Corrigendum: A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures

Davis, Sarah; James, Marrissa Martyn-St; Sanderson, Jeremy; Stevens, John; Goka, Edward; Rawdin, Andrew; Sadler, Susannah; Wong, Ruth; Campbell, Fiona; Stevenson, Matt; Strong, Mark; Selby, Peter L.; Gittoes, Neil

doi:10.3310/hta20780-c201803

Cited by 3 publications

(4 citation statements)

References 158 publications

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“…149 Table 37 of the analysis underpinning TA464 150 has something similar, although note that this is based on an uncorrected network metaanalysis, and the corrigendum does not include an updated version of the same information. 147 Whether adjusted for competing risk or not, the updated model estimates that alendronate prevents slightly more fractures than the previous models in all categories except wrist fracture, and this is because the longer duration of treatment (and consequent extension of offset period) gives more time for the intervention to provide benefit. The reduced efficacy for wrist fracture compared with the 2020 HTA 149 is probably a result of different inputs, for example the network meta-analysis developed for the 2020 HTA 149 included a wider range of comparators and estimated a greater mean effect for bisphosphonates in preventing wrist fractures.…”

Section: Accounting For Competing Riskmentioning

confidence: 94%

“…The analysis concluded that oral bisphosphonates are likely to represent an effective use of NHS resources for anyone whose 10-year risk of MOF exceeds 1.5%. 147 The same authors updated their model as part of a further health technology assessment (HTA) for a subsequent NICE appraisal, and this focused on antiosteoporosis medicines other than bisphosphonates, but included bisphosphonates as comparators, although NICE subsequently chose to suspend the appraisal. 148 The updated model found that a somewhat higher level of risk, than in TA464, 12 would be necessary for oral bisphosphonates to provide reasonable value for money, although the precise threshold is not quantified.…”

Section: Selection Of the Case Studymentioning

confidence: 99%

“…We took our estimates of the effectiveness of alendronate in preventing four categories of fragility fracture from TA464. (Note that these estimates are the outputs of the authors' corrected network meta-analysis, see corrigendum to Davis et al 147 )…”

Section: Treatment Effectivenessmentioning

confidence: 99%

“…Although we would reiterate that our results should not be seen as a present-day best estimate of the cost-effectiveness of bisphosphonates, our results are closely comparable with the results generated in previous iterations of the same underlying model. 147,149,150 Alendronate is associated with small but positive net benefit in people with approximately the highest-third of fracture risk (i.e. anything above around 5% per year).…”

Section: Main Findingsmentioning

confidence: 99%

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The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis

Guthrie,

Rogers,

Livingstone

et al. 2024

Health Soc Care Deliv Res

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Background Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to account for direct treatment disutility (i.e. the hassle of taking treatments). We explored these issues using two case studies: primary prevention of cardiovascular disease using statins and osteoporotic fracture using bisphosphonates. Objectives Externally validate three risk prediction tools [QRISK®3, QRISK®-Lifetime, QFracture-2012 (ClinRisk Ltd, Leeds, UK)]; derive and internally validate new risk prediction tools for cardiovascular disease [competing mortality risk model with Charlson Comorbidity Index (CRISK-CCI)] and fracture (CFracture), accounting for competing-cause death; quantify direct treatment disutility for statins and bisphosphonates; and examine the effect of competing risks and direct treatment disutility on the cost-effectiveness of preventative treatments. Design, participants, main outcome measures, data sources Discrimination and calibration of risk prediction models (Clinical Practice Research Datalink participants: aged 25–84 years for cardiovascular disease and aged 30–99 years for fractures); direct treatment disutility was elicited in online stated-preference surveys (people with/people without experience of statins/bisphosphonates); costs and quality-adjusted life-years were determined from decision-analytic modelling (updated models used in National Institute for Health and Care Excellence decision-making). Results CRISK-CCI has excellent discrimination, similar to that of QRISK3 (Harrell’s c = 0.864 vs. 0.865, respectively, for women; and 0.819 vs. 0.834, respectively, for men). CRISK-CCI has systematically better calibration, although both models overpredict in high-risk subgroups. People recommended for treatment (10-year risk of ≥ 10%) are younger when using QRISK-Lifetime than when using QRISK3, and have fewer observed events in a 10-year follow-up (4.0% vs. 11.9%, respectively, for women; and 4.3% vs. 10.8%, respectively, for men). QFracture-2012 underpredicts fractures, owing to under-ascertainment of events in its derivation. However, there is major overprediction among people aged 85–99 years and/or with multiple long-term conditions. CFracture is better calibrated, although it also overpredicts among older people. In a time trade-off exercise (n = 879), statins exhibited direct treatment disutility of 0.034; for bisphosphonates, it was greater, at 0.067. Inconvenience also influenced preferences in best–worst scaling (n = 631). Updated cost-effectiveness analysis generates more quality-adjusted life-years among people with below-average cardiovascular risk and fewer among people with above-average risk. If people experience disutility when taking statins, the cardiovascular risk threshold at which benefits outweigh harms rises with age (≥ 8% 10-year risk at 40 years of age; ≥ 38% 10-year risk at 80 years of age). Assuming that everyone experiences population-average direct treatment disutility with oral bisphosphonates, treatment is net harmful at all levels of risk. Limitations Treating data as missing at random is a strong assumption in risk prediction model derivation. Disentangling the effect of statins from secular trends in cardiovascular disease in the previous two decades is challenging. Validating lifetime risk prediction is impossible without using very historical data. Respondents to our stated-preference survey may not be representative of the population. There is no consensus on which direct treatment disutilities should be used for cost-effectiveness analyses. Not all the inputs to the cost-effectiveness models could be updated. Conclusions Ignoring competing mortality in risk prediction overestimates the risk of cardiovascular events and fracture, especially among older people and those with multimorbidity. Adjustment for competing risk does not meaningfully alter cost-effectiveness of these preventative interventions, but direct treatment disutility is measurable and has the potential to alter the balance of benefits and harms. We argue that this is best addressed in individual-level shared decision-making. Study registration This study is registered as PROSPERO CRD42021249959. 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: 15/12/22) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

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Section: Accounting For Competing Riskmentioning

confidence: 94%

Section: Selection Of the Case Studymentioning

confidence: 99%

Section: Treatment Effectivenessmentioning

confidence: 99%

Section: Main Findingsmentioning

confidence: 99%

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The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis

Guthrie,

Rogers,

Livingstone

et al. 2024

Health Soc Care Deliv Res

Self Cite

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Measuring Drug Therapy Effect on Osteoporotic Fracture Risk by Trabecular Bone Lacunarity: The LOTO Study

et al. 2023

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An MRI method providing one parameter (TBLβ: trabecular-bone-lacunarity-parameter-β) that is sensitive to trabecular bone architecture (TBA) changes with aging and osteoporosis is under study as a new tool in the early diagnosis of bone fragility fracture. A cross-sectional and prospective observational study (LOTO: Lacunarity Of Trabecular bone in Osteoporosis) on over-50s women, at risk for bone fragility fracture, was designed to validate the method. From the baseline data, we observed that in women with prevalent vertebral fractures (VF+), TBA was differently characterized by TBLβ when osteoporosis treatment is considered. Here we verify the potential of TBLβ as an index of osteoporosis treatment efficacy. Untreated (N = 156) and treated (N = 123) women were considered to assess differences in TBLβ related to osteoporosis treatment. Prevalent VFs were found in 31% of subjects, 63% of which were under osteoporosis medications. The results show that TBLβ discriminates between VF+ and VF− patients (p = 0.004). This result is mostly stressed in untreated subjects. Treatment, drug therapy in particular (89% Bisphosphonates), significantly counteracts the difference between VF+ and VF− within and between groups: TBLβ values in treated patients are comparable to untreated VF− and statistically higher than untreated VF+ (p = 0.014) ones. These results highlight the potential role of TBLβ as an index of treatment efficacy.

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A preliminary study on the mechanism of skeletal abnormalities in Turner syndrome using inducing pluripotent stem cells (iPS)-based disease models

Cui

Shi

et al. 2019

IRDR

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Osteoporosis represent one of main characteristics of Turner syndrome (TS), a rare diseases caused by aberrant deletion of X chromosomes, however, the underlying pathological mechanism remains unknown yet. In this study, we used pluripotent stem cells (iPSCs) derived from a Turner syndrome patient and a health control to induce functional osteoblasts and osteoclasts, in order to compare their difference in these two differentiation. We successfully produced functional osteoblasts and osteoclasts from iPSCs through embryoid bodies (EBs) and mesoderm stages, as demonstrated obvious mineralized nodules and multi-nuclear giant cells with positive tartrate-resistant acid phosphatase (TRAP) staining, and significant up-regulated differentiation marker genes. Interestingly, we found that there was no significant difference in phenotype and marker genes expression between osteoblasts from Turner syndrome and healthy control iPSCs. In contrast, Turner syndrome showed increased osteoclastogenesis compared to the healthy control indicating higher frequency of multi-nuclear TRAP staining cells and elevated osteoclast marker genes TRAP, MMP9, CA2, OSCAR. Therefore, our results suggest that the low bone density of Turner syndrome patients may be caused by aberrant osteoclast differentiation, and further investigation towards osteoclast function under Turner syndrome is deserved.

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Corrigendum: A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures

Cited by 3 publications

References 158 publications

The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis

The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis

Measuring Drug Therapy Effect on Osteoporotic Fracture Risk by Trabecular Bone Lacunarity: The LOTO Study

A preliminary study on the mechanism of skeletal abnormalities in Turner syndrome using inducing pluripotent stem cells (iPS)-based disease models

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