Response to the commissioned call
This report presents the findings from a National Institute for Health and Care Research (NIHR)-funded study that was conducted between May 2019 and February 2022. The study was developed in response to a Health Technology Assessment (HTA) programme call in 2018, inviting applications for a mixed-methods study to explore and ascertain the evidence for effectiveness and cost-effectiveness of the different bisphosphonate (BP) regimens compared to oral alendronate (ALN), as well as capturing the experience and opinion of these communities.
The commissioned research question was:
What is the clinical and cost-effectiveness of alternative regimens of BP use in comparison to the standard regimen of ALN in preventing osteoporotic fracture in adults?
- Intervention: Alternative BP regimens for the prevention of osteoporotic fracture in adults.
- Patient group: Adults diagnosed with osteoporosis and/or fragility fracture, where current guidelines recommend prophylactic treatment with BP.
- Setting: Primary care and any other suitable setting.
- Comparator: Current standard ALN regimen (as per guidelines).
- Study design: (1) A systematic review and cost-effectiveness analysis of different BP regimens. (2) A qualitative study to explore patient and clinician views and experiences of current regimens (including, but not limited to, individuals who are engaged in research) and to identify the most important research questions for these communities in relation to BP use.
- Outcomes/outputs: Findings of the systematic review and cost-effectiveness, patient and clinician experience and opinion; recommendations for future research, including research questions acceptable to patients, clinicians and researchers.
Bisphosphonate and adherence in context
Osteoporosis is a condition that is characterised by low bone mass and structural deterioration of bone tissue, resulting in bone fragility and susceptibility to fracture – ‘fragility fracture’.1 The condition is age-related and particularly common in postmenopausal women. Current National Institute for Health and Care Excellence (NICE) guidelines recommend that people with osteoporosis and fragility fracture or with osteoporosis and risk factors indicating high risk of future fracture should be offered BP treatment.2 This treatment has been shown to increase bone density and reduce the risk of fragility fracture by 20–70%, depending on the site of fracture.3–5
Alendronate is recommended as the first-line BP treatment in adults in England and Wales;2 however, complex dosing instructions are required to support drug absorption and reduce side effects. This medication is taken orally, once a week, at least 30 minutes before food or other medicines, with a minimum of 200 ml of plain water, and patients are recommended to remain upright while taking it and for at least 30 minutes after.6 Taking ALN correctly (treatment compliance) is challenging for some patients, in particular, older patients on multiple medications and those with underlying cognitive impairment.7,8 Long-term treatment persistence (defined as the cumulative time duration from initiation to discontinuation of therapy) is also poor with ALN. The reasons for this are multifactorial and include scepticism over benefits and safety, lack of understanding of the consequences of non-treatment and risk of or experienced side effects.9–14 In everyday clinical practice, long-term treatment adherence (encompassing both compliance and persistence)15 with ALN is poor, ranging from 16% to 42% over 2 years.16,17 Alternative BP regimens to ALN are available and vary in frequency of use and/or route of administration. These include monthly oral ibandronate (IBN), 3-monthly intravenous (IV) IBN and yearly IV zoledronate (ZOL). These alternative BP regimens have been shown to improve long-term adherence;18–21 however, the most clinically and cost-effective regimen remains unclear. Furthermore, clinicians should also take into account patient understanding, preferences and characteristics around medication. What is most cost-effective in clinical trials may not be the most cost-effective or acceptable in everyday clinical practice. Therefore, in keeping with the commissioning brief, a mixed-methods research study was undertaken to explore and ascertain the evidence for effectiveness and cost-effectiveness of the different BP regimens compared to ALN, as well as capturing the experience and opinions of clinicians and patients.
Importance in terms of improving the health of patients
Osteoporosis is a common clinical condition, affecting over 3 million people in the UK. This leads to weakening of the bones, making them fragile and more likely to fracture. In the UK, there are approximately 536,000 new fragility fractures each year, comprising 79,000 hip fractures, 66,000 clinically diagnosed vertebral fractures, 69,000 forearm fractures and 322,000 other fractures (i.e. fractures of the pelvis, rib and other long bones).22 The healthcare costs are enormous, estimated at £4.4 billion per year and are expected to rise by 25% over the next 5 years,23 due to an ageing society. Fragility fractures are a life-changing experience with consequent loss of mobility and independence, social isolation, depression and increased mortality.24,25 Any fragility fracture approximately doubles the risk of another fracture.22 A key priority of the NHS and NIHR (in its current themed call – complex health needs) is to promote healthy ageing and prevent unplanned hospital admissions. Hip fractures alone account for 85,000 unplanned admissions and 1.8 million bed-days in the UK per year.26 Effective fracture prevention is therefore an important strategy in meeting this aim and would impact favourably on several outcomes that are of importance to patients, including the ability to live independently, pain, disability and death. Improving long-term adherence alone with fracture prevention treatments from 60% to 80% would result in a saving to the NHS of £4.3 million over 5 years for secondary prevention.27,28
There is relatively little qualitative literature regarding patient experiences or preferences for BP regimens; for example, a systematic review and meta-ethnography of patient experiences of living with osteoporosis reported patient uncertainty about the purpose of medication but no findings relating to experiences of taking BP.29,30 Hiligsmann et al. reviewed existing quantitative preference studies in 2016 and concluded that patients generally preferred less frequent dosing regimens but noted variation in preferences.31,32 One important limitation of these discrete preference studies is that patients were asked to choose between hypothetical treatments and not real ones and were limited to four attributes (efficacy, side effects, route and frequency of administration). In real life, other practical attributes, such as how and how often the drug is administered, will also be important to patients. In a more recent qualitative study exploring the reasons for non-adherence, upper gastrointestinal (GI) side effects with ALN were graphically described, although anticipation of side effects was as much a deterrent to adherence as was actually experiencing the side effects.33 For those able to tolerate oral BP, various strategies have been proposed to try and improve long-term adherence, which include the use of reminders, patient education and treatment monitoring.34–37 A Cochrane review of strategies to improve treatment adherence highlighted the importance of more frequent patient interactions and regular discussion over compliance issues.38 The International Bone Working Group on treatment adherence recently recommended the routine use of bone turnover markers to aid treatment compliance.39 A preferred alternative to oral BP, whether daily, weekly or monthly is an annual, IV infusion of BP (ZOL). Patients have reported increased satisfaction with ZOL compared with weekly ALN and higher long-term adherence.40,41 Administering BP intravenously is an obvious strategy to improve compliance, and ZOL is inexpensive; however, needle phobia, infusion centre costs, side effects, scheduling reminders and the treatment burden of attending hospital for the infusion are potential barriers to long-term persistence. Across Nottinghamshire, to address some of these challenges, IV ZOL is now administered as first-line treatment to older patients with fragility fractures directly in their own home,42 with high patient preference and high satisfaction when compared to the same drug being administered during attendance at a hospital-based infusion centre.43 Within central Nottingham, IV ZOL is administered as part of the community osteoporosis service, thereby addressing not only issues around drug administration but also issues around patient education, benefits of treatment and long-term persistence.44 The recent HTA systematic review and economic evaluation of BP for the prevention of fragility fractures, led by our co-applicants SD and NG45 and which informed the NICE TA464 guideline,2 concluded that BP are effective in preventing fragility fractures; however, the benefit-to-risk ratio in the lowest-risk patients may be debatable given the low absolute quality-adjusted life-year (QALY) gains and the potential for adverse events. While the model was structured to allow direct comparisons between different BP, several simplifying assumptions were made that limited the accuracy of the comparisons between the different BP treatments. For example, the model assumed equivalent treatment persistence and adverse effects for all oral BP, whether they are given daily, weekly or monthly. One situation in which this may be problematic is when considering the frequency of GI adverse events, which relates to oral administration. Similarly, the adverse events and treatment persistence for quarterly IV IBN were assumed to be the same as those for yearly IV ZOL.