Osteoporosis in Post-menopausal Women
Conditions
Keywords
Randomized controlled trial, Romosozumab, Denosumab, High resolution peripheral computed tomography, Bone mineral density, Zoledronic acid, Postmenopausal, Osteoporosis, Fracture risk
Brief summary
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.
Interventions
DRUGRomosozumab
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.
DIETARY_SUPPLEMENTCalcium 500 mg and Vitamin D3 800 IU
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.
DRUGDenosumab
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.
Sponsors
Sahlgrenska University Hospital
Uppsala University Hospital
Karolinska University Hospital
Norrlands University Hospital
Sundsvall Hospital
Skane University Hospital
Region Stockholm
Skaraborg Hospital
University Hospital, Linkoeping
Göteborg University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The subject is a postmenopausal woman aged 60 years or older at screening. 2. The subject has provided written informed consent before any trial-specific procedure is performed. 3. 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. 4. 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. 5. Corrected plasma calcium or ionized calcium is within the local reference range before randomization. 6. Serum 25-hydroxyvitamin D concentration ≥50 nmol/L before randomization. 7. Adequate renal function for zoledronic acid treatment, defined as creatinine clearance ≥35 mL/min calculated using the clinical trial center specified calculation procedure (e.g. the Cockcroft-Gault equation) before randomization. 8. The subject is able and willing, in the investigator's judgment, to comply with the trial procedures and attend scheduled visits. 9. For participants entering the extension, separate written extension consent is obtained before any extension-specific procedure is performed.
Exclusion criteria
1. Severe osteoporosis, defined as total hip or lumbar spine T-score \< -3.5 and/or prevalent grade 2 or grade 3 vertebral fracture. 2. Previous myocardial infarction or stroke at any time before screening. 3. 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. 4. Use of intravenous bisphosphonate therapy or teriparatide within 3 years before randomization. 5. Use of oral bisphosphonate or denosumab within 12 months before randomization. 6. Any previous use of romosozumab. 7. Use of systemic estrogen, selective estrogen receptor modulator within 3 months. 8. Use of oral glucocorticoids for more than 14 consecutive days during the 6 months before screening. 9. Known metabolic bone disease other than postmenopausal osteoporosis, including but not limited to Pagets disease, osteomalacia, untreated hyperparathyroidism, osteogenesis imperfecta, or active renal osteodystrophy. 10. Creatinine clearance below 35 mL/min, rapidly deteriorating renal function, or another renal condition that makes zoledronic acid unsafe. 11. Hypocalcaemia (ionized calcium \<1.15 mmol/l or total albumin corrected calcium of \<2.15 mmol/l) or vitamin D 25-OH-vit-D \<50nmol/l, not corrected before randomization. 12. Unexplained serum alkaline phosphatase \>2 times the local upper limit of normal. 13. Malignancy within the last 5 years, except adequately treated basal-cell carcinoma of the skin, squamous-cell carcinoma in situ of the skin, or cervical carcinoma in situ. 14. Current osteonecrosis of the jaw, unhealed oral or jaw lesions, active dental or jaw infection, or planned invasive dental extraction/implant procedure that has not been completed and healed before randomization, if considered by the investigator to represent a contraindication or unacceptable risk for treatment with romosozumab, denosumab or zoledronic acid. 15. Known hypersensitivity or contraindication to romosozumab, denosumab, zoledronic acid, calcium supplementation, or vitamin D supplementation that cannot be safely managed under the protocol. 16. Inability to undergo protocol DXA/VFA reliably, for example because of body habitus exceeding scanner limits, inability to position safely, or interfering hardware or artefacts that prevent valid endpoint assessment. 17. Current participation, or recent participation within 30 days or five half-lives (whichever is longer), in another interventional clinical trial that could affect safety or data interpretation. 18. Any other medical, psychiatric, social or logistical condition that, in the investigators opinion, makes participation unsafe or would compromise protocol adherence or data reliability.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent change in total hip bone mineral density | 24 months | Percentage change from baseline to month 24 in total hip bone mineral density, measured by dual-energy X-ray absorptiometry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EuroQol 5-Dimension 5-Level (EQ-5D-5L) Health-State Utility Index | Baseline, Month 12, and Month 24 | 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. |
| Model-Estimated Lifetime Number of Fractures | Month 24 | 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. |
| Budget Impact of the Sequential Treatment Strategy | Month 24 | 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. |
| Percent change in lumbar spine bone mineral density at Months 6, 12 and 24. | Baseline to 6, 12 and 24 months. | Percentage change from baseline to months 6, 12 and 24 in lumbar spine bone mineral density, measured by dual-energy X-ray absorptiometry. |
| Percent Change From Baseline in Total Hip BMD at Months 6 and 12 | Baseline to 6 and 12 months. | Percentage change from baseline to month 6 and 12 total hip mineral density, measured by dual-energy X-ray absorptiometry. |
| Incident vertebral fracture | From baseline to months 12, 24 in the main study. For those entering the extension study, from baseline to months 36 and 48. | Incident morphometric vertebral fracture by Genant grading on centrally read vertebral fracture assessment (VFA) |
| First clinical fragility fracture | Baseline to month 24, and for those entering the extension study, to months 36 and 48. | Time to first clinical fragility fracture |
| Occurrence of any fracture during follow-up. | Baseline to Month 24, and for those entering the extension study, to Months 36 and 48. | Occurrence of any new morphometric vertebral fracture or clinical fragility fracture during follow-up. |
| Percent Change From Baseline in Plasma Procollagen Type I N-Terminal Propeptide | Baseline and Months 1, 3, 6, 12, and 24 | 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. |
| Percent Change From Baseline in plasma C-Terminal Telopeptide of Type I Collagen | Baseline and Months 1, 3, 6, 12, and 24 | 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. |
Countries
Sweden
Contacts
CONTACTMattias Lorentzon, MD, PhD
CONTACTLena Silberberg, BSc
PRINCIPAL_INVESTIGATORMattias Lorentzon, MD, PhD
Sahlgrenska University Hospital Mölndal, Västra Götalandsregionen and University of Gothenburg
Outcome results
None listed