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Sequential Treatment With Romosozumab Followed by Denosumab vs. Zoledronic Acid for Gains in HIP BMD

ConditionOsteoporosis in Post-menopausal Women
Trial statusNot yet recruiting
Trial phasePhase 4
Trial typeInterventional
Biological sexFemale
Age60+
SponsorSahlgrenska University Hospital

About this trial

Osteoporosis is associated with a high risk of fractures, disability, loss of independence, and excess mortality. Zoledronic acid is an established first-line treatment in Sweden, but many patients at high fracture risk remain at substantial residual fracture risk. Short-course treatment with romosozumab followed by denosumab produces large increases in bone mineral density, but has not been directly compared with zoledronic acid.

STRONG-HIP is a multicentre, randomized, active-controlled phase 4 trial in 216 postmenopausal women aged 60 years or older with osteoporosis and high fracture risk. Participants are randomized 1:1 to receive romosozumab 210 mg monthly for 3 months followed by denosumab 60 mg every 6 months, or zoledronic acid 5 mg intravenously at baseline and Month 12.

The primary objective is to determine whether the romosozumab-denosumab sequence produces a greater percentage increase in total hip bone mineral density from baseline to Month 24 than zoledronic acid. Secondary outcomes include total hip and lumbar spine BMD at earlier time points, vertebral and clinical fractures, bone turnover markers, safety, health-related quality of life, and health-economic outcomes. A mechanistic substudy will assess bone microarchitecture and estimated strength using HR-pQCT.

Participants are followed for 24 months in the main study and may enter an optional extension with follow-up to Month 48 to assess the durability of treatment effects.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

The subject is a postmenopausal woman aged 60 years or older at screening.

The subject has provided written informed consent before any trial-specific procedure is performed.

The subject has osteoporosis at screening defined as a T-score of -2.5 or lower at the total hip or lumbar spine (L1-L4) on central reader confirmed bone densitometry by DXA.

The subject is at high fracture risk, defined by at least one of the following: a previous low-trauma fracture after age 50 years (excluding skull, face, fingers and toes); FRAX probability at or above the age-specific Swedish intervention threshold (using Nordic and Nordic borne calculations, as appropriate) in use at screening.

Disqualifiers

Severe osteoporosis, defined as total hip or lumbar spine T-score < -3.5 and/or prevalent grade 2 or grade 3 vertebral fracture.

Previous myocardial infarction or stroke at any time before screening.

Transient ischemic attack, unstable angina, coronary or major peripheral revascularization within 12 months before screening, decompensated heart failure, uncontrolled clinically relevant arrhythmia, or any cardiovascular condition that in the investigator's judgment confers unacceptably high risk of a major adverse cardiovascular event during study participation.

Use of intravenous bisphosphonate therapy or teriparatide within 3 years before randomization.

Trial design

Design model

Parallel

Treatments tested in this trial

  • Romosozumab

    Drug

    Romosozumab 210 mg will be administered by subcutaneous injection once monthly for 3 consecutive months. Each monthly dose consists of two consecutive 105 mg injections.

  • Zoledronic Acid 5 MG in 5 ML Injection

    Drug

    Zoledronic acid 5 mg intravenously at Baseline and Month 12, with additional doses at Months 24 and 36 in the extension unless contraindicated or clinically inappropriate.

  • Calcium 500 mg and Vitamin D3 800 IU

    Dietary supplement

    Calcium and vitamin D supplementation, using 500 mg elemental calcium plus 20 micrograms cholecalciferol daily for 24 months. Participants entering the optional extension will receive daily calcium and vitamin D supplementation throughout the study.

  • Denosumab

    Drug

    Denosumab 60 mg by subcutaneous injection at Months 3, 9, 15, and 21. Participants entering the optional extension will continue denosumab at Months 27, 33, 39, and 45 unless contraindicated or clinically inappropriate.

Treatment groups

216 Participants
are divided into 2 treatment groups
Group A: Short-course Romosozumab Followed by DenosumabExperimental treatment 3 interventions
Group B: Zoledronic AcidActive comparator 2 interventions

Trial outcomes

Primary outcomes

1

Percent change in total hip bone mineral density

Percentage change from baseline to month 24 in total hip bone mineral density, measured by dual-energy X-ray absorptiometry.

Time frame
24 months

Secondary outcomes

1

Percent change in lumbar spine bone mineral density at Months 6, 12 and 24.

Percentage change from baseline to months 6, 12 and 24 in lumbar spine bone mineral density, measured by dual-energy X-ray absorptiometry.

Time frame
Baseline to 6, 12 and 24 months.
2

Percent Change From Baseline in Total Hip BMD at Months 6 and 12

Percentage change from baseline to month 6 and 12 total hip mineral density, measured by dual-energy X-ray absorptiometry.

Time frame
Baseline to 6 and 12 months.
3

Incident vertebral fracture

Incident morphometric vertebral fracture by Genant grading on centrally read vertebral fracture assessment (VFA)

Time frame
From baseline to months 12, 24 in the main study. For those entering the extension study, from baseline to months 36 and 48.
4

First clinical fragility fracture

Time to first clinical fragility fracture

Time frame
Baseline to month 24, and for those entering the extension study, to months 36 and 48.

Other outcomes

1

Model-Predicted Fracture Risk Reduction Based on Total Hip BMD

Fracture-specific relative and absolute risk reductions will be estimated from the adjusted randomized between-group difference in percent change from baseline in total hip BMD at Month 24. The treatment difference will be translated into expected fracture-risk reductions using prespecified validated meta-regression models underpinning the FDA-qualified total hip BMD surrogate endpoint. Estimates may include hip, vertebral, nonvertebral, and all clinical fractures, according to the available validated models.

Time frame
Month 24
2

Incremental Cost per Quality-Adjusted Life-Year (QALY) Gained

Incremental cost per quality-adjusted life-year gained for the sequential treatment strategy compared with zoledronic acid, estimated from a Swedish healthcare perspective using a lifetime health-economic model. The model will use treatment effects derived from the randomized Month-24 total hip BMD difference together with Swedish epidemiological, cost, mortality, and utility inputs.

Time frame
Month 24
3

Model-Estimated Lifetime Healthcare Costs

Discounted lifetime healthcare costs per participant, including treatment, administration, monitoring, adverse-event management, and fracture-related healthcare costs, estimated from a Swedish healthcare perspective using a lifetime health-economic model based on treatment effects and other study data available at Month 24.

Time frame
Month 24
4

Model-Estimated Quality-Adjusted Life-Years

Discounted lifetime quality-adjusted life-years (QALYs) per participant estimated using EQ-5D-5L and prespecified fracture-state utility inputs in a lifetime health-economic model based on treatment effects and other study data available at Month 24.

Time frame
Month 24

Sponsors and contacts

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Sahlgrenska University Hospital

Lead sponsor

Uppsala University Hospital

Collaborator

Karolinska University Hospital

Collaborator

Norrlands University Hospital

Collaborator

Sundsvall Hospital

Collaborator

Skane University Hospital

Collaborator

Region Stockholm

Collaborator

Skaraborg Hospital

Collaborator

University Hospital, Linkoeping

Collaborator

Göteborg University

Collaborator

Source ClinicalTrials.gov

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