment compliance, long-term persistence and safety. _x000D_ _x000D_ • Stage 1B-we will undertake a review of the published evidence on patients' and doctors' views, experiences and preferences regarding different bisphosphonate treatment regimens, followed by more structured interviews to explore the findings from the review. Interviews will be conducted with patients, doctors and other healthcare members that provide the care of patients with osteoporosis, including people doing research._x000D_ _x000D_ • Stage 2-we will identify questions that need to be answered about the effectiveness and acceptability of bisphosphonate treatment regimens. We will use the findings from Stage 1A and 1B to identify areas of uncertainty. We will then work with patients, doctors and researchers to generate research questions from these uncertainties, followed by a face-to-face event with a nationally representative group of patients, doctors and other healthcare workers/managers to rank these research questions in order of importance. _x000D_ _x000D_ Patient and public involvement_x000D_ We are working closely with the Royal Osteoporosis Society (ROS) and the Nottingham ROS (NotROS) Support Group, who together have influenced the design of this application, choice of study outcomes and will be involved throughout the study. _x000D_ _x000D_ Outputs:_x000D_ This study will benefit patients, clinicians and the NHS by identifying:_x000D_ • Which bisphosphonate treatment regimens are most effective at reducing fractures, provide value for money and are acceptable to patients._x000D_ • What patients, clinicians and researchers think are the most important research priorities in this area._x000D_ _x000D_ Dissemination_x000D_ We will work with the NOS to disseminate our results to policy makers, healthcare managers and professionals, researchers and PPI groups, through newsletters, websites, social media, research publications and national meetings.

Lay abstract: Research question_x000D_ To determine the most effective, cost-effective, acceptable and safe alternative bisphosphonate treatment regimen(s) compared to oral Alendronate, in preventing osteoporotic fractures._x000D_ _x000D_ Background _x000D_ Alendronate is recommended as the first line treatment to prevent osteoporotic fractures, however long term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates are available, which vary in frequency of use and/or route of administration, and have been shown to improve long-term adherence compared to oral Alendronate. However, the most clinically effective and cost effective alternative regimen remains unclear. Furthermore, clinicians should optimise dosing regimens on the basis of the patient’s understanding, preference and characteristics. What is the most cost-effective in clinically trials may not be the most cost-effective or acceptable to patients in everyday clinical practice._x000D_ _x000D_ Objectives_x000D_ 1. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates and estimate the value of further research into the relative benefits;_x000D_ 2. Explore patient, clinician and stakeholder views, experiences and preference of oral Alendronate compared to alternative bisphosphonates;_x000D_ 3. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities._x000D_ _x000D_ Methods _x000D_ The study will be conducted in two stages, stages 1A and 1B in parallel, followed by stage 2._x000D_ _x000D_ • Stage 1A will update and expand the existing HTA systematic review and clinical and cost-effective health economic model (2016), incorporating a more comprehensive review of treatment efficacy, safety, side-effects, compliance and long-term persistence._x000D_ • Stage 1B will elicit patient and clinician experiences of the different bisphosphonate regimens, and understand their preferences and those of other stakeholders compared to oral Alendronate. We will undertake a scoping qualitative literature review around clinician and patient views, followed by semi-structured qualitative interviews, with multi-disciplinary stakeholders. _x000D_ • Stage 2 using an approach based on the James Lind methodology for identification and prioritisation of research questions, we will identify questions that need to be answered about the effectiveness and acceptability of bisphosphonate regimens. Findings from Stages 1A and 1B, together with multidisciplinary meetings will be used to identify areas of uncertainty. These questions will then be ranked in a face-to-face, multidisciplinary, nationally representative stakeholder event. _x000D_ _x000D_ Timelines for delivery_x000D_ Oct 2019: Active;_x000D_ Oct-Dec 2019: Regulatory approval; staff recruit;_x000D_ Jan 2020-Mar 2021: Stage 1A: Systematic review and Health economic analysis; Stage 1B: Qualitative study;_x000D_ April-July 2021: Stage 2: Stakeholder engagement/consensus; _x000D_ Aug-Sept 2021: Write up._x000D_ _x000D_ Impact and dissemination_x000D_ The study will benefit patients, clinicians and the NHS by identifying:_x000D_ • Clinical effectiveness, cost-effectiveness, acceptability and safety of bisphosphonate treatments_x000D_ • What patients, clinicians and researchers think are the important research priorities _x000D_ _x000D_ We will work with the Royal Osteoporosis Society to disseminate our results to policy makers, healthcare managers, researchers and PPI groups, through newsletters, websites, social media (webinars), research publications and structured regional stakeholder events.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: MUSCULOSKELETAL