Abstract

Purpose: The purpose of this paper was to review the available approaches for bone strength assessment, osteoporosis diagnosis, and fracture risk prediction, and to provide insights into Radiofrequency Echographic Multi-Spectrometry (REMS), a non-ionizing axial skeleton technique for diagnosing osteoporosis and assessing fracture risk.

Methods: A working group convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) reviewed current image-based methods for bone strength assessment and fracture risk estimation, and discussed the clinical perspectives of REMS.

Results: Areal bone mineral density (BMD), measured by dual-energy X-ray absorptiometry (DXA), is the consolidated indicator for osteoporosis diagnosis and fracture risk assessment. However, a more reliable fracture risk estimation would require an improved assessment of bone strength, which should integrate bone quality information. Several different approaches have been proposed, including additional DXA-based parameters, quantitative computed tomography (QCT), and quantitative ultrasound (QUS). While these showed improved clinical performance, none satisfied all the requirements for widespread use, mainly due to issues such as unclear clinical usefulness, radiation exposure, limited accessibility, or inapplicability to spine and hip regions. REMS, however, is a clinically available technology for osteoporosis diagnosis and fracture risk assessment. By processing unfiltered ultrasound signals, REMS provides accurate BMD values, aiding fracture risk assessment.

Conclusions: Improved methods for bone strength and fracture risk estimations are essential for better managing osteoporotic patients. In this context, REMS offers a valuable alternative for diagnosing osteoporosis and predicting fracture risk.

Introduction

Osteoporosis is a systemic skeletal disease characterized by the reduction in bone mass and degeneration of bone structure, which leads to increased fracture risk. This condition not only affects the quality of life of patients but also leads to significant social, medical, and community care costs. Fractures caused by osteoporosis often result in long-term disability and increased mortality rates.

Bone strength refers to the ability of bones to resist fractures, which is determined by several factors such as composition, microarchitecture, size, and shape of bones. However, traditional bone assessments, such as BMD measurements through DXA, primarily focus on the quantity of bone and do not take bone quality into account.

Bone Strength and its Four Key Factors:

1. Composition: Bone mineralization and collagen crosslinking at the nanoscale level.
2. Microarchitecture: Trabecular and cortical properties, including porosity, thickness, and connectivity at a microscale level.
3. Size: Age, genetics, gender, and lifestyle habits that influence bone size and shape at a macroscale.
4. Shape: Geometrical factors and bone structure that play a critical role in bone strength.

An effective assessment of bone health requires methods that can capture these factors comprehensively. While DXA remains the gold standard for osteoporosis diagnosis, it fails to measure bone quality, which significantly impacts fracture risk.

Current Imaging Techniques for Bone Strength Assessment

Various imaging devices have been developed to assess bone strength, including DXA, QCT, HR-pQCT, and QUS. While each has its benefits, they also have limitations.

Dual-Energy X-ray Absorptiometry (DXA)

DXA is the most widely used technique for measuring BMD and diagnosing osteoporosis. It estimates areal BMD, expressed in g/cm², based on 2D X-ray scans of bone areas. Despite its accuracy in diagnosing osteoporosis, DXA only measures bone quantity and not quality. Furthermore, it has a low sensitivity for predicting fractures, especially in osteopenic patients whose BMD might fall in the middle range between normal and osteoporotic.

Factors contributing to bone strength. The ultimate definition of bone strength is complex, but four main categories of bone characteristics that contribute to bone strength can be outlined at different scale level: size, shape, architecture and composition

Quantitative CT (QCT) and HR-pQCT

Both QCT and HR-pQCT offer 3D reconstructions of bones, providing more detailed insights into bone structure. They are particularly useful for assessing trabecular and cortical bone separately. However, these methods require higher radiation doses than DXA and are generally not accessible in most clinical settings due to their high costs and complex equipment requirements.

Representation of the Hip Axis Length (HAL) definition, i.e.the distance from the base of the greater trochanter to the inner pelvicbrim (segment a–b). Angle c is the neck shaft angle, i.e. the anglebetween the derived axes of the femoral neck and shaft

Quantitative Ultrasound (QUS)

QUS is a non-ionizing technique used to assess bone properties using ultrasound waves. It is generally limited to peripheral skeletal sites like the heel, making it less suitable for comprehensive fracture risk assessment at central skeletal sites such as the hip and spine. Moreover, QUS is less sensitive than DXA and often fails to capture detailed information about bone quality.

Association between incidence of non-vertebral fracture and total hip BMD percent change from baseline at 36 months in Denosumab and placebo cohorts. The risk of non-vertebral fracture decreased with increasing per cent change in total hip BMD with similar relationships (slopes) for both treatment groups. The density curves at the bottom represent the distributions of total hip BMD change at 36 months for each treatment group

Radiofrequency Echographic Multi-Spectrometry (REMS)

REMS is a non-ionizing imaging technique that uses ultrasound signals to assess both BMD and bone quality. Unlike traditional imaging methods, REMS captures unfiltered ultrasound signals, which retain detailed information about the bone structure, crucial for accurately predicting fracture risk.

How REMS Works

• The REMS probe is placed on the abdomen or hip to scan the lumbar spine or femoral neck.
• Unfiltered ultrasound signals are collected during an echographic scan.
• The software automatically processes these signals and identifies the bone interfaces.
• These signals are compared to reference spectral models to estimate BMD and classify bone conditions as healthy, osteopenic, or osteoporotic.

Key Advantages of REMS

• Radiation-Free: REMS does not use ionizing radiation, making it safe for repeated use.
• Bone Quality Measurement: In addition to BMD, REMS assesses bone quality, offering a comprehensive evaluation of bone health.
• High Diagnostic Accuracy: REMS has shown high sensitivity (91.7%) and specificity (92%) in identifying osteoporotic patients.

Software-guided REMS acquisition on femoral neck. Before starting the acquisition, the operator sets transducer focus and scan depth in order to visualize the target bone interphase in the central part of the echographic field of view, immediately below the focus position. The software automatically detects the bone interface and identifies the region of interest (ROI)

Clinical Validation of REMS

A multicenter study conducted at 7 Italian centers enrolled over 1900 postmenopausal women to validate REMS against the gold standard of DXA. Results showed high diagnostic accuracy for REMS, with 91.7% sensitivity and 92% specificity for detecting osteoporosis.

Intra-operator precision was found to be 0.38% for lumbar spine and 0.32% for the femoral neck, indicating that REMS offers reliable results, comparable to DXA.

REMS analysis is characterised by the parallel processing of the native raw unfiltered signals of several scan lines, deriving one spectrum from each scan line (sample spectra are shown on the right)

Fragility Score (FS)

One of the key features of REMS is the Fragility Score (FS), which estimates fracture risk independently of BMD. The FS is a dimensionless score that compares the patient’s spectrum with reference spectral models for osteoporotic and healthy individuals. FS is strongly correlated with fracture risk, making it a valuable tool for predicting fractures in patients with normal BMD.

Patient-specific spectra undergo advanced comparisons with age-, sex-, BMI- and site-matched spectral models of pathologic and healthy conditions

Future Perspectives for REMS

Clinical Adoption and New Applications

• Early Diagnosis: REMS can be used for early diagnosis of osteoporosis, especially in populations for whom DXA is not feasible, such as children or pregnant women.
• Bone Quality Monitoring: REMS can also be used for monitoring bone health in patients on long-term treatments, offering short-term follow-up without radiation exposure.
• Wider Population Screening: Given its portability, REMS is suitable for population screenings and could be used in mass public health initiatives.

FDA Approval and Global Adoption

REMS has received FDA approval, making it the first non-ionizing technology for routine osteoporosis diagnosis and fracture risk prediction.

Conclusion

REMS is a revolutionary non-ionizing technique that offers a comprehensive approach to bone strength assessment and osteoporosis diagnosis. By evaluating BMD and bone quality, REMS overcomes the limitations of DXA and provides more accurate predictions of fracture risk. With FDA approval and growing clinical validation, REMS is poised to become an essential tool in the diagnosis and management of osteoporosis, offering a radiation-free alternative that is safe, accurate, and reliable.