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. 2026 Feb 26;16(2):e111364. doi: 10.1136/bmjopen-2025-111364

Efficacy of sequential denosumab after teriparatide for 6 months compared with denosumab monotherapy in reducing risk of osteoporotic fractures in patients with new fractures: a multicentre randomised controlled trial (STAND study) protocol

Yue Chi 1,0, Yidan Zhu 2,0, Jie Yuan 3, Qianqian Pang 1, Lijia Cui 1, Yan Jiang 1, Ruizhi Jiajue 1, Wei Liu 1, Ou Wang 1, Mei Li 1, Xiaoping Xing 1, Huijuan Li 4, Gaoqiang Xie 5, Yangfeng Wu 6,*, Weibo Xia 1,✉
PMCID: PMC12958968  PMID: 41748193

Abstract

Introduction

Osteoporosis (OP) is a systemic skeletal disorder that increases fragility and susceptibility to fractures. Despite the availability of teriparatide for the treatment of patients with acute fractures with better efficacy, its long-term daily injection and high cost limit its broader use among a wider patient population, especially for those living in low- and middle-income countries. This study aims to evaluate the efficacy of a novel sequential treatment with teriparatide daily for 6 months followed by denosumab every 6 months for another 18 months, in comparison with denosumab monotherapy every 6 months for 24 months, in reducing the risk of fractures in patients with newly diagnosed osteoporotic fractures. The study will also explore the possible difference between two sequential treatments (shifting to denosumab treatment at 6 or 12 months) in their effect on increasing bone mineral density (BMD).

Methods and analysis

This study is designed as a multicentre, open-label, randomised controlled trial among 2478 patients with newly diagnosed osteoporotic fractures from 58 hospitals across China. Participants will be randomly assigned in a 10:10:1 ratio to three treatment groups: 24 months of denosumab monotherapy, early sequential treatment (teriparatide for 6 months followed by denosumab for 18 months) and late sequential treatment (teriparatide for 12 months followed by denosumab for 12 months). The primary outcome is the incidence of vertebral fractures over 24 months of treatment. Secondary outcomes include changes in BMD at the lumbar spine, total hip and femoral neck, changes in bone turnover markers (β-carboxy-terminal telopeptide of type 1 collagen and procollagen type 1 N-terminal propeptide), treatment adherence and cost-effectiveness. Follow-up assessments are scheduled at 3, 6, 9, 12, 18 and 24 months post-randomisation for primary and secondary outcomes, and biannually afterwards for the primary outcome.

Ethics and dissemination

The study protocol has been registered on ClinicalTrials.gov and has received ethical approval from the Peking Union Medical College Hospital Medical Science Research Ethics Committee (1-22PJ939). The findings will be disseminated through peer-reviewed scientific journals.

Trial registration number

NCT05866029.

Keywords: Calcium & bone, Disease Management, Drug Therapy, Health Care Costs

STRENGTHS AND LIMITATIONS OF THIS STUDY.

  • This is a multicentre, randomised controlled trial that evaluates the treatment strategy with teriparatide sequential to denosumab in reducing imminent fracture risk, compared with denosumab monotherapy, in patients with osteoporosis.

  • The study employs a quality control system that includes an executive committee, a professional project management, an electronic data capture system with professional data management and a central laboratory of imaging.

  • The study includes both male and female participants and employs a comprehensive set of outcome measures, including fracture incidence, bone mineral density and bone turnover markers, which strengthens the reliability and value of its results.

  • The study is conducted solely in China and may limit its generalisability to other countries.

Background

Osteoporosis is a skeletal disorder that causes impairment of bone structure and strength and is considered a major health problem for the middle-aged and older adults. Over 20% of women aged 40 years or older in China have osteoporosis, and about 10% of them have sustained a vertebral fracture.1 The burden of fractures relates to the costs as well as the morbidity and associated mortality.2 Taking hip fractures as an example, the disability rate within 1 year after hip fractures is 50%, with a mortality rate of 20%, which is higher than that of various cancers.2,4 It is expected that the number of major osteoporotic fractures in China will be 5.99 million cases by 2050, with medical expenses reaching 22.3 billion dollars.5

The present challenge in clinical management of osteoporosis is the ‘imminent fracture risk after an initial fracture’, which refers to the extremely high risk of refracture within 24 months following an osteoporotic fracture, and the closer the fracture occurs, the higher the risk of refracture is.6

In recent years, significant progress has been made in the development of anti-osteoporosis drugs.7,9 Teriparatide is a synthetic analogue of parathyroid hormone (PTH)10 and has been shown to significantly enhance lumbar bone mineral density (BMD) in postmenopausal women11 12 and effectively reduce the risk of new vertebral fractures, providing strong evidence for its efficacy in osteoporosis management.13 14 Denosumab is a fully human monoclonal antibody targeting receptor activator of nuclear factor-κ B ligand (RANKL) and is effective at improving BMD in postmenopausal women with favourable safety and tolerability.15,17 In the FREEDOM trial, denosumab, compared with placebo, significantly reduced fracture incidence by 68% for vertebral fractures, 40% for hip fractures and 20% for non-vertebral fractures.15

Studies have explored the efficacy of sequential and combination therapies involving teriparatide and denosumab in the treatment of osteoporosis.18 19 A study by Leder et al18 showed that patients who received teriparatide for 24 months followed by denosumab experienced greater increases in BMD compared with those who received either treatment alone. Despite the demonstrated efficacy of teriparatide, adherence to this treatment regimen remains a significant concern.20,22 Research has shown that long-term compliance with teriparatide was suboptimal among Chinese patients,23 and the median treatment duration in patients of the USA was approximately 7.2 months.24 These findings suggest that the recommended sequential regimen of teriparatide for 2 years followed by denosumab may lack practical feasibility. In contrast, Shin et al25 found that short-term teriparatide use for ≥3 months before denosumab showed excellent results in reducing the risk of fragility fractures compared with denosumab monotherapy. Another study found that 6-month treatment with teriparatide significantly improved DXA scores in patients with osteoporosis.26 However, evidence supporting the efficacy of sequential denosumab following a shorter period of teriparatide treatment for osteoporosis in reducing risk of fracture is still lacking.

The present study comprises a main study and a substudy. The objective of the main study is to evaluate whether a 6-month course of teriparatide daily followed by denosumab therapy every 6 months (early sequential therapy) would reduce the risk of fracture over 2 years, compared with denosumab monotherapy every 6 months, among patients who had a fracture within the past 6 months. The objective of the substudy is to compare the early sequential therapy with teriparatide daily for 12 months followed by denosumab every 6 months for 12 months (late sequential therapy) in improving BMD among patients who have had a fracture within the past 6 months. The study will also explore changes in bone turnover markers (β-carboxy-terminal telopeptide of type 1 collagen (β-CTX) and procollagen type 1 N-terminal propeptide (P1NP)), treatment adherence and cost-effectiveness across different treatment groups.

Methods

Study design

The Sequential therapy with Teriparatide and Denosumab (STAND) study is a multicentre, randomised, open-label, active-controlled clinical trial designed to evaluate the efficacy of sequential therapies in Chinese patients with newly diagnosed osteoporotic fractures. The study protocol was developed following the Standard Protocol Items: Recommendations for Interventional Trials guidelines.27

The trial is being conducted across 58 hospitals in China. Patients with newly osteoporotic fractures will be randomised in a 10:10:1 ratio into the early sequential group, the monotherapy group and the late sequential group. The primary outcome for the main study (early sequential therapy vs monotherapy) is the incident vertebral fractures over 24 months of treatment, and the primary outcome for the substudy (early vs late sequential therapy) is the rate of per cent change in BMD from baseline for lumbar spine at 24 months.

The study has been approved by the Peking Union Medical College Hospital Medical Science Research Ethics Committee (1-22PJ939), and all study patients will provide written informed consent (see online supplemental material file 1). The study flowchart is shown in figure 1.

Figure 1. Flow chart of the study. Newly osteoporotic fractures refer to fragility fractures that occurred within the past 6 months; BMD, bone mineral density; BTMs, bone turnover markers.

Figure 1

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Patient and public involvement

Patients or the public will not participate in the design, conduct, reporting or dissemination plans of the research.

Study participants

Participants will be consecutively selected from patients in the departments of orthopaedics, endocrinology, rheumatology and geriatrics in the participating hospitals. Besides, to accelerate recruitment, the Chinese Osteoporotic Fracture Registration Network Platform cohort will also be searched for possible candidate patients.

Inclusion criteria

  1. Age range of 45–90 years old.

  2. Male or postmenopausal female.

  3. Be fully informed and sign an informed consent for trial participation.

  4. Meet one of the following conditions:

    1. Fragility hip fractures occurred in the past 6 months.

    2. Fragility vertebral fractures occurred in the past 6 months.

    3. Fragility fractures in other parts, including the proximal humerus, pelvis and distal forearm, with the T-score of either the total hip, femoral neck or L1-L4 BMD less than −1.0. Fractures affecting the fingers, toes, skull and ankles were excluded.

A fragility fracture is defined as a bone fracture resulting from minor trauma, equivalent to a fall from a standing height or less.

Exclusion criteria

  1. Presence of other metabolic bone disorders, including osteomalacia, osteogenesis imperfecta, Paget’s disease, Cushing’s syndrome, hyperprolactinaemia, etc.

  2. Current diagnosis of primary hyperparathyroidism or hypoparathyroidism.

  3. (a) History of current osteomyelitis or jaw necrosis; (b) unhealed dental or oral surgery wounds; (c) acute dental or maxillofacial conditions requiring oral surgery; (d) planned invasive dental surgery during the study period.

  4. Glomerular filtration rate <30 mL/min/1.73 m².

  5. Active infections.

  6. Use of intravenous bisphosphonates, fluorides or strontium ranelate within the past 2 years.

  7. Use of teriparatide or denosumab within the past 6 months.

  8. Use of glucocorticoids (equivalent to >5 mg/day prednisone) for more than 10 days in the past 6 weeks.

  9. Use of oral bisphosphonates within the last year, except for cases where the cumulative duration of use is less than 1 month.

  10. Diagnosis of malignant tumours or bone metastases within the past 5 years, except for tumours with expected curative outcomes (eg, completely resected basal cell or squamous cell carcinoma, cervical cancer or ductal carcinoma of the breast).

  11. Current hypocalcaemia or hypercalcaemia.

  12. Unexplained elevation of alkaline phosphatase levels.

  13. Severe vitamin D deficiency (25-hydroxyvitamin D <10 ng/mL) at screening (those who achieve ≥10 ng/mL after supplementation may be enrolled).

  14. Prior external irradiation or bone implantation radiation therapy.

  15. Uncontrolled comorbidities, including heart failure (New York Heart Association Functional Classification class III or higher), glycated haemoglobin >8.5%, or severe arrhythmia.

  16. Pregnancy or lactation during the study period.

  17. Allergic to teriparatide and denosumab.

  18. Participating in clinical trials of other drugs at present.

Data collection

Participants will be assessed at baseline and at 3-month intervals for the first year (3, 6, 9, 12 months), then at 6-month intervals thereafter (18, 24 months), resulting in a total of seven visits over 24 months. The study assessment schedule is presented in figure 2.

Figure 2. Study visit schedule and assessment timeline. BMD, bone mineral density; CBC, complete blood count; PTH, parathyroid hormone; 25(OH)D3, 25-hydroxyvitamin D3.

Figure 2

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Baseline assessments will be completed prior to randomisation. Data collected will include demographic characteristics, physical examinations, medical histories, laboratory tests and urine tests. Vertebral compression fractures were identified and confirmed by lateral thoracic and lumbar spine X-ray and were defined quantitatively based on the widely accepted Genant semi-quantitative method, which assigns a grade of 0 (normal) to 3 (severe fracture) to each vertebra from T4 to L4. Specifically, a vertebral fracture was defined as a reduction of ≥20% in anterior, middle and/or posterior vertebral height compared with adjacent normal vertebrae. A new incident vertebral fracture was defined as either: (1) A change from Genant grade 0 at baseline to a grade of 1, 2 or 3 at follow-up in a previously intact vertebra. (2) A worsening by at least one Genant grade (eg, from grade 1 to grade 2 or 3) in a vertebra that was already fractured at baseline. All suspected vertebral fractures were adjudicated by a central lab on the basis of the above definitions. BMD will be measured via dual-energy X-ray absorptiometry (DXA) at the lumbar spine (L1-L4), total hip and femoral neck. Our study specified the use of DXA scanners from two major manufacturers: Hologic and GE-Lunar. Each centre maintained the same DXA scanner model throughout the study duration. The left hip was the default and preferred site for measurement. The contralateral (right) hip was measured only in cases where the left hip was not suitable for accurate assessment (eg, due to prior arthroplasty, metal implants or other local conditions).

Participants will return to the study site for all follow-up assessments. These assessments will include evaluations for new fractures, vital signs, bone turnover markers and treatment adherence at every visit. Physical examinations, BMD, liver function, kidney function and electrolytes will be assessed at 6, 12 and 24 months. Radiographic examination will be performed at 12 and 24 months, and a complete blood count will be conducted at 24 months. At both enrolment and follow-up assessments, any vertebra that was fractured or had undergone procedures such as vertebroplasty (cement-augmented) was systematically excluded from the calculation of the mean lumbar spine (L1-L4) BMD. The final BMD value was derived from the average of the remaining evaluable vertebrae, with the requirement that a minimum of two vertebrae must be available for a valid measurement. All adverse events and serious adverse events occurring during the study will be systematically recorded.

Randomisation and blinding

This study will use the electronic interactive network response system provided by the Peking University Clinical Research Institute (PUCRI) for central randomisation. The randomisation will be stratified by sex and age (≤70 years, >70 years), with participants allocated in a 10:10:1 ratio to the early sequential, monotherapy and late sequential groups. Due to the inherent treatment differences among the study groups, blinding is not feasible. However, an independent central laboratory at Peking Union Medical College Hospital will conduct blinded endpoint adjudication to ensure objective outcomes assessment.

Interventions

Patients allocated to the denosumab monotherapy (control) group will receive subcutaneous denosumab 60 mg every 6 months for 24 months. Patients allocated to the early sequential group will receive teriparatide subcutaneous teriparatide 20 µg daily for 6 months, followed by subcutaneous denosumab 60 mg every 6 months until the end of the study. Participants allocated to the late sequential group will receive subcutaneous teriparatide 20 µg daily for 12 months, followed by subcutaneous denosumab 60 mg every 6 months until month 24. Prior to the initial intervention, all participants will receive injection training from the investigators.

Throughout the study period, all participants will be required to take calcium (500–1000 mg/day) and vitamin D supplementation (800–1200 IU/day). The combined use of other anti-osteoporosis drugs is prohibited.

Treatment will be terminated if any of the following occurs: significant BMD reduction (total hip BMD reduction >7% or other site BMD reduction ≥10%) with the corresponding T-score less than −3.0, any newly developed tumours or other serious diseases.

Study outcomes

For the main study comparing early sequential therapy and monotherapy, the primary outcome is new vertebral fractures confirmed by radiographic assessment in 24 months, with the time of fracture onset determined based on the patient’s report of back pain or restricted mobility. Secondary outcomes include new vertebral fractures in 12 months; new hip fractures, new fractures at other sites and all new fractures at 12 and 24 months; the rate of BMD change from the baseline at the lumbar spine, total hip and femoral neck in 12 and 24 months; the rate of changes from baseline in serum β-CTX and P1NP at 6, 12 and 24 months; the patients’ adherence to treatment; and cost-effectiveness.

For the substudy comparing early and late sequential therapies, BMD serves as a validated surrogate endpoint for fracture risk reduction. Therefore, the per cent change in lumbar spine BMD from baseline over 24 months was selected as the primary outcome. This approach prioritises research efficiency while maintaining scientific validity and cost-effectiveness. Secondary outcomes include BMD change at lumbar spine in 12 months; BMD changes at the total hip and femoral neck at 12 and 24 months; serum levels of β-CTX and P1NP at 12 and 24 months; and the incidence of new vertebral fractures, hip fractures, new fractures at other sites and all new fractures at 12 and 24 months.

Sample size

For the main study (early sequential vs monotherapy), the sample size calculation is based on a 2-year vertebral fracture incidence of 7% with denosumab.15 16 Assuming a 40% risk reduction (RR=0.6), with 80% power and a two-sided significance level of 5%, 1058 participants per group are needed. Accounting for a 10% dropout rate, 1180 subjects per group will be enrolled.

For the substudy (early vs late sequential), a 10:1 allocation ratio (1180:118) was used. With an assumed SD of 5%18 28 29and a two-sided α of 0.05, this sample size provides statistical power close to 100% to detect statistically significant differences in the 24-month lumbar spine BMD changes (10% vs 13%) between the early and late sequential treatment groups.

Quality control

PUCRI will be responsible for quality assurance and data management. An electronic data capture system has been developed using Research Electronic Data Capture, based on the case report forms. The system allows data entry checking, remote monitoring and data query. A manual of standard operating procedures was developed together with the study protocol and training on these key documents has been provided to all participating investigators. A risk-based site monitoring plus remote monitoring of all study sites has been implemented to ensure the quality and integrity of the study.

Statistical methods

The primary analysis will be conducted according to the intention-to-treat principle. Patient characteristics will be described by treatment allocation. χ2 or Fisher’s exact tests will be used for categorical variables, and t or Wilcoxon rank tests for quantitative variables. For the primary outcome of the main study, the incidence of new vertebral fractures over 24 months of treatment, the Kaplan-Meier method will be used to plot survival curves and the log-rank test will be applied to compare the survival curves between the two groups. HRs and their 95% CIs will be calculated using Cox proportional hazards models.

To account for potential baseline imbalances, a covariate-adjusted analysis will be performed as sensitivity analysis. For other time-to-event secondary outcomes, the same tests as for the primary outcome will be applied. For the rate of change in BMD and bone turnover markers from baseline, linear regression models will be used to analyse the differences between treatment groups.

For the substudy, the differences in the rate of BMD change in the lumbar spine from baseline in 24 months between early and late sequential groups will be analysed using linear regression.

Modification of the protocol

Once approved, the trial protocol shall not be altered arbitrarily. Any necessary modifications after study initiation require both expert committee consensus and formal approval by the ethics committee. The revised protocol may only be implemented after it has received ethics committee approval.

Current status

Patient recruitment of this multicentre trial has been completed. From May 2023 to September 2024, a total of 2486 eligible participants were enrolled from 58 hospitals: 1186 in the early sequential group, 1180 in the monotherapy group and 119 in the late sequential group. Follow-up visits are ongoing and the last visit of the last enrolled patient is scheduled to be completed by 30 September 2026.

Discussion

The findings of this study address critical gaps in clinical management of osteoporosis, particularly in optimising fracture prevention strategies while balancing efficacy, adherence and cost-effectiveness. Teriparatide, while highly effective in increasing BMD and reducing fracture risk,12 13 is limited by its 2-year treatment duration and daily injection requirements. In the overall cohort, teriparatide persistence rates after 6, 12 and 18 months were 73.6%, 62.4% and 59.2%, respectively.23 Rates of compliance with teriparatide have been shown to be 54.7% at 1 year of follow-up30 and 19% at 2 years of follow-up.31 Cost-effectiveness analysis found that among patients with osteoporosis with high fracture risk, 2-year teriparatide-based sequential approaches showed unfavourable results compared with alternative sequential treatments such as abaloparatide-based or romosozumab-based treatments and to bisphosphonate monotherapy.32 Our 6-month teriparatide protocol followed by denosumab would significantly reduce injection frequency while maintaining beneficial fracture risk reduction. Thus, our new sequential treatment strategy may confer significant advantages for the clinical management of osteoporosis in resource-constrained healthcare settings.

Our sequential treatment strategy is based on the potential synergistic mechanisms of teriparatide and denosumab. Teriparatide stimulates osteoblast activity via the Wnt/β-catenin pathway, increasing bone formation by binding to the PTHT1R (PTH/PTHrP Type 1 Receptor), particularly in trabecular bone. The fully human monoclonal antibody denosumab inhibits RANKL, which durably suppresses bone turnover to near-undetectable levels.33 Termination of osteoanabolic drug regimens typically triggers an accelerated BMD reduction shortly after treatment withdrawal. However, teriparatide demonstrates prolonged antifracture efficacy beyond its standard 24-month treatment duration, despite reductions in BMD.34 Overall, treatment-naïve patients with osteoporosis achieve maximal BMD gains through initial osteoanabolic therapy followed by antiresorptive agents. Conversely, prior exposure to bisphosphonates modestly attenuates the efficacy of subsequent bone-forming agents.35 Critically, our trial excluded patients with recent use of osteoporosis medications. The sequential use leverages the ‘anabolic window’ of teriparatide (the first 6–12 months) to maximise bone formation, followed by denosumab to consolidate gains and prevent post-teriparatide bone loss. If effective, our study will provide robust scientific validation for the above mechanism hypothesis of sequential therapy and clarify differential osteoporotic fracture-prevention strategies.

The incorporation of multiple exploratory indicators in this study addresses critical gaps in understanding the multifaceted impact of sequential therapy for osteoporosis. Beyond primary fracture risk reduction and BMD outcomes, the assessment of bone turnover markers (β-CTX and P1NP) provides dynamic insights into metabolic responses, enabling differentiation between rapid bone formation during teriparatide administration and sustained suppression of resorption under denosumab. These biomarkers, sensitive to early metabolic shifts (eg, β-CTX reductions within 3 months), complement delayed BMD measurements, offering a temporal dimension to evaluate therapeutic windows and optimise sequencing protocols. Collectively, these exploratory dimensions enhance the translational relevance of findings, bridging mechanistic insights with pragmatic clinical and policy decisions.

The decision to limit teriparatide administration to 6 months in the early sequential group, rather than the conventional 12–24 months, is supported by a combination of factors. These include practical concerns such as adherence and cost-effectiveness, as well as evidence-based efficacy considerations. Clinical trials have demonstrated that just 6 months of teriparatide treatment can significantly improve BMD.36 37 Mechanistically, intermittent PTH exposure activates osteoblast differentiation within weeks, driving rapid bone remodelling.38 Additionally, as mentioned above, adherence to long-term teriparatide therapy is alarmingly low globally. Cost-effectiveness analyses demonstrate that shorter teriparatide regimens (6–12 months) provide comparable fracture risk reduction to longer durations at lower financial burdens, suggesting that early switching to denosumab optimises resource utilisation.34

The smaller sample size in the late sequential group (10% of early sequential group) reflects methodological optimisations for statistical power and feasibility. Due to funding limitations, our study focuses on the early sequential treatment strategy that is believed to be ‘most appropriately’ balanced between the efficacy, feasibility, convenience and cost of the treatment. However, a different time point for switching treatment from teriparatide to denosumab is also a critical interest of our study. Thus, we include a substudy for this purpose and choice to use BMD as the primary endpoint of the substudy, which is a validated surrogate to fracture risk reduction.33 36 With this strategy, our approach prioritises research efficiency without compromising validity and cost.

A key strength lies in its robust multicentre randomised controlled trial design, which includes participants across 58 hospitals in China, ensuring diverse representation of demographic and clinical practices. The adoption of a 10:10:1 allocation ratio for the three treatment groups enables direct comparison of fracture risk reduction and BMD outcomes and maximises study efficiency. Furthermore, the integration of a comprehensive quality control system enhances data reliability and minimises bias. The inclusion of cost-effectiveness analysis addresses a critical gap in real-world applicability.

However, limitations warrant careful consideration. First, the study’s geographical focus on China may limit the generalisability of findings to other populations. Second, the open-label design risks introducing bias. To minimise the possible bias on key outcomes measurement, we used a central laboratory for image reading and a central endpoint adjudication for new vertebral fracture diagnosis unaware of the patients’ allocation. Additionally, the relatively short follow-up period (24 months) precludes the evaluation of long-term efficacy and safety, for which we have planned to follow the study participants in a longer period if further funding is obtained.

Ethics and dissemination

This study protocol has been registered with ClinicalTrials.gov. Ethical approval has been obtained from the Peking Union Medical College Hospital Medical Science Research Ethics Committee (1-22PJ939). The findings will be disseminated in scientific peer-reviewed journals.

Supplementary material

online supplemental file 1
bmjopen-16-2-s001.pdf (238.1KB, pdf)
DOI: 10.1136/bmjopen-2025-111364

Acknowledgements

We would like to thank all the patients and their families for their support and participation.

Footnotes

Funding: This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0532204); National Key R&D Program of China (2021YFC2501700); CAMS Innovation Fund for Medical Sciences (CIFMS) 2021-I2M-1-002; National High Level Hospital Clinical Research Funding (2022-PUMCH-D-006); National Natural Science Foundation of China Grants No.82270938 and No.81970757; and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2023-PT320-10).

Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2025-111364).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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