Clinical application of Radiofrequency Echographic Multi-Spectrometry (REMS) for diagnosis and follow-up in several rare bone disorders: A case series

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In particular, REMS has been shown to measure bone mineral density (BMD) at axial skeletal bones with a precision, repeatability and accuracy not inferior to those of dual-energy X-ray absorptiometry (DXA). Moreover, REMS may be useful in the assessment of impaired bone quality and to predict fragility fracture risk. Due to these characteristics, REMS could be usefully used in the diagnosis and follow up of osteoporosis in rare bone diseases. The clinical cases includes in this study were selected among those that best highlight the strengths of REMS technology. A recent study conducted on subjects affected by osteogenesis imperfecta has demonstrated that the REMS technique is able to assess BMD in the same way as the DXA evaluation. REMS has also demonstrated excellent diagnostic accuracy in some patients suffering from others rare disease such as McCune-Albright or Ehlers-Danlos syndromes. Furthermore, REMS could be particularly advantageous in children and in women of childbearing age or during pregnancy and breastfeeding. In conclusion, on the basis of these preliminary data, REMS can be usefulness for the evaluation and monitoring of bone in individuals with rare bone diseases Rare bone diseases radiofrequency echographic multispectrometry (REMS) bone mineral density (BMD) dual-energy X-ray absorptiometry (DXA) osteogenesis imperfecta Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Rare diseases, by definition, have a prevalence lower than a certain threshold, which for the European Union is set at 5 cases per 10,000 individuals. It's important to note that while each rare disease affects a relatively small population, the cumulative number of people affected by these conditions is significant. Among these diseases, rare disorders affecting the skeletal system are particularly complex. They arise from anomalies in the intricate processes of bone development, from growth to the maintenance of skeletal balance, and remain very difficult to clinically diagnose and treat, due to their considerable number and variability. So far, more than 300 different forms of rare skeletal disease have been classified and the treatment of these conditions is a significant burden for healthcare systems [ 1 ]. Timely diagnosis and careful monitoring of these diseases are crucial to minimizing complications and the associated economic and social costs. Dual-energy X-ray absorptiometry (DXA) is a widely accepted technique for measuring bone mineral density (BMD) and is universally regarded as the gold standard for diagnosing osteoporosis [ 2 ]. Nevertheless, DXA also has some important limitations as it uses ionizing radiation which limits its use in pediatrics and in women of childbearing age. Furthermore, DXA overestimates bone mineral content in the presence of artifacts such as aortic calcifications, vertebroplasties, vertebral fractures, and structural abnormalities caused by osteoarthritis [ 3 ]. Magnetic resonance imaging and high-resolution peripheral quantitative computed tomography are important tools for quantitative, qualitative, and structural evaluation of trabecular and cortical bone. However, due to higher exposure to ionizing radiation and the costs involved, they cannot be used in clinical practice [ 4 ]. For this reason, there is growing interest in new non-invasive techniques that can be used to assess bone status from both a quantitative and qualitative point of view. Due to these characteristics, there has been growing interest in recent years in evaluating the usefulness of radiofrequency echographic multispectrometry (REMS) for assessing metabolic bone diseases beyond osteoporosis, as well as certain rare bone diseases. In particular, many rare bone diseases present diagnostic challenges that cannot be adequately addressed by bone densitometry using the DXA technique [ 5 ]. These diseases predominantly affect young individuals of childbearing age who require frequent monitoring [ 5 ]. Moreover, these conditions are characterized by structural and qualitative alterations that are currently assessed through invasive methods, such as microindentation, or non-routine techniques like Magnetic Resonance Imaging (MRI) or peripheral quantitative computed tomography (pQCT). This single-center study aimed to explore the usefulness of REMS in the assessment of bone status in the rare bone diseases most frequently encountered in our outpatient clinic. Materials and Methods The study enrolled patients who attended at the Outpatients Clinics of Internal Medicine Unit at the University Hospital of Siena (Italy) between January 2018 and December 2024. The principal criterion for inclusion was the occurrence of to have undergone a bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry (DXA). Moreover, all patients included in this study underwent bone densitometry using REMS technology. Demographic details and medical history of each case were retrieved from the database. Further, radiographic and histopathology features of case were reviewed again to rule out any other diagnosis. The different clinical cases of rare bone diseases were selected to highlight the strengths and the specific features of this novel approach by REMS, this recent method for assessing bone status within a university hospital setting. An informed written consent was obtained from all participants, and the study was approved by the Institutional Review Board of Siena University Hospital (ID-14783/19). All the data were anonymized before to study inclusion. Radiofrequency Echographic Multispectrometry (REMS) REMS is a non-ionizing technology that evaluates bone status by analyzing raw, unfiltered native ultrasound signals, known as radiofrequency (RF) ultrasound signals, captured during an echographic examination of the lumbar vertebrae and proximal femur using a 3.5 MHz convex ultrasound probe. The probe is placed on the hip and abdomen to visualize the interface of the target bone. The clinician regulates the depth and the focus of the transducer. The software detects the sought bone interfaces in the acquired frame sequence and identifies regions of interest for a diagnostic evaluation. The analysis of native, unfiltered ultrasound signals - normally filtered during the conventional B-mode image reconstruction process - allows for capturing more information about the characteristics of the bone tissue being evaluated (Fig. 1 A). Bone status is assessed by comparing the spectra of analyzed signal with reference spectral models. The measured data are synthesized into a patient-specific spectrum that is compared to age-,gender-,BMI-and site matched reference spectral models for the pathological and normal conditions being considered. (Fig. 1 B). The spectral modifications introduced by the physical properties of bone structure that has back-scattered the ultrasound signals are identified via a comparison procedure to determine an estimate of the BMD. At the end of this analysis the software outputs the parameters BMD T-score and Z-score and the consequent diagnostic classification of the bone as healthy, osteopenic, or osteoporotic (Fig. 1 C) [ 6 ]. Some papers have reported that REMS offers good precision and a diagnostic accuracy similar to that of DXA in both female and male subjects [ 7 , 8 ]. Recent studies have demonstrated the ability of REMS to diagnose osteoporosis; in particular, in a follow-up period of 5 years, REMS showed a higher sensitivity than DXA in the detection of female subjects prone to fragility fractures [ 7 , 9 ]. Furthermore, lower BMD values at the lumbar spine, obtained by REMS, were significantly associated with a history of major fragility fractures in the type 2 diabetes mellitus (T2DM) population, whereas BMD values measured by DXA were not. This suggests that REMS may be useful in the assessment of impaired bone quality in patients with T2DM [ 10 ]. Recently, an additional REMS-based parameter, the fragility score (FS), has been introduced [ 11 ]. The FS is independent of BMD and it is obtained by comparing patient-specific spectral profiles with population-based anthropometrically-matched models of “fractured” and “non-fractured” subjects [ 11 ]. Additionally, a recent prospective study involving 1,989 patients demonstrated that the FS is a better predictor of fracture risk in both female and male subjects compared to BMD T-score values obtained through either DXA or REMS [ 12 ]. The possibility of evaluating bone status using REMS in young women is revolutionary because the technology can be used safely during the fertile years, as well as during pregnancy and breastfeeding. This is particularly interesting for women of childbearing age with rare bone diseases and for those with pregnancy- and lactation-associated osteoporosis (PLO), a rare form of osteoporosis that appears during the third trimester of pregnancy or breastfeeding [ 4 , 13 , 14 , 15 ]. Another advantage of REMS noted in the literature is its potential to address common artifacts - such as osteoarthritis, vascular calcifications, and vertebroplasty of the lumbar spine - that can impact BMD values obtained through DXA [ 15 ]. Moreover, a possible limitation of the REMS technology may be the presence of severe obesity (BMI > 40 kg/m²). Due to these characteristics, REMS could be effectively utilized in the diagnosis and monitoring of rare bone diseases. Results This study demonstrates the potential of REMS (Radiofrequency Echographic Multi Spectrometry) as a valid method for assessing osteoporosis or bone status in specific clinical conditions, including rare bone diseases. Real-world examples of its application are presented below. 1) REMS in Osteogenesis imperfecta Osteogenesis imperfecta (OI) is a rare hereditary connective tissue disorder, affecting approximately 1 in 15,000 to 20,000 individuals. It is primarily characterized by both qualitative and quantitative abnormalities in bone collagen, resulting in bone fragility and a heightened risk of fractures. Patients with OI have a very high risk of suffering fragility fractures, especially during childhood and adolescence [ 16 , 17 ]. According to the Sillence classification, which is based on clinical severity and radiographic criteria, OI type I, characterized by a primarily quantitative reduction in type I collagen, is the mildest clinical form. OI type III is the most severe non-lethal form, while OI type IV exhibits an intermediate phenotype between types I and III. OI type II is not found in adults, because it is lethal in the perinatal period [ 17 ]. Many studies have reported that bone microarchitecture is markedly altered in OI. In fact, trabecular thickness and volumetric bone mass are reduced, along with decreased cortical thickness and increased intracortical porosity [ 18 ]. All these changes in bone structure alter the bone biomechanics and increase bone fragility in individuals with OI [ 18 ]. In a recent study involving 41 adults with OI (mean age 40.5 ± 18.7 years) and a group of healthy controls, BMD at various skeletal sites was assessed using both the DXA and REMS techniques. Additionally, the trabecular bone score (TBS) was calculated from the standard antero-posterior DXA scan of the lumbar spine. The patients were categorized by OI type: type I (n = 32, 78.0%), type III (n = 5, 12.2%), and type IV (n = 4, 9.8%). Nearly all the OI patients had a history of multiple fragility fractures, primarily located at the radius, tibia, vertebrae, and femur [ 19 ]. BMD values, obtained using both DXA and REMS, were significantly lower in patients with OI compared with controls at all skeletal sites. The values of lumbar spine (LS) BMD, using both DXA and REMS techniques, and those of TBS were assessed in subjects with OI type I and OI Type III and IV. There were no differences between the LS-BMD values carried out using the DXA technique between the OI type I group and OI Type III and IV groups. On the contrary, the OI Type III and IV groups showed significantly lower values of both TBS and LS-BMD using REMS with respect to patients suffering from OI type I (p 0.001), but an only marginally significant one (p = 0.05) with lumbar spine BMD measured by DXA (Fig. 2 ) [ 19 ]. The data obtained in these patients allow us to draw two important considerations. First of all, they confirm that patients’ bone status can be evaluated using REMS, a technique that does not use ionizing radiation. This finding is important, because OI patients, given their high risk of fractures, require repeated radiological examinations. Furthermore, the use of a technique free of ionizing radiation, such as REMS, could be particularly advantageous during adolescence and in women of childbearing age or during pregnancy and breastfeeding [ 13 , 19 ]. Another consideration is that BMD assessment with REMS could overcome the limitations of BMD measurement by DXA in patients with OI. The literature data indicate that BMD measured by DXA is only slightly reduced and sometimes even increased in many patients with OI; moreover, only a small percentage of patients display osteoporotic T-scores, and fragility fractures in OI patients cannot be fully explained by low BMD [ 20 ]. In fact, OI is characterized by reduced bone quality due to the presence of defects in the bone matrix and mineralization which are in addition to the alterations of bone microarchitecture [ 18 ]. Moreover, REMS technology, similarly to the TBS, can identify severe bone status impairment between patients with moderate to severe OI-III–IV and those with the mildest OI-I [ 21 ]. Furthermore, the presence of scoliosis and vertebral fractures, particularly frequent in subjects with types III and IV OI, determine a marked overestimation in the evaluation of vertebral BMD by DXA, while not significantly influencing TBS and BMD by REMS values. The interest in the diagnostic potential of the REMS technique for children with bone fragility and osteogenesis imperfecta has been confirmed in recent articles [ 22 , 23 ]. 2) REMS in Vitamin D-dependent rickets type 1 Vitamin D-dependent rickets, known as VDDR, is a type of genetic rickets caused by a lack of vitamin D due to issues with vitamin D activation or receptors [ 24 ]. VDDR type 1A, also known as VDDR1A, is a uncommon autosomal recessive disease resulting from harmful mutations in the CYP27B1 gene on chromosome 12p13.3. Patients with VDDR1A typically experience stunted growth, weak muscles, delayed motor skills, seizures, and skeletal abnormalities within the first 2 years of life. Symptoms include low levels of calcium and phosphate, high levels of alkaline phosphatase and parathyroid hormone, normal to high levels of 25-hydroxyvitamin D, and low or normal levels of 1,25(OH)2D3 [ 24 ]. Although Vitamin D-resistant rickets is characterized by normal BMD values, certain situations like pregnancy or breastfeeding require monitoring [ 25 ]. In Fig. 3 reported the longitudinally assessment in the BMD at the femoral neck between the first and third trimester and a further check-up after delivery. The ability to assess bone status using ultrasound in young women is revolutionary, as it offers a safe option for evaluation during the reproductive years, including pregnancy and breastfeeding [ 13 , 14 , 15 , 26 ]. It is known that bone is a dynamic tissue with constant turnover, and this is especially the case in women when hormonal changes, pregnancy, breastfeeding, and menopause have a particular influence on the skeleton. Despite the activation of several adaptive mechanisms to counterbalance calcium drainage [ 14 , 15 ], there is a net reduction of the BMD during pregnancy, but above all, lactation is associated with BMD changes. Dual-energy X-ray absorptiometry studies have demonstrated a 3–10% reduction in BMD within the first 2 to 6 months postpartum, primarily affecting the trabecular bone of the lumbar spine. A less pronounced BMD decrease is observed in the predominantly cortical bone of the hip. This bone loss occurs at a rate of 1–3% per month during this period [ 27 , 28 ]. This case report highlights the ability of REMS, like DXA, to detect a reduction in BMD at lumbar spine, which is primarily composed of trabecular bone, during lactation (lumbar spine Z-score = -0.3 at first trimester of pregnancy to lumbar spine Z-score = -0.7 during breastfeeding), with stable cortical bone density. Therefore it is certainly important to have a tool that allows the evaluation and monitoring during the course of pregnancy and lactation. In this case, REMS technique represent the possibility to allow clinicians to assess bone status with periodic follow-up without radiation when there are no other usable radiological methods. 3) REMS in McCune-Albright syndrome McCune-Albright syndrome (MAS) is traditionally characterized by the clinical triad of bone fibrous dysplasia (FD), café-au-lait skin spots, and several hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, non-autoimmune hyperthyroidism, hyperprolactinemia, growth hormone (GH) excess, and neonatal hypercortisolism [ 29 , 30 ]. It is an uncommon illness due to somatic gain-of-function mutations of the GNAS gene with a prevalence estimated to be between 1 in 100,000 and 1 in 1,000,000. Fibrous dysplasia may affect one or more bones in the body and is characterized by a limp, pain, and sometimes a pathological fracture. Figure 4 illustrates the clinical case of a 52-year-old woman suffering from MAS. The patient had polyostotic fibrous dysplasia seen on both radiographic and scintigraphy scans, affecting various areas including the maxillary sinuses, left half of the jaw, right pelvis, and both femurs, and distal diaphysis of the left tibia. The individual was receiving bisphosphonates therapy and was regularly screened for bone mineral density. Assessment of BMD by DXA showed very high T-score values at the level of the lumbar spine and both femurs (e.g.at the left femur: Neck = 3.9 and Total Hip = 4.2 and at the right femur: Neck = 5.8 and Total Hip = 4.8 ). The BMD by REMS assessment instead showed markedly lower T-score values (-1.3 and − 0.8, for neck and total left hip and − 1.2 and − 0.9 for neck and total right hip, respectively), highlighting a better characterization of the bone structure using the REMS technique (Fig. 4 ). This clinical case suggests the usefulness of REMS in the therapeutic monitoring of individuals with MAS, a rare disease characterized in adulthood by an increased risk of fracture [ 30 , 31 ]. 4) REMS in Ehlers-Danlos syndromes Ehlers-Danlos syndromes (EDS) are a clinically and genetically diverse group of hereditary connective tissue disorders that primarily affect soft tissues, especially the skin, joints, and cardiovascular system. Skin hyperelasticity, joint hypermobility and fragility of vessels and internal organs are the clinical triad most representative of these syndromes [ 32 ]. The most common forms of EDS are due to alterations in the genes that code for collagen types III and V. The involvement of bones in this syndrome has been a topic of long-standing debate. However, more recent studies have shown that EDS patients tend to have reduced BMD values and a higher risk of fragility fractures. Additionally, recent research has reported a high prevalence of radiological vertebral fractures in adults with EDS, even when their BMD, as measured by DXA, appears normal. Moreover, the presence and severity of vertebral fractures were significantly associated with back pain [ 33 , 34 ]. The mechanisms leading to skeletal fragility in EDS may be similar to those occurring in OI, a disease due to a primitive defect in type I collagen synthesis. Moreover, EDS patients have a cortical bone size deficit compared with controls, which may be due to reduced muscle cross-sectional area [ 34 ]. Figure 5 illustrates the clinical case of a 61-year-old woman suffering from an EDS. A DXA assessment showed marked osteoporosis (T-score Neck: -3.4, T-score L1-L4: -4.8), and she was also found to have equally low TBS values (L1-L4: 1.204). Bone densitometry with REMS technology also highlighted osteoporosis (T-score Neck: -3.5, T-score L1-L4: -4.1). The results obtained in this patient show that the REMS method assesses bone status as correctly and reliably as DXA and TBS too. 5) REMS in Acromegaly Acromegaly is a rare disease characterized by elevated levels of GH and insulin-like growth factor I (IGF-I), primarily due to a pituitary adenoma. The condition may cause skeletal alterations and fragility fractures. In fact, the excess of GH and IGF-I promotes the development of cortical thickness, but at the same time stimulates cortical porosity, consequently increasing the risk of fractures, especially at the vertebral level. In a study conducted by Polish endocrinologists in 33 patients with acromegaly (25 women and 8 men), BMD values at all skeletal sites measured with REMS did not differ significantly from those measured with DXA [ 35 ]. Additionally, the BMD values obtained with REMS and DXA correlated similarly with IGF-I levels [ 35 ]. These data confirm that REMS can be usefully employed in the monitoring of patients with acromegaly. 6) REMS in Rett Syndrome Rett syndrome (RS) is a neurological disorder that mostly affects females, with a frequency of 1 in 10,000 to 20,000 live birth cases. Symptoms include stereotyped hand movements; impaired learning, language, and communication skills; sudden loss of speech; reduced lifespan; retarded growth; disturbance of sleep and breathing; seizures; autism; and gait apraxia [ 36 ]. The most common non-neurological comorbidities include, among others, orthopedic complications, mainly scoliosis but also early osteopenia/osteoporosis and a high frequency of fractures [ 37 , 38 ]. REMS technique offers an efficient, radiation-free way to assess bone mineral status in individuals with Rett Syndrome. It's often recognized that patients with RS can have significant mobility issues, which may prevent the proper execution of a DXA scan [ 38 , 39 ]. Recently, the use of REMS has been introduced in clinical practice for the BMD evaluation in patients with severe motor and intellectual disabilities showing high accuracy and precision, as well as DXA assessment [ 40 ]. One of the strong points regarding the use in people with Rett Syndrome is the fact that REMS technique could be carried out directly in the bed of the patient and in the absence of ionizing radiation [ 15 , 38 , 39 , 40 ]. Anyway, more evidence collected specifically in pediatric subjects is required to clarify the potential role of this technique, which appears promising as an alternative to DXA. Figure 6 illustrates the clinical case of a 13-year-old girl with Rett syndrome underwent a densitometric examination using the REMS technique directly in her wheelchair. This approach allows the examination to be performed without moving the child, simplifying the scanning process for extremely fragile patients. Discussions REMS is a radiation-free, portable technology used for assessing and monitoring bone status at lumbar and femoral sites. Due to its accuracy, precision, and demonstrated non-inferiority to DXA in predicting the 5-year risk of fragility fractures in a large population of Caucasian women, REMS is now regarded as a more accessible alternative to DXA for axial BMD measurement in osteoporosis management [ 4 , 5 , 7 ]. REMS has several strengths compared to DXA. First and foremost, the absence of ionizing radiation makes it suitable for use in pediatrics and in pregnant or childbearing women. Additionally, it is easily portable and can eliminate artefacts caused by vascular calcifications, vertebral cementation, osteophytes, and other factors that often lead to an overestimation of BMD in DXA. However, REMS also has some limitations compared to DXA. These include a relative lack of studies involving non-Caucasian populations, limited research on bone diseases other than osteoporosis, challenges in drug monitoring, and reduced accuracy in cases of severe obesity (BMI > 40–45 Kg/m 2 ) The analysis of real-world examples of REMS use in managing patients with rare bone diseases allows us to draw some conclusions. As demonstrated by the clinical case of a patient with vitamin D-dependent rickets type 1, REMS can be considered the optimal option for accurately and safely evaluating bone status in young women during their reproductive years, including pregnancy and breastfeeding [ 5 , 13 , 26 ]. It is well known that obtaining a correctly executed DXA scan can be challenging, and sometimes impossible, in patients with severe mobility impairments and communication difficulties, such as individuals with Rett syndrome or severe scoliosis. In particular, in young patients affected by Rett syndrome, REMS could become a valid alternative to DXA due to its ability to be performed at the patient’s bedside or in a wheelchair, without requiring a rigidly fixed position and without exposure to ionizing radiation [ 38 , 39 , 40 ]. Furthermore, the observation that in patients with osteogenesis imperfecta, REMS is better able than DXA to identify individuals with more severe disease and greater fracture risk highlights its potential to assess aspects of microarchitecture and bone quality relevant to bone fragility [ 19 ]. It is well known that patients with O.I. frequently suffer from fragility fractures despite often having only slightly reduced or even normal BMD [ 21 ]. In this context, an additional contribution could come from implementing the Fragility Score, a new REMS-based parameter that assesses bone fragility by comparing the spectral lines of the examined subject with reference models of normal and fragile (fractured) bone spectra [ 12 ]. Conclusions In rare bone diseases, REMS provides an accurate and reliable assessment of bone health, comparable to DXA and TBS. Furthermore, the possibility of using ultrasound technology without ionizing radiation makes REMS a valuable tool for evaluating and monitoring patients suffering from rare bone diseases. Finally, rare bone diseases, characterized by peculiar structural and bone matrix alterations, represent fascinating experimental models for studying and enhancing the potential of REMS technology to provide information on the qualitative characteristics of bone tissue. Declarations Acknowledgements Not Applicable Clinical Trial Number Not Applicable Author Contributions: CC: Conceptualization, Methodology, Writing – original draft. CM: Resources, Writing. AV: Resources, Writing. SG: Writing – review. GC: Resources, Writing. MDTP: Resources, Writing. GS: Supervision. AA: Resources, Writing – review & editing Funding This study was supported by the Bando 2022 Prot. 2022YSN898 Data availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethics approval and consent to partecipate Our research was carried out in accordance with the Declaration of Helsinki of the World Medical Association, and informed consent to participate in the study was obtained from all patients. For individuals younger than the age of 16 consent to participate was obtained from thear parent or legal guardians. 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Banica T, et al. Higher fracture prevalence and smaller bone size in patients with hEDS/HSD-a prospective cohort study. Osteoporos Int. 2020; 31:849-856. Rolla M, Halupczok-Żyła J, Jawiarczyk-Przybyłowska A, Bolanowski M. Bone densitometry by radiofrequency echographic multi-spectrometry (REMS) in acromegaly patients. Endokrynol Pol 2020; 71:524-531. Hagberg B. Clinical manifestations and stages of Rett syndrome. Ment Retard Dev Disabil Res Rev 2002; 8:61-65. Pecorelli A, et al Altered Bone Status in Rett Syndrome. Life (Basel) 2021; 11 :521. Caffarelli C, et al. Bone Fracture in Rett Syndrome: Mechanisms and Prevention Strategies. Children (Basel) 2023; 10:1861. Caffarelli C, Gonnelli S. The Management of Bone Defects in Rett Syndrome. Calcif Tissue Int. 2025;116:11. Sakai T, et al. Radiofrequency echographic multi-spectrometry-based measurement of bone mineral density in patients with severe motor and intellectual disability: An opportunity for patients with severe scoliosis and hip dislocation. Bone Rep 2024; 22:101781. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Sep, 2025 Read the published version in BMC Medical Imaging → Version 1 posted Editorial decision: Revision requested 12 Aug, 2025 Reviews received at journal 08 Aug, 2025 Reviews received at journal 19 Jul, 2025 Reviewers agreed at journal 18 Jul, 2025 Reviewers agreed at journal 29 Jun, 2025 Reviewers invited by journal 24 Jun, 2025 Editor assigned by journal 24 Jun, 2025 Editor invited by journal 23 Jun, 2025 Submission checks completed at journal 23 Jun, 2025 First submitted to journal 23 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6831093","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":475736385,"identity":"a7033610-c217-46fe-b336-fd4e87f74339","order_by":0,"name":"Carla Caffarelli","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIie2QsWrDMBCGzxjk5cCrAoa8whVB6ZDEr5JgcBe3BLpkNHTIIuiaPEceoBKCTsnusV08ZUjposFD5eClFKtrB33DHQh93H8HEAj8TyLV1+S5b+s7TF1TQIA+56rg29JV4jipB8Xn/FCA1PA8pqTb07uysJgii9vLhXgmmget7RqyfEThx3vSEoobyZjY71yw2+ZxadATjKAEhaCi12ktYrwqFRnfLpS2oDtQuWTJV9w5Rewq0tan8BKMm7KSDEXcX4x4RcoXjDctmIyKwilPkXQKP57J9AlRjVzspYw+zpvF3AU7gN3M8nRbiU/bzfKkHhkzHOH3eN//QCAQCPzBN6l0THkach2zAAAAAElFTkSuQmCC","orcid":"","institution":"University of Siena","correspondingAuthor":true,"prefix":"","firstName":"Carla","middleName":"","lastName":"Caffarelli","suffix":""},{"id":475736386,"identity":"08a9de9f-4294-4bb5-9316-d6596f0e7be4","order_by":1,"name":"Caterina Mondillo","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Caterina","middleName":"","lastName":"Mondillo","suffix":""},{"id":475736387,"identity":"2628c8c6-3afb-4c63-b1f2-b1c5436705bb","order_by":2,"name":"Alessandro Versienti","email":"","orcid":"","institution":"University Hospital of Nice","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Versienti","suffix":""},{"id":475736388,"identity":"da85877e-0fbe-4699-867b-2d9a0c52e8ed","order_by":3,"name":"Sara Gonnelli","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Gonnelli","suffix":""},{"id":475736389,"identity":"64f8498f-7230-4630-b09b-b01c0f9c1899","order_by":4,"name":"Guido Cavati","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Guido","middleName":"","lastName":"Cavati","suffix":""},{"id":475736390,"identity":"0f455669-60a0-466f-a418-0e4de6a4edee","order_by":5,"name":"Maria Dea Tomai Pitinca","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Dea Tomai","lastName":"Pitinca","suffix":""},{"id":475736391,"identity":"9e9335ac-b7d7-4724-a1b4-39e865b3612f","order_by":6,"name":"Stefano Gonnelli","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Gonnelli","suffix":""},{"id":475736392,"identity":"08d4838a-4590-4c07-bc1b-cafe53da127b","order_by":7,"name":"Antonella Al Refaie","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Antonella","middleName":"Al","lastName":"Refaie","suffix":""}],"badges":[],"createdAt":"2025-06-05 16:53:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6831093/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6831093/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12880-025-01924-6","type":"published","date":"2025-09-26T15:57:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85649457,"identity":"30a3607d-a48d-41ed-b4b9-f234787db150","added_by":"auto","created_at":"2025-06-30 08:57:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":894461,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of Radiofrequency Echographic Multispectrometry (REMS) tecnique\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6831093/v1/9b7e64525da70843668087f2.png"},{"id":85649455,"identity":"db409332-011d-4722-8b57-b1f3626b0d40","added_by":"auto","created_at":"2025-06-30 08:57:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":435632,"visible":true,"origin":"","legend":"\u003cp\u003eSpearman’s correlation of TBS and LS-BMD through DXA and REMS techniques in OI patients (image taken from [19])\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6831093/v1/5d06a2208f87fc6e4c2cbc64.png"},{"id":85647593,"identity":"b02d8f5c-f6c8-43a1-9cab-fd9fb821156a","added_by":"auto","created_at":"2025-06-30 08:49:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1177749,"visible":true,"origin":"","legend":"\u003cp\u003eLumbar and Femoral BMD by REMS at first trimester of pregnancy (A), at third trimester of pregnancy (B) and during breastfeeding (C) in a young woman with Vitamin D-dependent rickets type 1\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6831093/v1/eb43ae4774c65e726ec204c9.png"},{"id":85647594,"identity":"39646163-48e6-4cc8-8086-40a2ca8b3b9a","added_by":"auto","created_at":"2025-06-30 08:49:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1225752,"visible":true,"origin":"","legend":"\u003cp\u003eWhole-body bone scintigraphy (A) right and left femoral BMD by DXA (B) and by REMS (C) in a subject suffering of McCune-Albright syndrome\u003c/p\u003e","description":"","filename":"Figure4R3.png","url":"https://assets-eu.researchsquare.com/files/rs-6831093/v1/d8a51ffa7121dd01c730743b.png"},{"id":85647598,"identity":"958bffd0-d43c-4065-88a8-883bbc458a00","added_by":"auto","created_at":"2025-06-30 08:49:31","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":868227,"visible":true,"origin":"","legend":"\u003cp\u003eLumbar BMD by DXA (A) and by REMS (B) and TBS (C) in subject suffering from Ehlers-Danlos syndrome\u003c/p\u003e","description":"","filename":"Figure5R2.png","url":"https://assets-eu.researchsquare.com/files/rs-6831093/v1/f56742f4fdc0cb9c1d4d7452.png"},{"id":85647597,"identity":"7c878c62-c7a1-4eb0-b860-9d139f66d8ce","added_by":"auto","created_at":"2025-06-30 08:49:31","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1136401,"visible":true,"origin":"","legend":"\u003cp\u003eBMD assessment by REMS technique in a subject with Rett syndrome underwent directly in her wheelchair.\u003c/p\u003e","description":"","filename":"Figure6R2.png","url":"https://assets-eu.researchsquare.com/files/rs-6831093/v1/c732336699383d9f7691c908.png"},{"id":92430490,"identity":"2ae8da6c-b76f-43be-8976-0f96070ade10","added_by":"auto","created_at":"2025-09-29 16:05:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6939945,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6831093/v1/6d1eaf1f-8fa0-43e9-8823-e7b42205f5ca.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical application of Radiofrequency Echographic Multi-Spectrometry (REMS) for diagnosis and follow-up in several rare bone disorders: A case series","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRare diseases, by definition, have a prevalence lower than a certain threshold, which for the European Union is set at 5 cases per 10,000 individuals. It's important to note that while each rare disease affects a relatively small population, the cumulative number of people affected by these conditions is significant. Among these diseases, rare disorders affecting the skeletal system are particularly complex. They arise from anomalies in the intricate processes of bone development, from growth to the maintenance of skeletal balance, and remain very difficult to clinically diagnose and treat, due to their considerable number and variability. So far, more than 300 different forms of rare skeletal disease have been classified and the treatment of these conditions is a significant burden for healthcare systems [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Timely diagnosis and careful monitoring of these diseases are crucial to minimizing complications and the associated economic and social costs. Dual-energy X-ray absorptiometry (DXA) is a widely accepted technique for measuring bone mineral density (BMD) and is universally regarded as the gold standard for diagnosing osteoporosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Nevertheless, DXA also has some important limitations as it uses ionizing radiation which limits its use in pediatrics and in women of childbearing age. Furthermore, DXA overestimates bone mineral content in the presence of artifacts such as aortic calcifications, vertebroplasties, vertebral fractures, and structural abnormalities caused by osteoarthritis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Magnetic resonance imaging and high-resolution peripheral quantitative computed tomography are important tools for quantitative, qualitative, and structural evaluation of trabecular and cortical bone. However, due to higher exposure to ionizing radiation and the costs involved, they cannot be used in clinical practice [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. For this reason, there is growing interest in new non-invasive techniques that can be used to assess bone status from both a quantitative and qualitative point of view. Due to these characteristics, there has been growing interest in recent years in evaluating the usefulness of radiofrequency echographic multispectrometry (REMS) for assessing metabolic bone diseases beyond osteoporosis, as well as certain rare bone diseases. In particular, many rare bone diseases present diagnostic challenges that cannot be adequately addressed by bone densitometry using the DXA technique [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These diseases predominantly affect young individuals of childbearing age who require frequent monitoring [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Moreover, these conditions are characterized by structural and qualitative alterations that are currently assessed through invasive methods, such as microindentation, or non-routine techniques like Magnetic Resonance Imaging (MRI) or peripheral quantitative computed tomography (pQCT). This single-center study aimed to explore the usefulness of REMS in the assessment of bone status in the rare bone diseases most frequently encountered in our outpatient clinic.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThe study enrolled patients who attended at the Outpatients Clinics of Internal Medicine Unit at the University Hospital of Siena (Italy) between January 2018 and December 2024. The principal criterion for inclusion was the occurrence of to have undergone a bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry (DXA). Moreover, all patients included in this study underwent bone densitometry using REMS technology. Demographic details and medical history of each case were retrieved from the database. Further, radiographic and histopathology features of case were reviewed again to rule out any other diagnosis. The different clinical cases of rare bone diseases were selected to highlight the strengths and the specific features of this novel approach by REMS, this recent method for assessing bone status within a university hospital setting. An informed written consent was obtained from all participants, and the study was approved by the Institutional Review Board of Siena University Hospital (ID-14783/19). All the data were anonymized before to study inclusion.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eRadiofrequency Echographic Multispectrometry (REMS)\u003c/h2\u003e \u003cp\u003eREMS is a non-ionizing technology that evaluates bone status by analyzing raw, unfiltered native ultrasound signals, known as radiofrequency (RF) ultrasound signals, captured during an echographic examination of the lumbar vertebrae and proximal femur using a 3.5 MHz convex ultrasound probe. The probe is placed on the hip and abdomen to visualize the interface of the target bone. The clinician regulates the depth and the focus of the transducer. The software detects the sought bone interfaces in the acquired frame sequence and identifies regions of interest for a diagnostic evaluation. The analysis of native, unfiltered ultrasound signals - normally filtered during the conventional B-mode image reconstruction process - allows for capturing more information about the characteristics of the bone tissue being evaluated (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Bone status is assessed by comparing the spectra of analyzed signal with reference spectral models. The measured data are synthesized into a patient-specific spectrum that is compared to age-,gender-,BMI-and site matched reference spectral models for the pathological and normal conditions being considered. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). The spectral modifications introduced by the physical properties of bone structure that has back-scattered the ultrasound signals are identified via a comparison procedure to determine an estimate of the BMD. At the end of this analysis the software outputs the parameters BMD T-score and Z-score and the consequent diagnostic classification of the bone as healthy, osteopenic, or osteoporotic (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSome papers have reported that REMS offers good precision and a diagnostic accuracy similar to that of DXA in both female and male subjects [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Recent studies have demonstrated the ability of REMS to diagnose osteoporosis; in particular, in a follow-up period of 5 years, REMS showed a higher sensitivity than DXA in the detection of female subjects prone to fragility fractures [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, lower BMD values at the lumbar spine, obtained by REMS, were significantly associated with a history of major fragility fractures in the type 2 diabetes mellitus (T2DM) population, whereas BMD values measured by DXA were not. This suggests that REMS may be useful in the assessment of impaired bone quality in patients with T2DM [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Recently, an additional REMS-based parameter, the fragility score (FS), has been introduced [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The FS is independent of BMD and it is obtained by comparing patient-specific spectral profiles with population-based anthropometrically-matched models of \u0026ldquo;fractured\u0026rdquo; and \u0026ldquo;non-fractured\u0026rdquo; subjects [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, a recent prospective study involving 1,989 patients demonstrated that the FS is a better predictor of fracture risk in both female and male subjects compared to BMD T-score values obtained through either DXA or REMS [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The possibility of evaluating bone status using REMS in young women is revolutionary because the technology can be used safely during the fertile years, as well as during pregnancy and breastfeeding. This is particularly interesting for women of childbearing age with rare bone diseases and for those with pregnancy- and lactation-associated osteoporosis (PLO), a rare form of osteoporosis that appears during the third trimester of pregnancy or breastfeeding [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Another advantage of REMS noted in the literature is its potential to address common artifacts - such as osteoarthritis, vascular calcifications, and vertebroplasty of the lumbar spine - that can impact BMD values obtained through DXA [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Moreover, a possible limitation of the REMS technology may be the presence of severe obesity (BMI\u0026thinsp;\u0026gt;\u0026thinsp;40 kg/m\u0026sup2;). Due to these characteristics, REMS could be effectively utilized in the diagnosis and monitoring of rare bone diseases.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThis study demonstrates the potential of REMS (Radiofrequency Echographic Multi Spectrometry) as a valid method for assessing osteoporosis or bone status in specific clinical conditions, including rare bone diseases. Real-world examples of its application are presented below.\u003c/p\u003e\n\u003ch3\u003e1) REMS in Osteogenesis imperfecta\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eOsteogenesis imperfecta (OI) is a rare hereditary connective tissue disorder, affecting approximately 1 in 15,000 to 20,000 individuals. It is primarily characterized by both qualitative and quantitative abnormalities in bone collagen, resulting in bone fragility and a heightened risk of fractures. Patients with OI have a very high risk of suffering fragility fractures, especially during childhood and adolescence [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. According to the Sillence classification, which is based on clinical severity and radiographic criteria, OI type I, characterized by a primarily quantitative reduction in type I collagen, is the mildest clinical form. OI type III is the most severe non-lethal form, while OI type IV exhibits an intermediate phenotype between types I and III. OI type II is not found in adults, because it is lethal in the perinatal period [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Many studies have reported that bone microarchitecture is markedly altered in OI. In fact, trabecular thickness and volumetric bone mass are reduced, along with decreased cortical thickness and increased intracortical porosity [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. All these changes in bone structure alter the bone biomechanics and increase bone fragility in individuals with OI [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a recent study involving 41 adults with OI (mean age 40.5\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7 years) and a group of healthy controls, BMD at various skeletal sites was assessed using both the DXA and REMS techniques. Additionally, the trabecular bone score (TBS) was calculated from the standard antero-posterior DXA scan of the lumbar spine. The patients were categorized by OI type: type I (n\u0026thinsp;=\u0026thinsp;32, 78.0%), type III (n\u0026thinsp;=\u0026thinsp;5, 12.2%), and type IV (n\u0026thinsp;=\u0026thinsp;4, 9.8%). Nearly all the OI patients had a history of multiple fragility fractures, primarily located at the radius, tibia, vertebrae, and femur [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. BMD values, obtained using both DXA and REMS, were significantly lower in patients with OI compared with controls at all skeletal sites. The values of lumbar spine (LS) BMD, using both DXA and REMS techniques, and those of TBS were assessed in subjects with OI type I and OI Type III and IV. There were no differences between the LS-BMD values carried out using the DXA technique between the OI type I group and OI Type III and IV groups. On the contrary, the OI Type III and IV groups showed significantly lower values of both TBS and LS-BMD using REMS with respect to patients suffering from OI type I (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Furthermore, the TBS showed a highly significant correlation with BMD at the lumbar spine measured by REMS (p\u0026thinsp;\u0026gt;\u0026thinsp;0.001), but an only marginally significant one (p\u0026thinsp;=\u0026thinsp;0.05) with lumbar spine BMD measured by DXA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe data obtained in these patients allow us to draw two important considerations. First of all, they confirm that patients\u0026rsquo; bone status can be evaluated using REMS, a technique that does not use ionizing radiation. This finding is important, because OI patients, given their high risk of fractures, require repeated radiological examinations. Furthermore, the use of a technique free of ionizing radiation, such as REMS, could be particularly advantageous during adolescence and in women of childbearing age or during pregnancy and breastfeeding [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Another consideration is that BMD assessment with REMS could overcome the limitations of BMD measurement by DXA in patients with OI. The literature data indicate that BMD measured by DXA is only slightly reduced and sometimes even increased in many patients with OI; moreover, only a small percentage of patients display osteoporotic T-scores, and fragility fractures in OI patients cannot be fully explained by low BMD [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In fact, OI is characterized by reduced bone quality due to the presence of defects in the bone matrix and mineralization which are in addition to the alterations of bone microarchitecture [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Moreover, REMS technology, similarly to the TBS, can identify severe bone status impairment between patients with moderate to severe OI-III\u0026ndash;IV and those with the mildest OI-I [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Furthermore, the presence of scoliosis and vertebral fractures, particularly frequent in subjects with types III and IV OI, determine a marked overestimation in the evaluation of vertebral BMD by DXA, while not significantly influencing TBS and BMD by REMS values. The interest in the diagnostic potential of the REMS technique for children with bone fragility and osteogenesis imperfecta has been confirmed in recent articles [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003e2) REMS in Vitamin D-dependent rickets type 1\u003c/h3\u003e\n\u003cp\u003eVitamin D-dependent rickets, known as VDDR, is a type of genetic rickets caused by a lack of vitamin D due to issues with vitamin D activation or receptors [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. VDDR type 1A, also known as VDDR1A, is a uncommon autosomal recessive disease resulting from harmful mutations in the CYP27B1 gene on chromosome 12p13.3. Patients with VDDR1A typically experience stunted growth, weak muscles, delayed motor skills, seizures, and skeletal abnormalities within the first 2 years of life. Symptoms include low levels of calcium and phosphate, high levels of alkaline phosphatase and parathyroid hormone, normal to high levels of 25-hydroxyvitamin D, and low or normal levels of 1,25(OH)2D3 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Although Vitamin D-resistant rickets is characterized by normal BMD values, certain situations like pregnancy or breastfeeding require monitoring [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e reported the longitudinally assessment in the BMD at the femoral neck between the first and third trimester and a further check-up after delivery. The ability to assess bone status using ultrasound in young women is revolutionary, as it offers a safe option for evaluation during the reproductive years, including pregnancy and breastfeeding [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. It is known that bone is a dynamic tissue with constant turnover, and this is especially the case in women when hormonal changes, pregnancy, breastfeeding, and menopause have a particular influence on the skeleton. Despite the activation of several adaptive mechanisms to counterbalance calcium drainage [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], there is a net reduction of the BMD during pregnancy, but above all, lactation is associated with BMD changes. Dual-energy X-ray absorptiometry studies have demonstrated a 3\u0026ndash;10% reduction in BMD within the first 2 to 6 months postpartum, primarily affecting the trabecular bone of the lumbar spine. A less pronounced BMD decrease is observed in the predominantly cortical bone of the hip. This bone loss occurs at a rate of 1\u0026ndash;3% per month during this period [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. This case report highlights the ability of REMS, like DXA, to detect a reduction in BMD at lumbar spine, which is primarily composed of trabecular bone, during lactation (lumbar spine Z-score = -0.3 at first trimester of pregnancy to lumbar spine Z-score = -0.7 during breastfeeding), with stable cortical bone density. Therefore it is certainly important to have a tool that allows the evaluation and monitoring during the course of pregnancy and lactation. In this case, REMS technique represent the possibility to allow clinicians to assess bone status with periodic follow-up without radiation when there are no other usable radiological methods.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003e3) REMS in McCune-Albright syndrome\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eMcCune-Albright syndrome (MAS) is traditionally characterized by the clinical triad of bone fibrous dysplasia (FD), caf\u0026eacute;-au-lait skin spots, and several hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, non-autoimmune hyperthyroidism, hyperprolactinemia, growth hormone (GH) excess, and neonatal hypercortisolism [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It is an uncommon illness due to somatic gain-of-function mutations of the GNAS gene with a prevalence estimated to be between 1 in 100,000 and 1 in 1,000,000. Fibrous dysplasia may affect one or more bones in the body and is characterized by a limp, pain, and sometimes a pathological fracture. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e illustrates the clinical case of a 52-year-old woman suffering from MAS. The patient had polyostotic fibrous dysplasia seen on both radiographic and scintigraphy scans, affecting various areas including the maxillary sinuses, left half of the jaw, right pelvis, and both femurs, and distal diaphysis of the left tibia. The individual was receiving bisphosphonates therapy and was regularly screened for bone mineral density. Assessment of BMD by DXA showed very high T-score values at the level of the lumbar spine and both femurs (e.g.at the left femur: Neck\u0026thinsp;=\u0026thinsp;3.9 and Total Hip\u0026thinsp;=\u0026thinsp;4.2 and at the right femur: Neck\u0026thinsp;=\u0026thinsp;5.8 and Total Hip\u0026thinsp;=\u0026thinsp;4.8 ). The BMD by REMS assessment instead showed markedly lower T-score values (-1.3 and \u0026minus;\u0026thinsp;0.8, for neck and total left hip and \u0026minus;\u0026thinsp;1.2 and \u0026minus;\u0026thinsp;0.9 for neck and total right hip, respectively), highlighting a better characterization of the bone structure using the REMS technique (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This clinical case suggests the usefulness of REMS in the therapeutic monitoring of individuals with MAS, a rare disease characterized in adulthood by an increased risk of fracture [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e4) REMS in Ehlers-Danlos syndromes\u003c/h2\u003e \u003cp\u003eEhlers-Danlos syndromes (EDS) are a clinically and genetically diverse group of hereditary connective tissue disorders that primarily affect soft tissues, especially the skin, joints, and cardiovascular system. Skin hyperelasticity, joint hypermobility and fragility of vessels and internal organs are the clinical triad most representative of these syndromes [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The most common forms of EDS are due to alterations in the genes that code for collagen types III and V. The involvement of bones in this syndrome has been a topic of long-standing debate. However, more recent studies have shown that EDS patients tend to have reduced BMD values and a higher risk of fragility fractures. Additionally, recent research has reported a high prevalence of radiological vertebral fractures in adults with EDS, even when their BMD, as measured by DXA, appears normal. Moreover, the presence and severity of vertebral fractures were significantly associated with back pain [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The mechanisms leading to skeletal fragility in EDS may be similar to those occurring in OI, a disease due to a primitive defect in type I collagen synthesis. Moreover, EDS patients have a cortical bone size deficit compared with controls, which may be due to reduced muscle cross-sectional area [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Figure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e illustrates the clinical case of a 61-year-old woman suffering from an EDS. A DXA assessment showed marked osteoporosis (T-score Neck: -3.4, T-score L1-L4: -4.8), and she was also found to have equally low TBS values (L1-L4: 1.204). Bone densitometry with REMS technology also highlighted osteoporosis (T-score Neck: -3.5, T-score L1-L4: -4.1). The results obtained in this patient show that the REMS method assesses bone status as correctly and reliably as DXA and TBS too.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003e5) REMS in Acromegaly\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAcromegaly is a rare disease characterized by elevated levels of GH and insulin-like growth factor I (IGF-I), primarily due to a pituitary adenoma. The condition may cause skeletal alterations and fragility fractures. In fact, the excess of GH and IGF-I promotes the development of cortical thickness, but at the same time stimulates cortical porosity, consequently increasing the risk of fractures, especially at the vertebral level. In a study conducted by Polish endocrinologists in 33 patients with acromegaly (25 women and 8 men), BMD values at all skeletal sites measured with REMS did not differ significantly from those measured with DXA [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Additionally, the BMD values obtained with REMS and DXA correlated similarly with IGF-I levels [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. These data confirm that REMS can be usefully employed in the monitoring of patients with acromegaly.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e6) REMS in Rett Syndrome\u003c/h3\u003e\n\u003cp\u003eRett syndrome (RS) is a neurological disorder that mostly affects females, with a frequency of 1 in 10,000 to 20,000 live birth cases. Symptoms include stereotyped hand movements; impaired learning, language, and communication skills; sudden loss of speech; reduced lifespan; retarded growth; disturbance of sleep and breathing; seizures; autism; and gait apraxia [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The most common non-neurological comorbidities include, among others, orthopedic complications, mainly scoliosis but also early osteopenia/osteoporosis and a high frequency of fractures [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. REMS technique offers an efficient, radiation-free way to assess bone mineral status in individuals with Rett Syndrome. It's often recognized that patients with RS can have significant mobility issues, which may prevent the proper execution of a DXA scan [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Recently, the use of REMS has been introduced in clinical practice for the BMD evaluation in patients with severe motor and intellectual disabilities showing high accuracy and precision, as well as DXA assessment [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. One of the strong points regarding the use in people with Rett Syndrome is the fact that REMS technique could be carried out directly in the bed of the patient and in the absence of ionizing radiation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Anyway, more evidence collected specifically in pediatric subjects is required to clarify the potential role of this technique, which appears promising as an alternative to DXA. Figure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e illustrates the clinical case of a 13-year-old girl with Rett syndrome underwent a densitometric examination using the REMS technique directly in her wheelchair. This approach allows the examination to be performed without moving the child, simplifying the scanning process for extremely fragile patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussions","content":"\u003cp\u003eREMS is a radiation-free, portable technology used for assessing and monitoring bone status at lumbar and femoral sites. Due to its accuracy, precision, and demonstrated non-inferiority to DXA in predicting the 5-year risk of fragility fractures in a large population of Caucasian women, REMS is now regarded as a more accessible alternative to DXA for axial BMD measurement in osteoporosis management [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. REMS has several strengths compared to DXA. First and foremost, the absence of ionizing radiation makes it suitable for use in pediatrics and in pregnant or childbearing women. Additionally, it is easily portable and can eliminate artefacts caused by vascular calcifications, vertebral cementation, osteophytes, and other factors that often lead to an overestimation of BMD in DXA. However, REMS also has some limitations compared to DXA. These include a relative lack of studies involving non-Caucasian populations, limited research on bone diseases other than osteoporosis, challenges in drug monitoring, and reduced accuracy in cases of severe obesity (BMI\u0026thinsp;\u0026gt;\u0026thinsp;40\u0026ndash;45 Kg/m\u003csup\u003e2\u003c/sup\u003e) The analysis of real-world examples of REMS use in managing patients with rare bone diseases allows us to draw some conclusions. As demonstrated by the clinical case of a patient with vitamin D-dependent rickets type 1, REMS can be considered the optimal option for accurately and safely evaluating bone status in young women during their reproductive years, including pregnancy and breastfeeding [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt is well known that obtaining a correctly executed DXA scan can be challenging, and sometimes impossible, in patients with severe mobility impairments and communication difficulties, such as individuals with Rett syndrome or severe scoliosis. In particular, in young patients affected by Rett syndrome, REMS could become a valid alternative to DXA due to its ability to be performed at the patient\u0026rsquo;s bedside or in a wheelchair, without requiring a rigidly fixed position and without exposure to ionizing radiation [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Furthermore, the observation that in patients with osteogenesis imperfecta, REMS is better able than DXA to identify individuals with more severe disease and greater fracture risk highlights its potential to assess aspects of microarchitecture and bone quality relevant to bone fragility [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. It is well known that patients with O.I. frequently suffer from fragility fractures despite often having only slightly reduced or even normal BMD [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In this context, an additional contribution could come from implementing the Fragility Score, a new REMS-based parameter that assesses bone fragility by comparing the spectral lines of the examined subject with reference models of normal and fragile (fractured) bone spectra [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn rare bone diseases, REMS provides an accurate and reliable assessment of bone health, comparable to DXA and TBS. Furthermore, the possibility of using ultrasound technology without ionizing radiation makes REMS a valuable tool for evaluating and monitoring patients suffering from rare bone diseases. Finally, rare bone diseases, characterized by peculiar structural and bone matrix alterations, represent fascinating experimental models for studying and enhancing the potential of REMS technology to provide information on the qualitative characteristics of bone tissue.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCC: Conceptualization, Methodology, Writing \u0026ndash; original draft. CM: Resources, Writing. AV: Resources, Writing. SG: Writing \u0026ndash; review. GC: Resources, Writing. MDTP: Resources, Writing. GS: Supervision. AA: Resources, Writing \u0026ndash; review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Bando 2022 Prot. 2022YSN898\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to partecipate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur research was carried out in accordance with the Declaration of Helsinki of the World Medical Association, and informed consent to participate in the study was obtained from all patients. For individuals younger than the age of 16 consent to participate was obtained from thear parent or legal guardians. The study was approved by the Institutional Review Board of Siena University Hospital (ID-14783/19)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMasi L, et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015; 26:2529-2558. \u003c/li\u003e\n\u003cli\u003ePeck, W.A. Consensus development conference: Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993; 94: 646-650.\u003c/li\u003e\n\u003cli\u003eMessina C, et al. Prevalence and type of errors in dual-energy X-ray absorptiometry. Eur Radiol 2015; 25: 1504-1511. \u003c/li\u003e\n\u003cli\u003eDiez-Perez A, et al. 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Ment Retard Dev Disabil Res Rev 2002; 8:61-65. \u003c/li\u003e\n\u003cli\u003ePecorelli A, et al Altered Bone Status in Rett Syndrome. Life (Basel) 2021; 11 :521. \u003c/li\u003e\n\u003cli\u003eCaffarelli C, et al. Bone Fracture in Rett Syndrome: Mechanisms and Prevention Strategies. Children (Basel) 2023; 10:1861. \u003c/li\u003e\n\u003cli\u003eCaffarelli C, Gonnelli S. The Management of Bone Defects in Rett Syndrome. Calcif Tissue Int. 2025;116:11.\u003c/li\u003e\n\u003cli\u003eSakai T, et al. Radiofrequency echographic multi-spectrometry-based measurement of bone mineral density in patients with severe motor and intellectual disability: An opportunity for patients with severe scoliosis and hip dislocation. Bone Rep 2024; 22:101781.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmim","sideBox":"Learn more about [BMC Medical Imaging](http://bmcmedimaging.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmim/default.aspx","title":"BMC Medical Imaging","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rare bone diseases, radiofrequency echographic multispectrometry (REMS), bone mineral density (BMD), dual-energy X-ray absorptiometry (DXA), osteogenesis imperfecta ","lastPublishedDoi":"10.21203/rs.3.rs-6831093/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6831093/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRadiofrequency Echographic Multi Spectrometry (REMS) is a portable and radiation-free technology that can evaluate and monitor osteoporosis. In particular, REMS has been shown to measure bone mineral density (BMD) at axial skeletal bones with a precision, repeatability and accuracy not inferior to those of dual-energy X-ray absorptiometry (DXA). Moreover, REMS may be useful in the assessment of impaired bone quality and to predict fragility fracture risk. Due to these characteristics, REMS could be usefully used in the diagnosis and follow up of osteoporosis in rare bone diseases. The clinical cases includes in this study were selected among those that best highlight the strengths of REMS technology. A recent study conducted on subjects affected by osteogenesis imperfecta has demonstrated that the REMS technique is able to assess BMD in the same way as the DXA evaluation. REMS has also demonstrated excellent diagnostic accuracy in some patients suffering from others rare disease such as McCune-Albright or Ehlers-Danlos syndromes. Furthermore, REMS could be particularly advantageous in children and in women of childbearing age or during pregnancy and breastfeeding. In conclusion, on the basis of these preliminary data, REMS can be usefulness for the evaluation and monitoring of bone in individuals with rare bone diseases\u003c/p\u003e","manuscriptTitle":"Clinical application of Radiofrequency Echographic Multi-Spectrometry (REMS) for diagnosis and follow-up in several rare bone disorders: A case series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-30 08:49:26","doi":"10.21203/rs.3.rs-6831093/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-12T17:29:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-08T21:40:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-19T23:04:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"106204739984876056651258506854743662199","date":"2025-07-18T09:52:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217103349465477949759718728183677298939","date":"2025-06-29T19:52:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-24T11:47:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-24T11:35:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-23T18:12:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-23T16:59:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medical Imaging","date":"2025-06-23T16:55:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmim","sideBox":"Learn more about [BMC Medical Imaging](http://bmcmedimaging.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmim/default.aspx","title":"BMC Medical Imaging","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2651338a-7900-4310-b44b-0d08a412446c","owner":[],"postedDate":"June 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-29T16:01:01+00:00","versionOfRecord":{"articleIdentity":"rs-6831093","link":"https://doi.org/10.1186/s12880-025-01924-6","journal":{"identity":"bmc-medical-imaging","isVorOnly":false,"title":"BMC Medical Imaging"},"publishedOn":"2025-09-26 15:57:44","publishedOnDateReadable":"September 26th, 2025"},"versionCreatedAt":"2025-06-30 08:49:26","video":"","vorDoi":"10.1186/s12880-025-01924-6","vorDoiUrl":"https://doi.org/10.1186/s12880-025-01924-6","workflowStages":[]},"version":"v1","identity":"rs-6831093","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6831093","identity":"rs-6831093","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}