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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
216
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 intravenously at Baseline and Month 12, with additional doses at Months 24 and 36 in the extension unless contraindicated or clinically inappropriate.
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 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.
Skåne Universitetssjukhus
Malmö, Skåne County, Sweden
Karolinska University Hospital Huddinge
Huddinge, Stockholm County, Sweden
Sabbatsbergs sjukhus
Stockholm, Stockholm County, Sweden
Akademiska sjukhuset
Uppsala, Uppsala County, Sweden
Norrlands universitetssjukhus
Umeå, Västerbotten County, Sweden
Sundsvalls sjukhus
Sundsvall, Västernorrland County, Sweden
Sahlgrenska University Hospital Mölndal
Mölndal, Västra Götaland County, Sweden
Skaraborgs sjukhus
Skövde, Västra Götaland County, Sweden
Linköping University Hospital
Linköping, Östergötland County, Sweden
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
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.
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.
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.
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.
Occurrence of any fracture during follow-up.
Occurrence of any new morphometric vertebral fracture or clinical fragility fracture during follow-up.
Time frame: Baseline to Month 24, and for those entering the extension study, to Months 36 and 48.
Percent Change From Baseline in plasma C-Terminal Telopeptide of Type I Collagen
Percent change from baseline in plasma C-terminal telopeptide of type I collagen (CTX), a marker of bone resorption. Samples will be collected before study-drug administration at treatment visits and analysed centrally. Treatment-group differences over time will be assessed using a longitudinal repeated-measures model.
Time frame: Baseline and Months 1, 3, 6, 12, and 24
Percent Change From Baseline in Plasma Procollagen Type I N-Terminal Propeptide
Percent change from baseline in Plasma Procollagen Type I N-Terminal Propeptide, a marker of bone formation. Samples will be collected before study-drug administration at treatment visits and analysed centrally. Treatment-group differences over time will be assessed using a longitudinal repeated-measures model.
Time frame: Baseline and Months 1, 3, 6, 12, and 24
EuroQol 5-Dimension 5-Level (EQ-5D-5L) Health-State Utility Index
The EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire will be converted to a health-state utility index using the prespecified Swedish value set. Index values range from -0.31 to 1.00, where 1.00 represents full health and higher values indicate better health-related quality of life. Between-group changes from baseline will be evaluated at Months 12 and 24.
Time frame: Baseline, Month 12, and Month 24
Model-Estimated Lifetime Number of Fractures
Expected lifetime numbers of hip, vertebral, and other osteoporotic fractures will be estimated for each treatment strategy using a lifetime decision-analytic osteoporosis model informed by the randomized Month-24 total hip BMD treatment difference and Swedish epidemiological data.
Time frame: Month 24
Budget Impact of the Sequential Treatment Strategy
Estimated net financial impact over a prespecified 5-year implementation horizon of introducing the sequential treatment strategy in Swedish clinical practice, based on the eligible population, expected uptake, treatment costs, and projected fracture-related cost offsets.
Time frame: Month 24
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