Health Technology Assessment (Apr 2024)
Bisphosphonate alternative regimens for the prevention of osteoporotic fragility fractures: BLAST-OFF, a mixed-methods study
Abstract
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 Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. 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. Plain language summary Background 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. Aim 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. Design and methods 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. Results 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. Conclusions 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. Scientific summary Background Alendronate (ALN) is recommended as the first-line osteoporosis treatment to prevent osteoporotic fractures; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates (BP) are available, which vary in frequency of use and/or route of administration and have been shown to improve long-term adherence compared to ALN. 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 BP in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice. Objectives Explore patient, clinician and stakeholder views, experiences and preferences of ALN compared to alternative BP. Update and refine the 2016 systematic review and cost-effectiveness analysis of BP and estimate the value of further research into the relative benefits. 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 clinician experiences of different BP regimens to understand their preferences and those of other stakeholders compared to ALN. This was undertaken by performing a systematic review and framework synthesis of qualitative studies around clinician and patient views, followed by semistructured qualitative interviews with multidisciplinary stakeholders. Stage 1B: we updated and expanded the existing Health Technology Assessment 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. The model takes a NHS and Personal Social Services perspective, with future costs and quality-adjusted life-years (QALYs) discounted at 3.5% per annum. Costs are reported in pound sterling based on 2021 prices. Stage 2: using an approach based on the James Lind methodology for identification and prioritisation of research questions, we identified questions that needed to be answered about the effectiveness and acceptability of BP. Findings from stages 1A and 1B, together with multidisciplinary meetings, identified areas of uncertainty. These questions were then ranked in a multidisciplinary, nationally representative stakeholder event, conducted online over MS Teams. Results We identified, through a systematic review of previous studies on patient and clinician experiences of BP treatment, how patients and healthcare professionals make sense (coherence) of BP by balancing perceptions of need against concerns, how uncertainty prevails about BP-perceived effectiveness and a number of individual and service factors that have potential to increase self-efficacy in recommending and adhering to BP. The qualitative interview study examining experiences of alternate BP regimens found that intravenous (IV) BP zoledronate (ZOL) treatment was generally more acceptable to patients. Such IV regimens were perceived to be more straightforward to engage in, although a portion of patients taking ALN were satisfied with their current treatment. The systematic review and network meta-analysis of previous studies of effectiveness found that IV ZOL was the most effective BP compared to ALN, risedronate and oral ibandronate for reducing the risk of fragility fractures. Adherence was higher in IV ZOL users. It was found that clinical decision-making could be facilitated by considering adherence patterns in BP users who were at increased risk of fracture. However, the higher hospital administration costs for IV ZOL meant that the incremental cost-effectiveness ratios for IV ZOL compared to ALN were greater than £30,000 per QALY across all risk categories. This was despite the fact that IV ZOL was predicted to result in fewer fractures than ALN, due to its higher treatment persistence and a longer offset period. The prioritisation exercise highlighted a need for further research to tackle the issues relating to patient factors influencing treatment selection and effectiveness, including in younger adults, how to optimise long-term care and support patient and clinician decision-making and the clinical and cost-effectiveness of giving IV ZOL in alternate settings to hospital care. Conclusions We have identified the factors that influence how patients and clinicians make sense of BP, described the experience of BP taking in terms of burden and identified factors that both facilitate and hinder confidence in taking and prescribing and monitoring BP. IV ZOL treatment was generally more acceptable to patients. IV ZOL was found to be the most effective BP and with greater adherence; however, the cost-effectiveness of IV ZOL relative to ALN was limited by the high hospital administration costs. Further research is needed to support people to make decisions influencing treatment selection and effectiveness and establish how to optimise long-term care. In addition, research is needed to explore the clinical and cost-effectiveness of IV ZOL delivered in alternate settings, such as in the community, compared to ALN treatment. Patient and public involvement We have worked 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 were involved throughout the study. Trial registration This trial is registered as ISRCTN10491361. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR127550) and is published in full in Health and Social Care Delivery Research; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.
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