Clinical Study to Predict the Risk of Bone Fractures With the POROUS Ultrasound Device
NCT Number: NCT06567054
Acronym: POROUS-preFX
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Healthy|Osteopenia|Osteoporosis
Interventions: DEVICE: Measurements with the POROUS R3C ultrasound device at the midshaft tibia|DEVICE: DXA measurement of the hip and lumbar spine|DEVICE: DXA-based Vertebral Fracture Assessment (VFA)|DEVICE: Projectional radiography of thoracic spine (alternative to DXA-based VFA, if VFA is not available)
Sponsor: POROUS GmbH
Collaborators: European Commission
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 1600
Study Design: Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: DIAGNOSTIC
Start Date: 2024-11
Completion Date: 2029-03
Locations: Division for Endocrinology and Metabolism, Department of Medicine 3, Medical University Vienna, Vienna, 1090, Austria|Department of Rheumatology, Charité Universitätsmedizin Berlin, Charite Campus Mitte, Berlin, 10117, Germany|Centre of Muscle and Bone Research (ZMK), Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, 12207, Germany|Department for Orthopedy, Trauma and Reconstructive Surgery, Section of Geriatric Traumatology, University Hospital Halle (Saale), Halle, 06120, Germany|Department of Endocrinology, Reproductive Medicine and Osteology Clinic for Gynecology and Obstetrics, University Hospital of Giessen and Marburg, Marburg, 35043, Germany|VieCuri Medisch Centrum, Department of Internal Medicine, Venlo, Venlo, 5912 BI, Netherlands

Summary:
Osteoporosis is a widespread medical condition among older people. It causes the bones to weaken and become more likely to break. Osteoporosis and bone fracture risk are currently evaluated by looking at clinical risk factors and measuring bone mineral density (BMD). The lower the BMD is, the higher the risk of osteoporotic fractures in the future. However, most bone fractures occur in people who do not have very low BMD values. This means that osteoporosis and fracture risk are often not diagnosed. Many of these non-diagnosed patients would benefit from treatment to reduce the probability of bone fractures.

An X-ray device called DXA is the main tool used to diagnose osteoporosis and fracture risk clinically. DXA measures two-dimensional BMD in the hip and spine. The POROUS ultrasound device measures various properties of the outer layer of the bone in the lower leg. It has several advantages over DXA: (1) its image resolution is higher and three-dimensional; (2) it can detect bone changes without radiation; (3) it can detect these bone changes early and how they change over time.

For this clinical study, we will recruit men and women over 55 years old. Most will have clinical risk factors, such as background diseases, for developing osteoporosis. The study is anticipated to last 4 years.

Our major research questions are:

* Can the POROUS ultrasound device predict fracture risk?
* How does its performance compare to DXA?
* What is the safety of the new device?

The participants will:

* answer questions about their medical history.
* be measured for height and weight, and take a physical test.
* be examined for the presence of 'silent' fractures in the spine.
* be examined at the beginning and end of the study with the two devices, DXA and POROUS.
* be called by telephone every six months and asked if they suffer from new bone fractures, take any medication that might affect their bones, or if their health status has changed.

The participants will be monitored for 3 years.

Primary Outcome Measures: Clinical Endpoint, Part 1 - POROUS-Score based on prevalent fractures, Prevalent fractures are the focus of the analysis in Part 1, i.e., fractures that occurred prior to the Baseline visit. This is reflected in establishing corrected standardized odds ratio (sOR) for the POROUS R3C ultrasound device-derived POROUS-Score. Statistically significant discriminative power of the sOR will be achieved if the lower limit of the 90% confidence interval of the sOR is greater than 1. The POROUS-Score will be evaluated to demonstrate the discriminative performance of the POROUS R3C ultrasound device for prevalent fractures.

Outcome measure: POROUS-Score (units on scale), 12 months|Clinical Endpoint, Part 2 - POROUS-Score based on incident fractures, Incident fractures are the focus of the analysis in Part 2, i.e., fractures that occur after the Baseline visit until the EoS. This is reflected in establishing corrected standardized relative risk (sRR) for the POROUS R3C ultrasound device-derived POROUS-Score. Statistically significant prediction power of the sRR will be achieved if the lower limit of the 90% confidence interval of the sRR is greater than 1. The POROUS-Score will be evaluated to demonstrate the predictive performance of the POROUS R3C ultrasound device for incident fractures. Fractures, which are associated with cortical bone and/or increasing age, will be considered for collecting information on both prevalent and incident fractures. Any incident fractures caused by high-energy external forces will be excluded (censored) from the analysis.

Outcome measure: POROUS-Score (units on scale), 24 or 36 months
Secondary Outcome Measures: Safety Endpoint, In order to establish that the POROUS R3C ultrasound device is safe with a minimal number of adverse events affecting the participants or the healthcare professionals using the device, the following safety endpoints are investigated:

* Incidence of procedural/device-related adverse events caused by the

  * Absorbed energy
  * Probe/transducer heating
  * Irritation by ultrasound gel
  * Release of substances
  * Inappropriate hygiene measures.
* Other (serious) adverse events., 36 or 48 months|Performance Endpoint, Part 1 - DXA T-score, Outcome measure: DXA T-score (units on scale), Immediately after the intervention|Performance Endpoint, Part 1 - discriminative performance based on prevalent fractures, Establish discriminative performance of the POROUS R3C ultrasound device in comparison with DXA based on prevalent fractures. sOR values for both POROUS-Score and DXA T-Score will be compared by applying ROC analysis.

Outcome measure: POROUS-Score (units on scale), 12 months|Performance Endpoint, Part 2 - DXA T-score, Outcome measure: DXA T-score (units on scale), Immediately after the intervention|Performance Endpoint, Part 2 - predictive performance based on incident fractures, Establish predictive performance of the POROUS R3C ultrasound device in comparison with DXA based on incident fractures. Standardized hazard ratio (sHR) values for both POROUS-Score and DXA T-Score will be compared by applying Cox-proportional hazard modelling.

Outcome measure: POROUS-Score (units on scale), 24 or 36 months
Other Outcome Measures: Exploratory Performance Endpoint 1, Part 1 - ultrasound cortical sound velocity in the radial direction, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: ultrasound cortical sound velocity in the radial direction (m/s), 12 months|Exploratory Performance Endpoint 1, Part 1 - cortical thickness, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: ultrasound cortical thickness (mm), 12 months|Exploratory Performance Endpoint 1, Part 1 - ultrasound frequency-dependent attenuation coefficient, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: ultrasound frequency-dependent attenuation coefficient (dB), 12 months|Exploratory Performance Endpoint 1, Part 1 - ultrasound frequency-dependent attenuation coefficient, intercept value of linear fit, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: ultrasound frequency-dependent attenuation coefficient, intercept value of linear fit (dB/mm), 12 months|Exploratory Performance Endpoint 1, Part 1 - ultrasound frequency-dependent attenuation coefficient, slope value of linear fit, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: ultrasound frequency-dependent attenuation coefficient, slope value of linear fit (dB/MHz/mm), 12 months|Exploratory Performance Endpoint 1, Part 1 - ultrasound cortical pore diameter distribution, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: ultrasound cortical pore diameter distribution (μm), 12 months|Exploratory Performance Endpoint 1, Part 1 - ultrasound backscatter coefficient, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: ultrasound backscatter coefficient (dB), 12 months|Exploratory Performance Endpoint 1, Part 1 - DXA-BMD, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: DXA-BMD (g/cm\^2), 12 months|Exploratory Performance Endpoint 1, Part 1 - age, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: age (years), 12 months|Exploratory Performance Endpoint 1, Part 1 - sex, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: sex (binary answer - m/f), 12 months|Exploratory Performance Endpoint 1, Part 1 - weight, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: weight (kg), 12 months|Exploratory Performance Endpoint 1, Part 1 - height, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: height (m), 12 months|Exploratory Performance Endpoint 1, Part 1 - BMI, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: BMI (kg/m\^2), 12 months|Exploratory Performance Endpoint 1, Part 1 - prevalent fractures, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: prevalent fractures (number), 12 months|Exploratory Performance Endpoint 1, Part 1 - DVO clinical risk factors/indicators for vertebral and hip fractures, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and prevalent fractures.

Outcome measure: clinical risk factors/indicators for vertebral and hip fractures (questionnaire, the answers are binary), 12 months|Exploratory Performance Endpoint 2, Part 1, Establish corrected sOR for prevalent fractures (e.g. hip, vertebral, and major osteoporotic fractures) and demonstrate significant performance.

Outcome measure: POROUS-Score (units on scale), 12 months|Exploratory Performance Endpoint 3, Part 1, Establish reference data for developing age-matched POROUS Z-scores using the POROUS R3C ultrasound device based on prevalent fractures.

Outcome measure: POROUS-Score (units on scale), 12 months|Exploratory Performance Endpoint 1, Part 2 - ultrasound cortical sound velocity in the radial direction, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: ultrasound cortical sound velocity in the radial direction (m/s), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - cortical thickness, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: cortical thickness (mm), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - ultrasound frequency-dependent attenuation coefficient, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: ultrasound frequency-dependent attenuation coefficient (dB), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - ultrasound frequency-dependent attenuation coefficient, intercept value of linear fit, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: ultrasound frequency-dependent attenuation coefficient, intercept value of linear fit (dB/mm), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - ultrasound frequency-dependent attenuation coefficient, slope value of linear fit, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: ultrasound frequency-dependent attenuation coefficient, slope value of linear fit (dB/MHz/mm), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - ultrasound cortical pore diameter distribution, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: ultrasound cortical pore diameter distribution (μm), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - ultrasound backscatter coefficient, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: ultrasound backscatter coefficient (dB), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - DXA-BMD, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: DXA-BMD (g/cm\^2), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - age, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: age (years), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - sex, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: sex (binary answer - m/f), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - weight, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: weight (kg), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - height, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: height (m), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - BMI, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: BMI (kg/m\^2), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - incident fractures, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: incident fractures (number), 24 or 36 months|Exploratory Performance Endpoint 1, Part 2 - DVO clinical risk factors/indicators for vertebral and hip fractures, Establish a correlation of an ultrasound parameter measured by the POROUS R3C ultrasound device with specific clinical risk factors/indicators for vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex, BMI, and incident fractures.

Outcome measure: clinical risk factors/indicators for vertebral and hip fractures (questionnaire, the answers are binary), 24 or 36 months|Exploratory Performance Endpoint 2, Part 2, Establish corrected sRR for incident fractures (e.g. hip, vertebral, and major osteoporotic fractures) and demonstrate significant performance.

Outcome measure: POROUS-Score (units on scale), 24 or 36 months|Exploratory Performance Endpoint 3, Part 2, Establish reference data for developing age-matched POROUS Z-scores using the POROUS R3C ultrasound device based on incident fractures.

Outcome measure: POROUS-Score (units on scale), 24 or 36 months|Treatment Effect Endpoint 1 - POROUS-Score, Treatment effect of anti-osteoporotic (anti-resorptive/anabolic) medication on DXA T-Scores and POROUS-Scores with respect to fracture incidence.

Outcome measure: POROUS-Score (units on scale), 24 or 36 months|Treatment Effect Endpoint 1 - DXA T-Score, Treatment effect of anti-osteoporotic (anti-resorptive/anabolic) medication on DXA T-Scores and POROUS-Scores with respect to fracture incidence.

Outcome measure: DXA T Score (units on scale), 24 or 36 months|Treatment Effect Endpoint 2 - POROUS-Score, Treatment effect of drugs known to influence bone metabolism on DXA T-Scores and POROUS-Scores (oral glucocorticoid of ≥ 2.5 mg/day prednisone equivalent for \> 3 months, proton pump inhibitors, aromatase inhibitors, hormone ablation therapy/antiandrogens in male participants).

Outcome measure: POROUS-Score (units on scale), 24 or 36 months|Treatment Effect Endpoint 2 - DXA T-Score, Treatment effect of drugs known to influence bone metabolism on DXA T-Scores and POROUS-Scores (oral glucocorticoid of ≥ 2.5 mg/day prednisone equivalent for \> 3 months, proton pump inhibitors, aromatase inhibitors, hormone ablation therapy/antiandrogens in male participants).

Outcome measure: DXA T-Score (units on scale), 24 or 36 months