Osteoarthritis in Italy: Updated Clinical Insights from the ESORT Registry - a multicentric, registry-based cross-sectional study - by the Italian Society of Rheumatology (SIR)

Osteoarthritis in Italy: Updated Clinical Insights from the ESORT Registry - a multicentric, registry-based cross-sectional study - by the Italian Society of Rheumatology (SIR) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Osteoarthritis in Italy: Updated Clinical Insights from the ESORT Registry - a multicentric, registry-based cross-sectional study - by the Italian Society of Rheumatology (SIR) Riccardo Terribili, Suhel Gabriele Al Khayyat, Mario Bentivegna, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8185872/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background osteoarthritis (OA) is a prevalent chronic joint disorder, primarily affecting older adults, with higher frequency in females. It involves progressive cartilage degeneration, leading to pain and disability. The global prevalence of OA continues to rise, especially in aging populations, with the knee being the most affected site. OA is a multifactorial disease associated with obesity, mechanical stress, and systemic inflammation. No disease-modifying OA drugs are currently approved, and treatment is mostly symptomatic. This study aimed to provide updated epidemiological data and insight into clinical characteristics and treatment patterns of OA in Italy, through the implementation of a national rheumatology registry. Methods the ESORT registry, coordinated by the Italian Society of Rheumatology (SIR), included eight rheumatologic centers across Italy. Patients with clinical and radiographic OA at different joint sites were enrolled between 2016 and 2022. Data collected included demographics, BMI, affected joints, baseline VAS pain scores, and current or initiated treatments. Descriptive statistical analyses were performed on the pooled dataset. Results a total of 322 patients were included. The cohort had a female-to-male ratio of 2:1, with a mean age of 73.3 ± 14.7 years and mean BMI of 26.2 ± 4.5 kg/m². The most affected site was the knee (62%), followed by hip (40%), spine (38.2%), and hand (35%). Mean baseline VAS was 49.3 ± 22.2. Regarding treatment, 39.1% used non-selective NSAIDs, 28.8% paracetamol, 45% received hyaluronic acid injections, and 15.2% corticosteroid injections. Conclusions the ESORT registry offers critical insights into OA epidemiology in Italy, underscoring the need for further phenotype-driven research, and integrated care. osteoarthritis prevalence real-world data treatment injections Figures Figure 1 Figure 2 Introduction Osteoarthritis (OA) is one of the most common chronic joint diseases, characterized by progressive thinning and degeneration of articular cartilage, leading to excessive bone formation and ultimately ankylosis and deformity, with severe functional impairment. Females are more frequently affected than males (approximately a 1.5:1 ratio, especially over the age of 50), and prevalence increases with age[ 1 ]. Estimates from 2021 reported a global prevalence of 7.6% (595 million individuals), steadily increasing since 1990 and expected to rise further by 2050[ 1 ]. Currently, about 15% of individuals over 30 years old are affected by OA globally[ 2 ]. The World Health Organization (WHO) reports that approximately 73% of people living with OA are older than 55 years, and 60% are female[ 3 ]. The 2017 Global Burden of Disease (GBD) study revealed 14.9 million new cases of OA, with an age-standardized incidence rate of 181.2 per 100,000 person-years[ 4 ]. The knee is the most frequently affected site, followed by the hand and the hip[ 2 ]. The distinctive pathogenetic feature of OA is represented by the disruption and degradation of hyaline articular cartilage, once believed to be triggered by a "wear and tear" phenomenon related to repeated use and excessive mechanical load. In fact, obesity, high-impact sports, and knee injuries have long been recognized as risk factors for developing OA[ 5 ]. However, a growing body of evidence has revealed a more complex etiology behind OA, suggesting it is a bone-synovium-cartilage disease. Inappropriate mechanical stress[ 6 ], chondrocyte senescence[ 7 ], systemic low-grade inflammation[ 6 ], and other potential factors ultimately drive increased protease activity at the joint site, leading to extracellular matrix destruction and the release of inflammatory mediators, which may result in synovitis and subchondral bone damage[ 8 ]. OA typically presents with joint swelling, prolonged morning stiffness, and reduced range of motion[ 9 ]. However, pain is undoubtedly the most prominent and earliest symptom[ 10 ]. Its intensity and course are not necessarily related to, or predictable by, disease progression and radiographic features[ 10 , 11 ]. This reflects the complex pain mechanisms in OA: cartilage itself is not innervated, so pain arises from other structures (such as the synovium, subchondral bone, periosteum, ligaments, and tendons) and can be modulated by central sensitization[ 10 ]. Currently, OA is considered the leading cause of disability in adults aged 60 years and older[ 12 ]. It is also associated with increased mortality[ 13 – 15 ] and a significant loss in quality-adjusted life years (QALYs)[ 1 ], contributing substantially to healthcare expenditures through both direct costs (e.g., joint replacement surgery) and indirect costs (e.g., loss of productivity)[ 16 ]. In Italy, OA likewise poses a significant public health burden. National surveys indicate that OA is among the most prevalent chronic conditions, affecting approximately 18% of the population over 6 years of age[ 17 , 18 ]. This corresponds to over 10 million individuals, with a markedly higher prevalence in women (around 21.8%) than in men (14.6%)[ 17 , 18 ]. The Italian National Institute of Statistics (ISTAT) has identified OA as the leading cause of chronic illness in women in Italy[ 17 ], surpassing even hypertension and allergies. Other estimates calculate that at least four million Italians have a clinical diagnosis of OA[ 19 ]. Consistent with global trends, OA in Italy is associated with substantial disability and healthcare expenditures. Given Italy’s ageing population, the burden of OA is expected to continue rising in the coming decades. For example, a 2021 study estimated direct costs of approximately €2.5 billion per year for the roughly 3.9 million OA patients in Italy[ 20 ]. Unfortunately, despite ongoing research, no effective disease-modifying osteoarthritis drugs (DMOADs) are currently approved for OA. Clinical management primarily focuses on symptom reduction (pain relief and improvement of function) using nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics (e.g., paracetamol or weak opioids), intra-articular therapies, and non-pharmacologic approaches (exercise, weight loss, physiotherapy). However, symptom control is not always easily achievable in practice, and many patients present persistent pain or functional limitations. Efforts are underway to identify distinct disease phenotypes, as it has been observed that various groups of OA patients share both overlapping and unique clinical characteristics [ 21 ]. These traits have been grouped into varying categories [ 21 – 23 ]. Each clinical expression is likely linked to specific pathogenic processes, involving different cellular and cytokine pathways (molecular endotypes), which can also coexist within a single phenotype[ 24 ]. This understanding would offer the potential for more targeted therapeutic strategies. The ESORT registry was established within the Italian Society of Rheumatology (SIR) to estimate the prevalence and characteristics of OA in Italy, thereby achieving a more accurate characterization of the disease at a national level. This study presents updated results from the ESORT registry on the prevalence of OA, its clinical presentation characteristics, and therapeutic approaches in Italy. Materials and Methods The realization of the ESORT registry involved eight rheumatologic centers across the Nation, under the coordination of the SIR. In each center, patients with a clinical and radiographic diagnosis of OA (knee, hip, hand, spine, or other sites) were selected for enrollment between 2016 and 2022. A clinical diagnosis of OA was defined by the presence of chronic joint pain with characteristic features on history and examination (e.g., age > 50 years, crepitus on active motion, bony enlargement and < 30 or ≤ 60 minutes of morning stiffness), along with the exclusion of other causes of arthritis, in line with established international criteria[ 25 , 26 ]. Radiographic confirmation required the presence of osteophytes or joint space narrowing on X-ray, corresponding to at least grade 2 on the Kellgren-Lawrence classification[ 27 ]. After obtaining signed informed consent and privacy disclosure for the use of personal data, a baseline visit was performed, reporting demographic features, body mass index (BMI), affected joint sites, Visual Analogue Scale for pain (VAS), and ongoing or started treatment. Data from each center were sent electronically and processed to create a single shared database, on which descriptive statistical analysis were performed (GraphPad Prism software 10.2.0 version). The distribution of continuous variables was assessed for normality using the Shapiro–Wilk test. Approximately normally distributed variables were reported as mean ± standard deviation (SD); non-normal variables as median [interquartile range, IQR]. Categorical variables were summarized as counts and percentages. No hypothesis testing or model-based inference was performed, and no p-values are reported. Missing data were handled using an available-case (complete-case) approach without imputation. Results Population characteristics and OA prevalence by site A total of 322 patients met the inclusion criteria and were added to the registry. The cohort had a female-to-male ratio of approximately 2:1 (214 females, 104 males, and 2 not specified), with a mean age of 73.3 ± 14.7 years. The average BMI of the sample was 26.2 ± 4.5 kg/m², indicating that most patients were in the overweight range. In terms of disease localization, 62% of patients were affected by knee OA, 40% by hip OA, 38.2% by spine OA, 35% by hand OA, and 16.4% by OA in another joint site (e.g., ankle, shoulder); patients often had OA in multiple locations (these categories are overlapping, not mutually exclusive) (Fig. 1 ). The mean reported VAS pain score (0–100 scale) at the baseline evaluation was 49.3 ± 22.2, reflecting a moderate level of pain on average. Different OA treatments prescription Regarding the types of OA treatment recorded, 39.1% of patients were taking non-selective NSAIDs at baseline, and an additional 10.5% were on COX-2 selective NSAID inhibitors. 28.8% of patients were using paracetamol for analgesia (with about 4% on a combination of paracetamol plus a weak opioid such as codeine or tramadol). Intra-articular therapies were common: 45% of patients had received hyaluronic acid (HA) injections (viscosupplementation) in an affected joint at some point, including 11% who started such treatment at the baseline visit, while 15.2% had received corticosteroid injections (5.9% initiating steroid injection therapy at baseline). Lastly, 10.5% of patients reported current use of chondroitin supplements, 5.9% were taking glucosamine, and 11.1% were taking a combined formulation of glucosamine and chondroitin (Figure 2). Discussion Data from the ESORT registry on age- and sex-related prevalence of OA are consistent with the available literature. As expected, advancing age and female sex were associated with higher OA prevalence in our cohort, mirroring global trends. However, while the knee was confirmed as the most common site of OA involvement in our sample, the hip emerged as the second most common site. This contrasts with the GBD 2021 global findings, which identified the hip as the third most frequent site of OA after the hand (with knee and hand OA being more common)[2]. According to the GBD study, hip OA was the smallest contributor to overall OA prevalence in most regions, except in high-income areas like North America and Western Europe (which includes Italy), where hip OA contributed relatively more to the OA burden[2]. Our registry’s finding of a high frequency of hip OA might therefore reflect regional factors (such as lifestyle, demographics, or genetic predispositions in European populations) or it may be influenced by the rheumatology setting of our study (since patients with hip involvement may be more likely to be referred to specialists). Detailed data on the overall and site-specific prevalence of OA in Italy have historically been scarce, which makes direct comparisons challenging. The ESORT registry provides one of the first multi-centric glimpses into these patterns. Interestingly, we observed the spine as the third most affected site in our cohort (38.2% of patients had symptomatic spine OA). Spine involvement in OA represents an important yet frequently under-recognized facet of OA epidemiology. Notably, the GBD study did not count cervical or lumbar spine OA as a separate category – those cases were captured under the broader categories of neck pain and lower back pain in the GBD methodology, rather than under “other osteoarthritis”[2]. Our findings underscore that degenerative disease of the spine is a significant part of the OA spectrum, deserving greater attention in epidemiologic studies and in clinical practice due to its contribution to pain and disability. Our study population was generally overweight (mean BMI ~26 kg/m², with a substantial proportion of patients likely meeting criteria for obesity). This finding is not surprising, as both overweight and, particularly, obesity are well-established risk factors for the development of OA[28]. However, there is moderate evidence suggesting a causal relationship even in non-weightbearing joints, such as the hands[29]. This observation has led to the hypothesis that the connection between OA and overweight may involve (low-grade) systemic inflammation beyond just mechanical overload. Indeed, excess adipose tissue produces pro-inflammatory molecules known as adipokines (e.g., tumor necrosis factor, interleukin [IL]-1, IL-6, leptin, and adiponectin), which have been implicated in cartilage catabolism[30]. This includes the inhibition of chondrocyte proliferation, degradation of matrix components, infiltration of joint tissues by immune cells, differentiation of mesenchymal stem cells (MSCs), dedifferentiation of chondrocytes, and activation of osteoclasts[31–33]. Overall, it then seems reasonable to consider Metabolic Syndrome (MetS) as a significant contributor to the onset and progression of OA. Indeed, some studies have indicated a significant association between MetS and an increased incidence of OA[34–36]. A 2020 meta-analysis revealed bidirectional associations between MetS and OA, which could be explained by the synergistic effects of multiple MetS components[36]. Conversely, two informative Mendelian randomization studies using data from Malmo and the UK Biobank provided robust evidence supporting a causal role of elevated BMI in the development of OA in the hip and knee, but not the hand[38]. Despite the reported benefits of weight loss on symptoms, a 2019 systematic review did not find consistent evidence of the effects of weight loss on OA structural pathology in overweight or obese individuals[39]; the authors propose that this discrepancy could stem from the choice of different outcome measurement instruments. Additionally, another 2019 systematic review found most evidence pointing to a null association between MetS and knee and hip OA before and after BMI adjustment[40]. On average, patients in our cohort reported experiencing a moderate level of pain, underlining that pain was a significant issue even in a specialist care setting. Pain is the cardinal symptom of OA and a major driver of disability and healthcare seeking. As mentioned, the paradox of OA is that structural damage on imaging correlates only weakly with pain intensity[11]. Many patients with relatively mild radiographic changes suffer severe pain, and conversely some patients with advanced joint damage report surprisingly low pain, indicating that pain perception in OA is influenced by factors beyond just cartilage loss. Since hyaline cartilage is aneural, it cannot directly generate pain. Instead, nociceptive signals in OA originate from other innervated joint structures that undergo pathological changes: for example, the periosteum (bone lining), subchondral bone itself (which can develop microfractures and bone marrow lesions), ligaments and entheses, the joint capsule, menisci (in the knee), and particularly the synovium when inflamed[41–45]. In this context, synovitis, and bone marrow lesions (BMLs) have been observed to varying degrees in OA patients and are associated with greater pain severity[10]. Moreover, the phenomenon of peripheral sensitization is regarded to significantly contribute to chronic OA pain[10]. Repeated nociceptive input from an OA joint can lower the activation threshold of peripheral nerves in that region (peripheral sensitization) and lead to alterations in the central nervous system’s processing of pain (central sensitization). This manifests as phenomena like hyperalgesia (heightened pain response to normally painful stimuli) and allodynia (pain due to normally non-painful stimuli, e.g. light touch) in some OA patients[46]. Indeed, some individuals with knee OA develop a chronic pain syndrome with features akin to neuropathic pain or fibromyalgia, where the pain is disproportionate to local joint pathology[47]. These observations support the notion that OA is a heterogeneous disease encompassing multiple phenotypes or subgroups, each with unique clinical and biological characteristics[48]. In more detail, a systematic review of the literature conducted by Dell’Isola et al. in 2016 found evidence for six distinct knee OA phenotypes, namely chronic pain phenotype, inflammatory phenotype, metabolic syndrome phenotype, bone and cartilage metabolism phenotype, mechanical overload phenotype and minimal joint disease phenotype[21]. Similarly, Karsdal et al. had proposed five potential phenotypes, including mechanotransduction, hormonal, metabolic, auto-inflammation, and genetic subtypes[23], while later Herrero-Beaumont et al. examined the existence of four distinct phenotypes: biomechanical, osteoporotic, metabolic, and inflammatory[22]. This suggests that individualized treatments may be essential to effectively manage symptoms and prevent radiographic progression in each specific phenotype. All the previously cited authors agree that a more precise understanding of the clinical presentation profiles and the key pathogenic processes in each patient would undoubtedly improve diagnostic accuracy and lead to the development of more targeted and effective treatment strategies. With particular reference to the inflammatory phenotype, since pronounced synovitis is closely tied to pain and progressive joint failure, patients with knee OA and a marked inflammatory profile are more likely to respond to NSAIDs[24]. In our cohort, the most frequently employed pharmacological treatment was intra-articular HA injections (used by 45% of patients at baseline or initiated during the baseline visit), followed by oral NSAIDs (39.1% on non-selective NSAIDs, plus an additional 10.5% on COX-2 inhibitors) and paracetamol (28.8%). A notable proportion of patients (around one-quarter in total) were taking symptomatic slow-acting drugs for OA (SYSADOAs), such as glucosamine and chondroitin (either alone or in combination). These real-world treatment patterns only partially align with current international guidelines for OA management. For example, HA intra-articular injections are not recommended by the American College of Rheumatology (ACR) for knee and hip OA (the ACR guidelines formally recommend against their use, reflecting uncertainty about their benefit)[49]. The Osteoarthritis Research Society International (OARSI) guidelines consider HA injections “conditionally recommended” for knee OA, meaning evidence of benefit is modest or controversial[50]. While the mechanism of HA injections is thought to be both mechanical (improving viscoelastic properties of synovial fluid) and biological (potentially anti-inflammatory and analgesic effects within the joint), the quality of evidence from trials is mixed. Meta-analyses suggest that HA injections can be safe and may provide symptomatic relief in OA, but heterogeneity between studies (different molecular weight HA products, injection protocols, trial designs) has made it difficult to issue a universally strong recommendation[51–53]. Interestingly, while acknowledging heterogeneity between trials and different reported magnitude of clinical benefits from different HA products, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Disease (ESCEO) considers the evidence from meta-analyses, RCTs, and real-life experience on the beneficial effects on pain, function, and global patient assessment to be sufficiently robust to recommend the use of intra-articular hyaluronic acid injections, particularly in patients who have contraindications to NSAIDs or who remain symptomatic despite their use[54]. Furthermore, the European Viscosupplementation Consensus Group (EUROVISCO) recently published the Good Practice Recommendations for Initial Viscosupplementation in Patients with Knee Osteoarthritis in an effort to optimize the use of a highly effective tool for managing knee OA and to provide guidance for standardizing clinical practice[55]. Similar considerations apply to the use of glucosamine and chondroitin, known as Symptomatic Slow-Acting Drugs for Osteoarthritis (SYSADOAs), which are key precursors of cartilage components. Although preclinical and clinical studies have shown some efficacy, especially in reducing pain over the medium and long term[56], the evidence is considered neither sufficient nor reliable, and various guidelines do not recommend their use. However, in its latest recommendations for managing knee OA, the ESCEO emphasizes a significant difference between over the counter and prescription-grade SYSADOAs, particularly glucosamine and chondroitin. While over-the-counter products lack substantial evidence of efficacy and a clear rationale for use, prescription-grade options (especially crystalline glucosamine sulfate and pharmacological-grade chondroitin) are supported by compelling data, demonstrating their ability to significantly reduce pain (comparable to NSAIDs[57,58]), improve functional outcomes, and even slow radiographic progression[54]. Consequently, these prescription-grade products are strongly recommended as the first step in long-term background therapy for managing knee OA[54]. The usage rates in our registry (roughly 27% of patients on some form of glucosamine and/or chondroitin) likely reflect a subset of patients either adhering to rheumatologists’ advice for SYSADOAs or self-medicating in hope of symptom relief. The evidence suggests that if these are used, the pharmaceutical-grade versions should be preferred for any chance of benefit. By contrast, NSAIDs and paracetamol are universally recognized as first-line pharmacological treatments for OA pain in virtually all guidelines [49,50,54,55]. NSAIDs (topical or oral) have proven efficacy for pain and are often more effective than paracetamol, albeit with more side effects [59]. Paracetamol has a more modest analgesic effect in OA and recent meta-analyses have questioned its clinical relevance at safe doses, but it remains an option for milder pain or for patients who cannot tolerate NSAIDs[59]. In our cohort, the majority of patients were on at least one of these agents, which aligns with expectations from standard care (paracetamol ~29%, NSAIDs ~50% if we include COX-2 inhibitors). There is ongoing debate about which to prioritize: given safety concerns with prolonged NSAID use, paracetamol may be initially favored first for mild pain, but its limited efficacy has led major international organizations to provide recommendations in favor of NSAIDs as long as there are no contraindications. Our data simply reflect that both drug classes are frequently used, often in combination or sequence, to manage symptoms. When comparing our findings to data from other countries, certain similarities and differences emerge. The prevalence of NSAID and paracetamol use in our Italian registry is comparable to reports from other European cohorts and the United States, where these remain the mainstays of OA pharmacotherapy[60–64]. The available evidence shows fewer data on the use of SYSADOA and intra-articular HA injections (respectively employed in a significant proportion of patients in Spain [60] and the US [61]) while the use/prescription of opioids (both weak and strong) is consistently higher compared to what was observed in our cohort, particularly among older individuals with a greater number of comorbidities[60,62,63]. This discrepancy, while reflecting an appropriate prescribing pattern in our country in accordance with major international guidelines (which recommend the use of opioids in later lines of treatment for the shortest duration and at the lowest possible dose) could nonetheless be partially influenced by biases in our data collection and by intrinsic differences in the selection of the study populations. The fact that many patients in our registry were using treatments that are not unequivocally supported by guidelines (like HA, glucosamine, etc.) suggests two possibilities. First, it may indicate that the pain relief from core treatments (NSAIDs, physical therapy, etc.) is often insufficient, leading physicians and patients to seek additional relief from adjunctive therapies even if evidence is debated. Second, it could reflect that some of these alternative therapies do provide subjective benefit in certain patients, and thus clinicians have incorporated them into practice due to positive experiences, despite what generic guidelines state. This underscores a key point: there are considerable unmet needs in the management of OA, prompting the use of varied modalities to improve patient outcomes. It also highlights the importance of conducting high-quality studies on these controversial treatments (e.g., identifying which subgroups might benefit most from viscosupplementation or supplements) to better inform future guidelines. Our study has certain limitations, especially related to its observational design. Being a registry-based descriptive study (with a relatively modest sample size of 322), there are inherent issues such as potential selection biases and incomplete data in some records. The data were collected in rheumatology outpatient centers, which could bias the findings toward more complex or severe cases (since milder OA is often managed in primary care and might not be referred to a specialist). This specialist setting might have influenced both the spectrum of joint involvement observed (for example, rheumatologists might see more uncommon or multifocal OA cases than a GP would) and the therapeutic approaches (possibly skewing towards interventions like injections that are more commonly performed by specialists). Furthermore, we did not track longitudinal outcomes in this analysis – the registry captures a cross-sectional snapshot at baseline, but without a predefined follow-up period in this report, we cannot assess how treatments affected outcomes over time or how the disease progressed. Another limitation is that while we documented the types of treatments used, we lack detailed information on dosages, duration of therapy, and patient adherence to those treatments. This granularity could be important, for example, an NSAID taken only intermittently may have different efficacy than one taken regularly, and side effect profiles also depend on dose and duration. Finally, being a real-world study, we relied on the clinical judgment of many different investigators across centers for diagnosing and classifying OA (though we did harmonize criteria as described). There may have been subtle differences in interpretation (e.g., what constitutes “clinical OA” or the threshold for radiographic OA) between investigators, despite our attempt to use consistent inclusion criteria. Conclusions This study presents significant epidemiological and clinical data from the Italian national ESORT registry, a pivotal initiative aimed at understanding the prevalence and characteristics of OA in Italy, where systematic data collection on OA has been limited. Our findings confirm that OA, particularly of the knee, is a widespread health concern associated with considerable pain and functional impairment in the affected population. The symptomatic burden observed highlights the inadequacy of current treatments to fully address patient needs, especially in the absence of disease-modifying options. The high use of adjunct therapies (like injections and supplements) in our cohort suggests that many patients seek additional relief beyond conventional analgesics, underlining a perceived gap in effective long-term management. The ESORT registry data underscore the importance of efforts to refine OA phenotyping and pursue targeted therapies. A deeper characterization of clinical and molecular OA phenotypes will be essential to identify patient subgroups who might be eligible for tailored treatments, for example, anti-inflammatory drugs for inflammation-dominant OA, metabolic interventions for metabolic OA, or novel analgesics for those with central sensitization. In this regard, the application of precision medicine in OA remains at an early stage of development, but our findings support its necessity: not all OA patients are the same, and recognizing these differences could improve outcomes. Looking ahead, longitudinal data collection will be crucial. Following patients over time in the registry will help elucidate the natural course of OA in Italy (e.g., rates of progression to advanced stages or surgery) and assess the long-term effectiveness of interventions (including their potential to modify structural progression, not just symptoms). Such data can inform health policy, for instance, reinforcing the need for obesity prevention programs or better access to physical therapy as means to curb the OA burden. Moreover, broadening the scope of the registry to include patients seen in multidisciplinary and primary care settings would enhance the representativeness of our epidemiological estimates. OA is often first managed by general practitioners, and many patients are cared for by orthopedic surgeons, physiatrists, and other specialists. Including these perspectives would better reflect real-world management across diverse healthcare settings. It could also highlight if certain effective modalities (like exercise programs or pain coping skills training) are underutilized and should be promoted. In conclusion, OA remains a challenging disease with substantial unmet needs in both diagnosis and treatment. Initiatives like ESORT are valuable for shining a light on current practice and outcomes, thereby guiding future improvements. The fight against OA will likely require a combination of public health measures (to address risk factors and encourage early lifestyle interventions), clinical innovations (developing new medications or biologic therapies that can alter disease pathways), and health system adaptations (ensuring patients have access to comprehensive care including non-pharmacologic management and timely surgery when needed). The data presented here serve as an updated benchmark for OA in Italy and reinforce the call for intensified research and resource allocation to improve the quality of life of millions of individuals living with OA. Abbreviations ACR: American College of Rheumatology BMI: Body Mass Index BMLs: Bone Marrow Lesions COX-2: Cyclooxygenase-2 DMOADs: Disease-Modifying Osteoarthritis Drugs ESCEO: European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Disease EUROVISCO: European Viscosupplementation Consensus Group GBD: Global Burden Disease HA: Hyaluronic Acid IL: Interleukin IQR: Interquartile Range ISTAT: Italian National Institute of Statistics MetS: Metabolic Syndrome MSCs: Mesenchymal Stem Cells NSAIDs: Non-Steroidal Anti-Inflammatory Drugs OA: Osteoarthritis OARSI: Osteoarthritis Research Society International QALY: Quality-Adjusted Life Year SD: Standard Deviation SIR: Società Italiana di Reumatologia SYSADOAs: Symptomatic Slow-Acting Drugs for Osteoarthritis VAS: Visual Analogue Scale WHO: World Health Organization Declarations Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Area Vasta Sud-Est (RHELABUS 22271, approval date 22 May 2022) for studies involving humans. Informed consent was obtained from all subjects involved in the study. Clinical Trial Number Non applicable. Consent for publication Not applicable. This manuscript contains no individual person’s data (including images, videos, or details). Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare no competing interests. Funding This research received no external funding. Authors' contributions AMi conceptualized the study. AMi, ODL, MB, LD, AF, MG, UM, AMo, AMu, SP, FP, RR and ST contributed to data collection. AMi, SGA and RT performed data processing and analysis. RT drafted the manuscript. MM contributed to the supervision of the study. All authors reviewed and approved the final version of the manuscript. Acknowledgements The authors thank Enrico Tirri, Domenico Capocotta, and Enrico Fusaro for their contribution to data collection. 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Patterns of therapy switching, augmentation, and discontinuation after initiation of treatment with select medications in patients with osteoarthritis. Clin Ther. 2011;33:1914–31. 10.1016/j.clinthera.2011.10.019 . Arendt-Nielsen L, Schepman P, Hygge Blakeman K, Wilhelm S, Robinson R, Beck C, et al. Prescription patterns and predictors of unmet pain relief in patients with difficult-to-treat osteoarthritis in the Nordics: analyses from the BISCUITS study. Scand J Pain. 2022;23:149–60. 10.1515/sjpain-2021-0211 . Postler A, Luque Ramos A, Goronzy J, Günther KP, Lange T, Schmitt J, et al. Prevalence and treatment of hip and knee osteoarthritis in people aged 60 years or older in Germany: an analysis based on health insurance claims data. Clin Interv Aging. 2018;13:2339–49. 10.2147/cia.s174741 . Knoop J, van Tunen J, van der Esch M, Roorda LD, Dekker J, van der Leeden M, et al. Analgesic use in patients with knee and/or hip osteoarthritis referred to an outpatient center: a cross-sectional study within the Amsterdam Osteoarthritis Cohort. Rheumatol Int. 2017;37:1747–55. 10.1007/s00296-017-3785-3 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 24 Dec, 2025 Reviews received at journal 22 Dec, 2025 Reviews received at journal 15 Dec, 2025 Reviewers agreed at journal 15 Dec, 2025 Reviewers agreed at journal 12 Dec, 2025 Reviewers invited by journal 12 Dec, 2025 Editor invited by journal 27 Nov, 2025 Editor assigned by journal 27 Nov, 2025 Submission checks completed at journal 27 Nov, 2025 First submitted to journal 23 Nov, 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. 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1","display":"","copyAsset":false,"role":"figure","size":104782,"visible":true,"origin":"","legend":"\u003cp\u003eSite-specific prevalence of osteoarthritis in the ESORT registry (Italy).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend:\u003c/strong\u003e Bar chart reporting the proportion of patients affected at each anatomical site at baseline. Involvement at multiple sites was common, so percentages may sum to \u0026gt;100%. Values are shown as percentages of patients with available site information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations: \u003c/strong\u003eOA (Osteoarthritis).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8185872/v1/c557954756fa21d78f2c20de.jpeg"},{"id":98749669,"identity":"775119fa-e826-41de-a9da-1f96092a2ec4","added_by":"auto","created_at":"2025-12-22 09:02:57","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":139748,"visible":true,"origin":"","legend":"\u003cp\u003ePharmacological and intra-articular treatments at baseline in the ESORT registry.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend:\u003c/strong\u003e Distribution of current treatments recorded at baseline among patients with available treatment data. The figure summarizes use of non-selective NSAIDs, COX-2–selective NSAIDs, paracetamol (including a small subset on paracetamol plus a weak opioid, e.g., codeine or tramadol), intra-articular therapies (e.g., hyaluronic acid and corticosteroid injections), and SYSADOAs/supplements (e.g., glucosamine, chondroitin, and glucosamine–chondroitin combination). Values are expressed as percentages of patients; where applicable, the legend or bars indicate patients who initiated an injection therapy at the baseline visit versus those with prior exposure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e FANS (NSAIDs), Non-Steroidal Anti-Inflammatory Drugs.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8185872/v1/daf59aae4b5646f083bd575b.jpeg"},{"id":98783566,"identity":"0d158baf-bb72-427d-84a8-7dccfa39a2bf","added_by":"auto","created_at":"2025-12-22 12:42:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":962107,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8185872/v1/81121640-e77d-4143-840a-09fddb46fdcb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Osteoarthritis in Italy: Updated Clinical Insights from the ESORT Registry - a multicentric, registry-based cross-sectional study - by the Italian Society of Rheumatology (SIR)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOsteoarthritis (OA) is one of the most common chronic joint diseases, characterized by progressive thinning and degeneration of articular cartilage, leading to excessive bone formation and ultimately ankylosis and deformity, with severe functional impairment. Females are more frequently affected than males (approximately a 1.5:1 ratio, especially over the age of 50), and prevalence increases with age[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Estimates from 2021 reported a global prevalence of 7.6% (595\u0026nbsp;million individuals), steadily increasing since 1990 and expected to rise further by 2050[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Currently, about 15% of individuals over 30 years old are affected by OA globally[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The World Health Organization (WHO) reports that approximately 73% of people living with OA are older than 55 years, and 60% are female[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The 2017 Global Burden of Disease (GBD) study revealed 14.9\u0026nbsp;million new cases of OA, with an age-standardized incidence rate of 181.2 per 100,000 person-years[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The knee is the most frequently affected site, followed by the hand and the hip[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The distinctive pathogenetic feature of OA is represented by the disruption and degradation of hyaline articular cartilage, once believed to be triggered by a \"wear and tear\" phenomenon related to repeated use and excessive mechanical load. In fact, obesity, high-impact sports, and knee injuries have long been recognized as risk factors for developing OA[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, a growing body of evidence has revealed a more complex etiology behind OA, suggesting it is a bone-synovium-cartilage disease. Inappropriate mechanical stress[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], chondrocyte senescence[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], systemic low-grade inflammation[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and other potential factors ultimately drive increased protease activity at the joint site, leading to extracellular matrix destruction and the release of inflammatory mediators, which may result in synovitis and subchondral bone damage[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. OA typically presents with joint swelling, prolonged morning stiffness, and reduced range of motion[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, pain is undoubtedly the most prominent and earliest symptom[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Its intensity and course are not necessarily related to, or predictable by, disease progression and radiographic features[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This reflects the complex pain mechanisms in OA: cartilage itself is not innervated, so pain arises from other structures (such as the synovium, subchondral bone, periosteum, ligaments, and tendons) and can be modulated by central sensitization[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrently, OA is considered the leading cause of disability in adults aged 60 years and older[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. It is also associated with increased mortality[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and a significant loss in quality-adjusted life years (QALYs)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], contributing substantially to healthcare expenditures through both direct costs (e.g., joint replacement surgery) and indirect costs (e.g., loss of productivity)[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In Italy, OA likewise poses a significant public health burden. National surveys indicate that OA is among the most prevalent chronic conditions, affecting approximately 18% of the population over 6 years of age[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This corresponds to over 10\u0026nbsp;million individuals, with a markedly higher prevalence in women (around 21.8%) than in men (14.6%)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The Italian National Institute of Statistics (ISTAT) has identified OA as the leading cause of chronic illness in women in Italy[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], surpassing even hypertension and allergies. Other estimates calculate that at least four million Italians have a clinical diagnosis of OA[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Consistent with global trends, OA in Italy is associated with substantial disability and healthcare expenditures. Given Italy\u0026rsquo;s ageing population, the burden of OA is expected to continue rising in the coming decades. For example, a 2021 study estimated direct costs of approximately \u0026euro;2.5\u0026nbsp;billion per year for the roughly 3.9\u0026nbsp;million OA patients in Italy[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Unfortunately, despite ongoing research, no effective disease-modifying osteoarthritis drugs (DMOADs) are currently approved for OA. Clinical management primarily focuses on symptom reduction (pain relief and improvement of function) using nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics (e.g., paracetamol or weak opioids), intra-articular therapies, and non-pharmacologic approaches (exercise, weight loss, physiotherapy). However, symptom control is not always easily achievable in practice, and many patients present persistent pain or functional limitations. Efforts are underway to identify distinct disease phenotypes, as it has been observed that various groups of OA patients share both overlapping and unique clinical characteristics [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These traits have been grouped into varying categories [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Each clinical expression is likely linked to specific pathogenic processes, involving different cellular and cytokine pathways (molecular endotypes), which can also coexist within a single phenotype[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This understanding would offer the potential for more targeted therapeutic strategies.\u003c/p\u003e \u003cp\u003eThe ESORT registry was established within the Italian Society of Rheumatology (SIR) to estimate the prevalence and characteristics of OA in Italy, thereby achieving a more accurate characterization of the disease at a national level. This study presents updated results from the ESORT registry on the prevalence of OA, its clinical presentation characteristics, and therapeutic approaches in Italy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThe realization of the ESORT registry involved eight rheumatologic centers across the Nation, under the coordination of the SIR. In each center, patients with a clinical and radiographic diagnosis of OA (knee, hip, hand, spine, or other sites) were selected for enrollment between 2016 and 2022. A clinical diagnosis of OA was defined by the presence of chronic joint pain with characteristic features on history and examination (e.g., age\u0026thinsp;\u0026gt;\u0026thinsp;50 years, crepitus on active motion, bony enlargement and \u0026lt;\u0026thinsp;30 or \u0026le;\u0026thinsp;60 minutes of morning stiffness), along with the exclusion of other causes of arthritis, in line with established international criteria[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Radiographic confirmation required the presence of osteophytes or joint space narrowing on X-ray, corresponding to at least grade 2 on the Kellgren-Lawrence classification[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. After obtaining signed informed consent and privacy disclosure for the use of personal data, a baseline visit was performed, reporting demographic features, body mass index (BMI), affected joint sites, Visual Analogue Scale for pain (VAS), and ongoing or started treatment.\u003c/p\u003e \u003cp\u003eData from each center were sent electronically and processed to create a single shared database, on which descriptive statistical analysis were performed (GraphPad Prism software 10.2.0 version). The distribution of continuous variables was assessed for normality using the Shapiro\u0026ndash;Wilk test. Approximately normally distributed variables were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD); non-normal variables as median [interquartile range, IQR]. Categorical variables were summarized as counts and percentages. No hypothesis testing or model-based inference was performed, and no p-values are reported. Missing data were handled using an available-case (complete-case) approach without imputation.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePopulation characteristics and OA prevalence by site\u003c/h2\u003e \u003cp\u003eA total of 322 patients met the inclusion criteria and were added to the registry. The cohort had a female-to-male ratio of approximately 2:1 (214 females, 104 males, and 2 not specified), with a mean age of 73.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7 years. The average BMI of the sample was 26.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 kg/m\u0026sup2;, indicating that most patients were in the overweight range. In terms of disease localization, 62% of patients were affected by knee OA, 40% by hip OA, 38.2% by spine OA, 35% by hand OA, and 16.4% by OA in another joint site (e.g., ankle, shoulder); patients often had OA in multiple locations (these categories are overlapping, not mutually exclusive) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean reported VAS pain score (0\u0026ndash;100 scale) at the baseline evaluation was 49.3\u0026thinsp;\u0026plusmn;\u0026thinsp;22.2, reflecting a moderate level of pain on average.\u003c/p\u003e\u003ch2\u003eDifferent OA treatments prescription\u003c/h2\u003e\n\u003cp\u003eRegarding the types of OA treatment recorded, 39.1% of patients were taking non-selective NSAIDs at baseline, and an additional 10.5% were on COX-2 selective NSAID inhibitors. 28.8% of patients were using paracetamol for analgesia (with about 4% on a combination of paracetamol plus a weak opioid such as codeine or tramadol). Intra-articular therapies were common: 45% of patients had received hyaluronic acid (HA) injections (viscosupplementation) in an affected joint at some point, including 11% who started such treatment at the baseline visit, while 15.2% had received corticosteroid injections (5.9% initiating steroid injection therapy at baseline). Lastly, 10.5% of patients reported current use of chondroitin supplements, 5.9% were taking glucosamine, and 11.1% were taking a combined formulation of glucosamine and chondroitin (Figure 2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eData from the ESORT registry on age- and sex-related prevalence of OA are consistent with the available literature. As expected, advancing age and female sex were associated with higher OA prevalence in our cohort, mirroring global trends. However, while the knee was confirmed as the most common site of OA involvement in our sample, the hip emerged as the second most common site. This contrasts with the GBD 2021 global findings, which identified the hip as the third most frequent site of OA after the hand (with knee and hand OA being more common)[2]. According to the GBD study, hip OA was the smallest contributor to overall OA prevalence in most regions, except in high-income areas like North America and Western Europe (which includes Italy), where hip OA contributed relatively more to the OA burden[2]. Our registry\u0026rsquo;s finding of a high frequency of hip OA might therefore reflect regional factors (such as lifestyle, demographics, or genetic predispositions in European populations) or it may be influenced by the rheumatology setting of our study (since patients with hip involvement may be more likely to be referred to specialists). Detailed data on the overall and site-specific prevalence of OA in Italy have historically been scarce, which makes direct comparisons challenging. The ESORT registry provides one of the first multi-centric glimpses into these patterns. Interestingly, we observed the spine as the third most affected site in our cohort (38.2% of patients had symptomatic spine OA). Spine involvement in OA represents an important yet frequently under-recognized facet of OA epidemiology. Notably, the GBD study did not count cervical or lumbar spine OA as a separate category \u0026ndash; those cases were captured under the broader categories of neck pain and lower back pain in the GBD methodology, rather than under \u0026ldquo;other osteoarthritis\u0026rdquo;[2]. Our findings underscore that degenerative disease of the spine is a significant part of the OA spectrum, deserving greater attention in epidemiologic studies and in clinical practice due to its contribution to pain and disability. Our study population was generally overweight (mean BMI ~26 kg/m\u0026sup2;, with a substantial proportion of patients likely meeting criteria for obesity). This finding is not surprising, as both overweight and, particularly, obesity are well-established risk factors for the development of OA[28]. However, there is moderate evidence suggesting a causal relationship even in non-weightbearing joints, such as the hands[29]. This observation has led to the hypothesis that the connection between OA and overweight may involve (low-grade) systemic inflammation beyond just mechanical overload. Indeed, excess adipose tissue produces pro-inflammatory molecules known as adipokines (e.g., tumor necrosis factor, interleukin [IL]-1, IL-6, leptin, and adiponectin), which have been implicated in cartilage catabolism[30]. This includes the inhibition of chondrocyte proliferation, degradation of matrix components, infiltration of joint tissues by immune cells, differentiation of mesenchymal stem cells (MSCs), dedifferentiation of chondrocytes, and activation of osteoclasts[31\u0026ndash;33]. Overall, it then seems reasonable to consider Metabolic Syndrome (MetS) as a significant contributor to the onset and progression of OA. Indeed, some studies have indicated a significant association between MetS and an increased incidence of OA[34\u0026ndash;36]. A 2020 meta-analysis revealed bidirectional associations between MetS and OA, which could be explained by the synergistic effects of multiple MetS components[36]. Conversely, two informative Mendelian randomization studies using data from Malmo and the UK Biobank provided robust evidence supporting a causal role of elevated BMI in the development of OA in the hip and knee, but not the hand[38]. Despite the reported benefits of weight loss on symptoms, a 2019 systematic review did not find consistent evidence of the effects of weight loss on OA structural pathology in overweight or obese individuals[39]; the authors propose that this discrepancy could stem from the choice of different outcome measurement instruments. Additionally, another 2019 systematic review found most evidence pointing to a null association between MetS and knee and hip OA before and after BMI adjustment[40]. On average, patients in our cohort reported experiencing a moderate level of pain, underlining that pain was a significant issue even in a specialist care setting. Pain is the cardinal symptom of OA and a major driver of disability and healthcare seeking. As mentioned, the paradox of OA is that structural damage on imaging correlates only weakly with pain intensity[11]. Many patients with relatively mild radiographic changes suffer severe pain, and conversely some patients with advanced joint damage report surprisingly low pain, indicating that pain perception in OA is influenced by factors beyond just cartilage loss. Since hyaline cartilage is aneural, it cannot directly generate pain. Instead, nociceptive signals in OA originate from other innervated joint structures that undergo pathological changes: for example, the periosteum (bone lining), subchondral bone itself (which can develop microfractures and bone marrow lesions), ligaments and entheses, the joint capsule, menisci (in the knee), and particularly the synovium when inflamed[41\u0026ndash;45]. In this context, synovitis, and bone marrow lesions (BMLs) have been observed to varying degrees in OA patients and are associated with greater pain severity[10]. Moreover, the phenomenon of peripheral sensitization is regarded to significantly contribute to chronic OA pain[10]. Repeated nociceptive input from an OA joint can lower the activation threshold of peripheral nerves in that region (peripheral sensitization) and lead to alterations in the central nervous system\u0026rsquo;s processing of pain (central sensitization). This manifests as phenomena like hyperalgesia (heightened pain response to normally painful stimuli) and allodynia (pain due to normally non-painful stimuli, e.g. light touch) in some OA patients[46]. Indeed, some individuals with knee OA develop a chronic pain syndrome with features akin to neuropathic pain or fibromyalgia, where the pain is disproportionate to local joint pathology[47]. These observations support the notion that OA is a heterogeneous disease encompassing multiple phenotypes or subgroups, each with unique clinical and biological characteristics[48]. In more detail, a systematic review of the literature conducted by Dell\u0026rsquo;Isola et al. in 2016 found evidence for six distinct knee OA phenotypes, namely chronic pain phenotype, inflammatory phenotype, metabolic syndrome phenotype, bone and cartilage metabolism phenotype, mechanical overload phenotype and minimal joint disease phenotype[21]. Similarly, Karsdal et al. had proposed five potential phenotypes, including mechanotransduction, hormonal, metabolic, auto-inflammation, and genetic subtypes[23], while later Herrero-Beaumont et al. examined the existence of four distinct phenotypes: biomechanical, osteoporotic, metabolic, and inflammatory[22]. This suggests that individualized treatments may be essential to effectively manage symptoms and prevent radiographic progression in each specific phenotype. All the previously cited authors agree that a more precise understanding of the clinical presentation profiles and the key pathogenic processes in each patient would undoubtedly improve diagnostic accuracy and lead to the development of more targeted and effective treatment strategies. With particular reference to the inflammatory phenotype, since pronounced synovitis is closely tied to pain and progressive joint failure, patients with knee OA and a marked inflammatory profile are more likely to respond to NSAIDs[24]. In our cohort, the most frequently employed pharmacological treatment was intra-articular HA injections (used by 45% of patients at baseline or initiated during the baseline visit), followed by oral NSAIDs (39.1% on non-selective NSAIDs, plus an additional 10.5% on COX-2 inhibitors) and paracetamol (28.8%). A notable proportion of patients (around one-quarter in total) were taking symptomatic slow-acting drugs for OA (SYSADOAs), such as glucosamine and chondroitin (either alone or in combination). These real-world treatment patterns only partially align with current international guidelines for OA management. For example, HA intra-articular injections are not recommended by the American College of Rheumatology (ACR) for knee and hip OA (the ACR guidelines formally recommend against their use, reflecting uncertainty about their benefit)[49]. The Osteoarthritis Research Society International (OARSI) guidelines consider HA injections \u0026ldquo;conditionally recommended\u0026rdquo; for knee OA, meaning evidence of benefit is modest or controversial[50]. While the mechanism of HA injections is thought to be both mechanical (improving viscoelastic properties of synovial fluid) and biological (potentially anti-inflammatory and analgesic effects within the joint), the quality of evidence from trials is mixed. Meta-analyses suggest that HA injections can be safe and may provide symptomatic relief in OA, but heterogeneity between studies (different molecular weight HA products, injection protocols, trial designs) has made it difficult to issue a universally strong recommendation[51\u0026ndash;53]. Interestingly, while acknowledging heterogeneity between trials and different reported magnitude of clinical benefits from different HA products, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Disease (ESCEO) considers the evidence from meta-analyses, RCTs, and real-life experience on the beneficial effects on pain, function, and global patient assessment to be sufficiently robust to recommend the use of intra-articular hyaluronic acid injections, particularly in patients who have contraindications to NSAIDs or who remain symptomatic despite their use[54]. Furthermore, the European Viscosupplementation Consensus Group (EUROVISCO) recently published the Good Practice Recommendations for Initial Viscosupplementation in Patients with Knee Osteoarthritis in an effort to optimize the use of a highly effective tool for managing knee OA and to provide guidance for standardizing clinical practice[55]. Similar considerations apply to the use of glucosamine and chondroitin, known as Symptomatic Slow-Acting Drugs for Osteoarthritis (SYSADOAs), which are key precursors of cartilage components. Although preclinical and clinical studies have shown some efficacy, especially in reducing pain over the medium and long term[56], the evidence is considered neither sufficient nor reliable, and various guidelines do not recommend their use. However, in its latest recommendations for managing knee OA, the ESCEO emphasizes a significant difference between over the counter and prescription-grade SYSADOAs, particularly glucosamine and chondroitin. While over-the-counter products lack substantial evidence of efficacy and a clear rationale for use, prescription-grade options (especially crystalline glucosamine sulfate and pharmacological-grade chondroitin) are supported by compelling data, demonstrating their ability to significantly reduce pain (comparable to NSAIDs[57,58]), improve functional outcomes, and even slow radiographic progression[54]. Consequently, these prescription-grade products are strongly recommended as the first step in long-term background therapy for managing knee OA[54]. The usage rates in our registry (roughly 27% of patients on some form of glucosamine and/or chondroitin) likely reflect a subset of patients either adhering to rheumatologists\u0026rsquo; advice for SYSADOAs or self-medicating in hope of symptom relief. The evidence suggests that if these are used, the pharmaceutical-grade versions should be preferred for any chance of benefit. By contrast, NSAIDs and paracetamol are universally recognized as first-line pharmacological treatments for OA pain in virtually all guidelines [49,50,54,55]. NSAIDs (topical or oral) have proven efficacy for pain and are often more effective than paracetamol, albeit with more side effects [59]. Paracetamol has a more modest analgesic effect in OA and recent meta-analyses have questioned its clinical relevance at safe doses, but it remains an option for milder pain or for patients who cannot tolerate NSAIDs[59]. In our cohort, the majority of patients were on at least one of these agents, which aligns with expectations from standard care (paracetamol ~29%, NSAIDs ~50% if we include COX-2 inhibitors). There is ongoing debate about which to prioritize: given safety concerns with prolonged NSAID use, paracetamol may be initially favored first for mild pain, but its limited efficacy has led major international organizations to provide recommendations in favor of NSAIDs as long as there are no contraindications. Our data simply reflect that both drug classes are frequently used, often in combination or sequence, to manage symptoms. When comparing our findings to data from other countries, certain similarities and differences emerge. The prevalence of NSAID and paracetamol use in our Italian registry is comparable to reports from other European cohorts and the United States, where these remain the mainstays of OA pharmacotherapy[60\u0026ndash;64]. The available evidence shows fewer data on the use of SYSADOA and intra-articular HA injections (respectively employed in a significant proportion of patients in Spain [60] and the US [61]) while the use/prescription of opioids (both weak and strong) is consistently higher compared to what was observed in our cohort, particularly among older individuals with a greater number of comorbidities[60,62,63]. This discrepancy, while reflecting an appropriate prescribing pattern in our country in accordance with major international guidelines (which recommend the use of opioids in later lines of treatment for the shortest duration and at the lowest possible dose) could nonetheless be partially influenced by biases in our data collection and by intrinsic differences in the selection of the study populations. The fact that many patients in our registry were using treatments that are not unequivocally supported by guidelines (like HA, glucosamine, etc.) suggests two possibilities. First, it may indicate that the pain relief from core treatments (NSAIDs, physical therapy, etc.) is often insufficient, leading physicians and patients to seek additional relief from adjunctive therapies even if evidence is debated. Second, it could reflect that some of these alternative therapies do provide subjective benefit in certain patients, and thus clinicians have incorporated them into practice due to positive experiences, despite what generic guidelines state. This underscores a key point: there are considerable unmet needs in the management of OA, prompting the use of varied modalities to improve patient outcomes. It also highlights the importance of conducting high-quality studies on these controversial treatments (e.g., identifying which subgroups might benefit most from viscosupplementation or supplements) to better inform future guidelines. Our study has certain limitations, especially related to its observational design. Being a registry-based descriptive study (with a relatively modest sample size of 322), there are inherent issues such as potential selection biases and incomplete data in some records. The data were collected in rheumatology outpatient centers, which could bias the findings toward more complex or severe cases (since milder OA is often managed in primary care and might not be referred to a specialist). This specialist setting might have influenced both the spectrum of joint involvement observed (for example, rheumatologists might see more uncommon or multifocal OA cases than a GP would) and the therapeutic approaches (possibly skewing towards interventions like injections that are more commonly performed by specialists). Furthermore, we did not track longitudinal outcomes in this analysis \u0026ndash; the registry captures a cross-sectional snapshot at baseline, but without a predefined follow-up period in this report, we cannot assess how treatments affected outcomes over time or how the disease progressed. Another limitation is that while we documented the types of treatments used, we lack detailed information on dosages, duration of therapy, and patient adherence to those treatments. This granularity could be important, for example, an NSAID taken only intermittently may have different efficacy than one taken regularly, and side effect profiles also depend on dose and duration. Finally, being a real-world study, we relied on the clinical judgment of many different investigators across centers for diagnosing and classifying OA (though we did harmonize criteria as described). There may have been subtle differences in interpretation (e.g., what constitutes \u0026ldquo;clinical OA\u0026rdquo; or the threshold for radiographic OA) between investigators, despite our attempt to use consistent inclusion criteria.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study presents significant epidemiological and clinical data from the Italian national ESORT registry, a pivotal initiative aimed at understanding the prevalence and characteristics of OA in Italy, where systematic data collection on OA has been limited. Our findings confirm that OA, particularly of the knee, is a widespread health concern associated with considerable pain and functional impairment in the affected population. The symptomatic burden observed highlights the inadequacy of current treatments to fully address patient needs, especially in the absence of disease-modifying options. The high use of adjunct therapies (like injections and supplements) in our cohort suggests that many patients seek additional relief beyond conventional analgesics, underlining a perceived gap in effective long-term management. The ESORT registry data underscore the importance of efforts to refine OA phenotyping and pursue targeted therapies. A deeper characterization of clinical and molecular OA phenotypes will be essential to identify patient subgroups who might be eligible for tailored treatments, for example, anti-inflammatory drugs for inflammation-dominant OA, metabolic interventions for metabolic OA, or novel analgesics for those with central sensitization. In this regard, the application of precision medicine in OA remains at an early stage of development, but our findings support its necessity: not all OA patients are the same, and recognizing these differences could improve outcomes. Looking ahead, longitudinal data collection will be crucial. Following patients over time in the registry will help elucidate the natural course of OA in Italy (e.g., rates of progression to advanced stages or surgery) and assess the long-term effectiveness of interventions (including their potential to modify structural progression, not just symptoms). Such data can inform health policy, for instance, reinforcing the need for obesity prevention programs or better access to physical therapy as means to curb the OA burden. Moreover, broadening the scope of the registry to include patients seen in multidisciplinary and primary care settings would enhance the representativeness of our epidemiological estimates. OA is often first managed by general practitioners, and many patients are cared for by orthopedic surgeons, physiatrists, and other specialists. Including these perspectives would better reflect real-world management across diverse healthcare settings. It could also highlight if certain effective modalities (like exercise programs or pain coping skills training) are underutilized and should be promoted. In conclusion, OA remains a challenging disease with substantial unmet needs in both diagnosis and treatment. Initiatives like ESORT are valuable for shining a light on current practice and outcomes, thereby guiding future improvements. The fight against OA will likely require a combination of public health measures (to address risk factors and encourage early lifestyle interventions), clinical innovations (developing new medications or biologic therapies that can alter disease pathways), and health system adaptations (ensuring patients have access to comprehensive care including non-pharmacologic management and timely surgery when needed). The data presented here serve as an updated benchmark for OA in Italy and reinforce the call for intensified research and resource allocation to improve the quality of life of millions of individuals living with OA.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eACR:\u003c/strong\u003e American College of Rheumatology\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMI:\u003c/strong\u003e Body Mass Index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMLs:\u003c/strong\u003e Bone Marrow Lesions\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOX-2:\u003c/strong\u003e Cyclooxygenase-2\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDMOADs:\u003c/strong\u003e Disease-Modifying Osteoarthritis Drugs\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eESCEO:\u003c/strong\u003e European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEUROVISCO:\u003c/strong\u003e European Viscosupplementation Consensus Group\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGBD:\u003c/strong\u003e Global Burden Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHA:\u003c/strong\u003e Hyaluronic Acid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIL:\u003c/strong\u003e Interleukin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIQR:\u003c/strong\u003e Interquartile Range\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eISTAT:\u003c/strong\u003e Italian National Institute of Statistics\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMetS:\u003c/strong\u003e Metabolic Syndrome\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMSCs:\u003c/strong\u003e Mesenchymal Stem Cells\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNSAIDs:\u003c/strong\u003e Non-Steroidal Anti-Inflammatory Drugs\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOA:\u003c/strong\u003e Osteoarthritis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOARSI:\u003c/strong\u003e Osteoarthritis Research Society International\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQALY:\u003c/strong\u003e Quality-Adjusted Life Year\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSD:\u003c/strong\u003e Standard Deviation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSIR:\u003c/strong\u003e Societ\u0026agrave; Italiana di Reumatologia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSYSADOAs:\u003c/strong\u003e Symptomatic Slow-Acting Drugs for Osteoarthritis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVAS:\u003c/strong\u003e Visual Analogue Scale\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWHO:\u003c/strong\u003e World Health Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Area Vasta Sud-Est (RHELABUS 22271, approval date 22 May 2022) for studies involving humans. Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNon applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript contains no individual person\u0026rsquo;s data (including images, videos, or details).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAMi conceptualized the study. AMi, ODL, MB, LD, AF, MG, UM, AMo, AMu, SP, FP, RR and ST contributed to data collection. AMi, SGA and RT performed data processing and analysis. RT drafted the manuscript. MM contributed to the supervision of the study. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Enrico Tirri, Domenico Capocotta, and Enrico Fusaro for their contribution to data collection. We also acknowledge Giovanni Iolascon (President of SINFER) for his support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSteinmetz JD, Culbreth GT, Haile LM, Rafferty Q, Lo J, Fukutaki KG, et al. Global, regional, and national burden of osteoarthritis, 1990\u0026ndash;2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. 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Rheumatol Int. 2017;37:1747\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00296-017-3785-3\u003c/span\u003e\u003cspan address=\"10.1007/s00296-017-3785-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"osteoarthritis, prevalence, real-world data, treatment, injections","lastPublishedDoi":"10.21203/rs.3.rs-8185872/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8185872/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eosteoarthritis (OA) is a prevalent chronic joint disorder, primarily affecting older adults, with higher frequency in females. It involves progressive cartilage degeneration, leading to pain and disability. The global prevalence of OA continues to rise, especially in aging populations, with the knee being the most affected site. OA is a multifactorial disease associated with obesity, mechanical stress, and systemic inflammation. No disease-modifying OA drugs are currently approved, and treatment is mostly symptomatic. This study aimed to provide updated epidemiological data and insight into clinical characteristics and treatment patterns of OA in Italy, through the implementation of a national rheumatology registry.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ethe ESORT registry, coordinated by the Italian Society of Rheumatology (SIR), included eight rheumatologic centers across Italy. Patients with clinical and radiographic OA at different joint sites were enrolled between 2016 and 2022. Data collected included demographics, BMI, affected joints, baseline VAS pain scores, and current or initiated treatments. Descriptive statistical analyses were performed on the pooled dataset.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ea total of 322 patients were included. The cohort had a female-to-male ratio of 2:1, with a mean age of 73.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7 years and mean BMI of 26.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 kg/m\u0026sup2;. The most affected site was the knee (62%), followed by hip (40%), spine (38.2%), and hand (35%). Mean baseline VAS was 49.3\u0026thinsp;\u0026plusmn;\u0026thinsp;22.2. Regarding treatment, 39.1% used non-selective NSAIDs, 28.8% paracetamol, 45% received hyaluronic acid injections, and 15.2% corticosteroid injections.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ethe ESORT registry offers critical insights into OA epidemiology in Italy, underscoring the need for further phenotype-driven research, and integrated care.\u003c/p\u003e","manuscriptTitle":"Osteoarthritis in Italy: Updated Clinical Insights from the ESORT Registry - a multicentric, registry-based cross-sectional study - by the Italian Society of Rheumatology (SIR)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:02:48","doi":"10.21203/rs.3.rs-8185872/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-24T08:49:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-22T09:42:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-15T09:04:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291392658265269696576928035245832668604","date":"2025-12-15T07:59:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"72810105165465837073198191170555920054","date":"2025-12-12T08:49:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-12T08:46:25+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-27T12:45:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-27T10:37:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-27T10:32:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Musculoskeletal Disorders","date":"2025-11-23T13:50:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c164c0e0-700d-469e-a363-aa67ef20bcee","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-25T18:23:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-22 09:02:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8185872","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8185872","identity":"rs-8185872","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}