Is Bone Marrow Edema syndrome (BMEs) associated with Osteoporosis? a single-center study

Is Bone Marrow Edema syndrome (BMEs) associated with Osteoporosis? a single-center study | 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 Is Bone Marrow Edema syndrome (BMEs) associated with Osteoporosis? a single-center study Carla Caffarelli, Caterina Mondillo, Alessandro Versienti, Guido Cavati, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7495683/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background The term "bone marrow edema syndrome" (BMEs) refers to some primary clinical conditions characterized by a high signal on fluid-sensitive MRI sequences at the subchondral bone level, accompanied by pain. This study aimed to evaluate bone status and bone turnover in patients with BMEs compared to a control group. Materials and Methods A cohort of 150 patients with Complex Regional Pain Syndrome type 1(CRPS-I) (n = 56), hip BMEs (n = 37), and knee BMEs (n = 57) and 150 age- and sex-matched healthy controls were recruited for this study. In all we measured bone turnover markers, vitamin D and Bone Mineral Density (BMD) at lumbar spine and at femur by DXA. For a better estimate of bone tissue microarchitecture, we also calculated the Trabecular Bone Score (TBS). Results patients with BMEs exhibited significantly lower BMD at all skeletal sites and lower TBS values compared to healthy controls. The three groups of BMEs patients have significantly higher rates of osteoporosis compared to healthy controls and the rate of osteoporosis higher in patients with CRPS-I and hip BMEs than in those with knee BMEs. Vitamin D and markers of bone turnover show no significant differences among BEMs patients and controls. Conclusion This study indicates that patients with CRPS-I, as well as those with hip and knee BMEs, exhibit a significantly higher prevalence of osteoporosis and a notable reduction in TBS compared to age- and sex-matched healthy controls, thus confirming the pivotal role of bone tissue in the pathogenesis of these diseases. Bone marrow edema syndromes (BMEs) complex regional pain syndrome type-1 hip-BMEs knee-BMEs bone mineral density trabecular bone score bone markers Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Bone marrow edema (BME) is a radiological term used to describe an area that appears with low signal intensity on T1-weighted magnetic resonance imaging (MRI) but shows high signal intensity on T2-weighted MRI or short tau inversion recovery (STIR) sequences [ 1 ]. The term was first introduced in 1988 by Wilson et al. to describe increased water content in the bone among a small group of patients experiencing significant hip or knee pain [ 2 ]. In 2004, Hofmann et al. [ 3 ] introduced the term "bone marrow edema syndrome" (BMEs) as a general term to describe a diagnosis of exclusion for clinical conditions marked by pain and increased interstitial fluid in the bone marrow without a clear cause. The advent of MRI has led to the association of this condition with various terms, including "transient osteoporosis", "transient demineralization", "regional migratory osteoporosis". A recent scoping review by Gravle on this confusing terminology found that while many publications used osteoporosis-related terms, only a few of these studies measured Bone Mineral Density (BMD). This suggests that an overarching term should be linked to bone marrow edema rather than osteoporosis [ 4 , 5 ]. Although the pathophysiology of BMEs is still under discussion, past studies have suggested that even minor trauma may be a significant risk factor [ 6 ]. Emerging evidence now suggests that bone metabolic damage may be the primary driver of BMEs, affecting its clinical characteristics, diagnostic process, and treatment strategy [ 7 ]. Recently, Molfetta et al. [ 7 ], in an paper on the pathogenesis of bone edema, concluded that even Complex Regional Pain Syndrome type 1(CRPS-I), despite its distinctly unique clinical presentation, can be included among BMEs because it shares similarities in imaging, pathophysiology, and therapeutic response to bisphosphonates [ 7 ]. A common feature of BMEs is the characteristic preservation of the articular surface and the presence of varying degrees of pain. [ 4 ]. Complex regional pain syndrome type-1 is a rare clinical condition generally affecting a single limb that is more common in the female population, with a variable ratio between 2:1 and 4:1. It is characterized by intense pain that is disproportionate to the initial cause and is typically accompanied by sensorimotor, vasomotor, sudomotor, and trophic changes in the affected area [ 8 , 9 ]. Bone involvement played a key role in the early descriptions of the disease. In particular, Paul Sudeck identified a radiological picture of patchy osteoporosis as a pivotal element for the diagnosis [ 10 ]. Despite the pivotal role of fractures, sprains and repeated skeletal microtraumas in the development of CRPS-I, in recent decades there has been little focus on bone involvement in the disease. In fact, the current diagnostic criteria from the International Association for the Study of pain (AISP), known as the Budapest criteria, rely solely on clinical symptoms and signs, without incorporating imaging [ 11 ]. Nevertheless, MRI and triphasic bone scintigraphy with technetium-labeled bisphosphonates are imaging techniques that are commonly used in clinical practice to confirm diagnostic suspicions and determine the stage of the disease.The lack of attention that has been paid over the years to the involvement of bone tissue in CRPS-I may explain why the literature contains limited and controversial data on bone turnover markers and axial BMD levels in patients with CRPS-I [ 12 ]. The femur is the skeletal segment most commonly affected by BMEs, a condition characterized by bone marrow edema without an identifiable cause, affecting both the proximal and distal regions. Transient osteoporosis of the hip (TOH) is the most common form of BMEs affecting the hip [ 13 ]. TOH is an idiopathic, self-limiting condition characterized by unexplained hip pain and limping, primarily affecting middle-aged men and women in the third trimester of pregnancy or the immediate postpartum period. In TOH patients, pain intensifies with weight-bearing activities, lessens with rest, but worsens at night. MRI is the most effective method for detecting bone edema and can identify TOH within a few days of symptom onset [ 7 , 14 , 15 ]. A significant proportion of TOH patients exhibit low BMD, although bone densitometry evaluations are infrequent [ 13 , 14 , 16 ]. Primary BMEs involving the knee are either a form transient osteoporosis (TOP) similar to TOH or, more frequently, regional migratory osteoporosis (RMO). RMO manifests with arthralgia localized to a single joint, which then moves, after several months, to another, generally more distal location [ 17 , 18 ]. The pathogenetic features and imaging characteristics of RMO are identical to those of TOH. The term "transient BMEs of the knee" is clinically and radiologically indistinguishable from TOP on MRI. Therefore, transient BMEs is considered the same as TOP when detected clinically before the development of osteopenia [ 17 , 19 ] Moreover, the most recent studies consider it unlikely that TOH and RMO can directly evolve into hip or knee osteonecrosis [ 20 ]. This single-center observational study aimed to evaluate axial BMD using DXA, Trabecular Bone Score (TBS), and bone turnover markers in all patients diagnosed with BMEs (including CRPS-I, hip BMEs and knee BMEs) at the time of initial diagnosis and prior to initiating pharmacological therapy . Methods Study population The patients for this observational study were recruited from the outpatient clinic of the Internal Medicine Unit at the University Hospital of Siena (Italy) between January 2017 and December 2024. Patients had to meet the following criteria: 1) Diagnosis of CRPS-I or BMEs of the hip or knee confirmed by MRI, characterized by an abnormal signal or a well-defined area of hypointensity on T1-weighted sequences and hyperintensity on T2-weighted or STIR sequences ; 2) spontaneous pain in the affected limb of ≥ 50 mm on a visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (maximum pain) during the previous week; 3) age between 18 and 70 years. Exclusion criteria were: 1) disease duration longer than 6 months; 2) clinical history of severe chronic diseases or the presence of another chronic pain syndrome that interferes with pain ratings; 3) prior treatment with bisphosphonates or other anti-osteoporosis drugs (excluding calcium and vitamin D supplements) or undergoing therapies that could impact bone metabolism (such as glitazones, glucocorticoids, anticonvulsants, etc.); 4) for patients with suspected diagnosis of CRPS-I the lack of IASP diagnostic criteria (Budapest criteria) or major nerve damage suggestive of CRPS-II [ 11 ]. A cohort of 175 patients was evaluated. From the initial group, an additional 25 patients were excluded: 12 patients with suspected CRPS-I who did not meet the IASP diagnostic criteria (Budapest criteria) [ 11 ]; 1 patient due to major nerve damage indicative of CRPS-II; 5 patients secondary BMEs diagnosis; and 7 patients with BMEs involving skeletal sites outside the hip and knee. The remaining 150 BMEs patients were then divided into three groups: CRPS-I (n = 56 ), hip BMEs (n = 37), and knee BMEs (n = 57); the flow chart showing the distribution of study participants is presented in Fig. 1 . In addition, in Fig. 2 shows three characteristic MRI scans from the three patient groups investigated. All MRI examinations were evaluated by an experienced radiologist before recruitment, especially to exclude conditions of bone edema due to osteoarthritis. Age- and sex-matched healthy controls were recruited from a subgroup of individuals living in the Siena area (Italy) who had been participating in a larger epidemiological study [ 21 ], as well as from healthy volunteers enrolled from the hospital personnel. Female controls were also matched for menopausal status. All patients underwent measurement of weight, height and body mass index (BMI). The body mass index expresses the ratio between weight in kilograms divided by the square of height in meters. Vital parameters, such as blood pressure and heart rate, were evaluated. For all patients a detailed personal and familiar medical history was obtained. The study was conducted in accordance with the 1964 Helsinki Declaration and its later amendments, and the research protocol received approval from the Ethics Committee of Siena University Hospital (ID-21211). Informed written consent was obtained from all participants. Prior to statistical analysis, all collected data underwent anonymization procedures. Laboratory and densitometric assessments After fasting for at least 12 hours, patients underwent blood sampling for the evaluation of: glycemia, creatinine, calcium, phosphate, albumin, total alkaline phosphatase, C-terminal telopeptide of type 1 collagen (β-CTX), bone isoenzyme of alkaline phosphatase (B-ALP), parathyroid hormone (PTH), 25hydroxyvitaminD (25OHD). Serum β-CTX was measured by an ELISA method (Immunotopics INT, San Clemente, CA, USA) and the intra- and inter-assay precision was 2.5 and 3.5%, respectively. Serum B-ALP was measured by a chemiluminescence immunoassay method (LIAISON BAP Ostase, DiaSorin Inc., Stillwater, MN, USA); in our institution, the intra-and inter-assay coefficients of variation for B-ALP were 4.2% and 7.9%, respectively. Serum PTH was assessed by immunoradiometric assay (Total Intact PTH, Antibodies Lab. Inc.; Santee, CA, USA) and the intra- and inter-assay coefficients of variation were 3.6% and 4.9%, respectively. Serum 25OHD was determined by a chemi-luminescence immunoassay (LIAISON 25OHD Total Assay, DiaSorin Inc, Stillwater, MN, USA); in our institution, the intra- and inter-assay coefficients of variation were 6.8% and 9.2%, respectively. In all subjects we measured BMD at the lumbar spine (LS-BMD), at femoral neck (FN-BMD) and total hip (TH-BMD) using a dual-energy X-ray absorptiometry device (Discovery W, Hologic, Waltham, MA, USA). All DXA scans were performed according to the standard clinical routine procedures. Obviously, femoral BMD was measured on the limb contralateral to the one possibly affected by BMEs. Osteoporosis and osteopenia were diagnosed according to the World Health Organization (WHO) definition: a T value lower than − 2.5 was diagnosed as osteoporosis and a T value less than − 1.0 but higher than − 2.5 was diagnosed as osteopenia; sex-matched Italian reference data were used for the calculation of T-score. For a better estimate of bone tissue microarchitecture, we also calculated the Trabecular Bone Score (TBS). TBS was calculated by using TBS iNsight software (Version 2.1, Medimaps SA, Bordeaux, France) in an operator-independent automated manner. The TBS was calculated from the standard DXA scan of the antero-posterior lumbar spine. TBS values were calibrated to standard values using the TBS calibration phantom (17 cm thickness and 25% fat mass equivalent), and were adjusted for BMI to 21.78. In our centre the short-term, precision of TBS calculation was 1.5% (CV). Statistical Analysis The values in the study are presented as "mean” ± standard deviation (SD). The normality of the distribution of outcome variables was assessed using the Kolmogorov–Smirnov test. Clinical data and initial values of the measured variables in the study groups were compared using Student’s t-test and Mann–Whitney U-test, depending on the appropriateness of the data distribution. Categorical variables were subjected to comparison using the Chi-square test or Fisher’s exact test, as deemed appropriate. Associations between different parameters were examined through Pearson’s correlation or Spearman’s correlation, as appropriate, or via partial correlation analysis. All statistical analyses were performed using the SPSS statistical package for Windows version 16.0 (SPSS Inc., Chicago). Results Table 1 presents the clinical and densitometric parameters of the study population and healthy controls. As expected, the two groups were similar not only in age and gender but also in BMI. However, patients with BMEs exhibited significantly lower BMD at all skeletal sites and lower TBS values compared to healthy controls (p < 0.01). The clinical characteristics and biochemical parameters of patients grouped by the localization of BMEs are shown in Table 2 . Notably, BMI was significantly higher in patients with knee BMEs compared to those with CRPS-I or hip BMEs. The time since diagnosis was 3.3 ± 4.0 weeks for hip BME, 4.8 ± 3.8 weeks for knee BME and 4.0 ± 4.2 for CRPS-I. Additionally, B-ALP and β-CTX values were significantly higher in patients with knee BMEs (p < 0.05). However, no significant differences were observed among the three groups regarding blood count, calcium, phosphorus, total alkaline phosphatase, vitamin D, and parathyroid hormone levels. Table 1 – Clinical and densitometric characteristics of the patients with BMEs and controls BMEs (N = 150) controls (N = 150) p Sex (F/M) 88/62 88/62 n.s. Age (yrs) 57.7 ± 12.4 55.7 ± 12.1 n.s. BMI (Kg/m 2 ) 25.9 ± 3.4 26.3 ± 4.6 n.s. LS-BMD (g/cm 2 ) 0.949 ± 0.192 1.098 ± 0.145 0.01 LS T-score -1.38 ± 1.65 -0.68 ± 1.17 0.01 TBS 1.248 ± 0.146 1.392 ± 0.087 0.01 FN-BMD (g/cm 2 ) 0.751 ± 0.143 0.869 ± 0.111 0.01 FN T-score -1.44 ± 1.06 -1.03 ± 0.89 0.01 TH-BMD (g/cm 2 ) 0.854 ± 0.148 0.951 ± 0.118 0.01 TH T-score -1.12 ± 1.05 -0.62 ± 0.91 0.01 Table 2 – Clinical and biochemical characteristics of the patients with BMEs CRPS-I (N = 56) Knee BMEs (N = 57) Hip BMEs (N = 37) Sex (F/M) 38/18 28/29 22/15 Age (yrs) 57.17 ± 10.73 58.88 ± 12.49 57.51 ± 14.11 BMI (Kg/m 2 ) 25.47 ± 4.44 27.25 ± 4.78 25.42 ± 4.00* Calcium (mg/dl) 9.42 ± 0.39 9.48 ± 0.48 9.45 ± 0.35 Phosphate (mg/dl) 3.37 ± 0.45 3.37 ± 0.46 3.35 ± 0.57 Creatinine (mg/dl) 0.75 ± 0.13 0.85 ± 0.17 0.88 ± 0.18* Alalkaline phosphatase (U/L) 79.43 ± 34.33 78.43 ± 20.75 82.47 ± 31.68 25OHD (ng/ml) 25.88 ± 13.88 25.39 ± 13.18 27.14 ± 15.72 PTH (pg/ml) 32.51 ± 16.91 32.99 ± 17.78 31.38 ± 19.05 B-ALP (µg/L) 13.16 ± 6.13 15.42 ± 14.07 13.72 ± 7.15* β-CTX (ng/L) 0.469 ± 0.411 0.516 ± 0.252 0.455 ± 0.244* Red blood count (x109/L) 4.65 ± 0.55 4.86 ± 0.46 4.44 ± 0.77 White blood count (x109/L) 6.68 ± 2.11 6.52 ± 1.78 6.02 ± 1.90 Hemoglobin (g/dL) 13.74 ± 1.31 14.45 ± 1.53 14.17 ± 1.56 Mean corpuscular volume (fL) 88.55 ± 10.83 88.63 ± 6.92 92.41 ± 5.32 Red cell distribution width (%) 14.04 ± 1.91 13.52 ± 0.99 12.97 ± 0.62 Thrombocyte count (x109/L) 255.26 ± 60.71 248.94 ± 66.78 228.38 ± 61.43 * p < 0.05 Figure 3 shows the mean BMD values at the total hip in patients with BMEs and healthy controls, expressed as T-scores. It is evident that BMD T-scores were lower in patients with BMEs compared to healthy controls (p < 0.05). Additionally, based on the localization of BMEs, the total hip T-score was lower in patients with CRPS-I. Figure 4 shows the percentages of BMEs patients and healthy controls who, based on WHO criteria, exhibit a pattern of “osteoporosis”, “osteopenia”, or “normal BMD”. All three groups of BMEs patients have significantly higher rates of osteoporosis compared to healthy controls. Additionally, the rate of osteoporosis is notably higher in patients with CRPS-I and hip BMEs than in those with knee BMEs. Figure 5 shows the LS-BMD and TBS values in patients with BMEs, categorized by the location of the disease. Patients with knee BMEs had higher LS-BMD values compared to those with CRPS-I or hip BMEs, although the difference was not statistically significant. In contrast, TBS values did not show significant differences among the three groups. Figure 6 presents the FN-BMD and TH-BMD values in patients with BMEs, also categorized by the location of the disease. FN-BMD and TH-BMD values were lower in patients with CRPS-I or hip BMEs compared to those with knee BMEs, but the difference was statistically significant only for TH-BMD (p < 0.05). Table 3 presents the age- and BMI-adjusted partial correlations of B-ALP and β-CTX values with BMD values at all skeletal sites according to BMEs localization. We observed that B-ALP and β-CTX were significantly correlated with BMD values at all skeletal sites in patients with hip BMEs (p < 0.05). However, in patients with CRPS-I and hip BMEs, β-CTX values presented a significant inverse correlation (p < 0.05) only with LS-BMD. Table 3 Age-adjusted partial correlation between β-CTX and B-ALP and BMD according to with BMEs localization LS-BMD (g/cm 2 ) FN-BMD (g/cm 2 ) TH-BMD (g/cm 2 ) CRPS-I (N = 56) B-ALP (µg/L) -0.28 -0.19 -0.17 β-CTX (ng/L) -0.56** -0.23 -0.24 Knee BMEs (N = 57) B-ALP (µg/L) -0.53* -0.52* -0.56* β-CTX (ng/L) -0.54* -0.61* -0.75** Hip BMEs (N = 37) B-ALP (µg/L) 0.34 0.28 0.27 β-CTX (ng/L) -0.60** -0.46* -0.48* *p < 0.05, ** p < 0.01 Discussion The main finding of this study is that patients with bone marrow edema syndromes, particularly those with CRPS-I and hip BMEs, have reduced BMD compared to healthy controls of the same age and sex. For over 20 years, several studies on patients with CRPS-I have observed reduced BMD values by DXA, not only in the limb affected but also in the contralateral limb [ 22 ] and at the lumbar level [ 23 ]. Additionally, other studies have reported a prevalence of osteopenia or osteoporosis in these patients [ 24 , 25 ] and, in particular, de Mos et al., in a large study of the Dutch population, found that menopause and osteoporosis were key risk factors for CRPS-I [ 24 ]. To our knowledge, this is the first study reporting that the values of trabecular bone score, a densitometric parameter influenced by the structural and qualitative characteristics of the bone, are significantly reduced in patients with BMEs compared to healthy controls. Furthermore, Oehler et al. by using high-resolution peripheral quantitative computed tomography (HR-pQCT) revealed significant microstructural alterations in cortical and trabecular bone tissues in CRPS-1, offering new insights into the morphological and pathophysiological processes specific to bone changes caused by CRPS-I [ 25 ]. The potential link between CRPS-I and bone quantity/quality was further supported by the observation of several cases of Sudeck's algodystrophy in patients with osteogenesis imperfecta [ 26 ]. Despite these data and the undeniable importance of fractures and bone trauma in the development of CRPS-I, research and the taxonomic classification of the disease have, for many years, remained focused on the role of sympathetic system hyperactivation in its pathogenesis. More recently, Varenna and Crotti in their 2018 expert opinion, identified bone involvement as a key feature in the pathogenesis of CRPS-I and described the underlying pathophysiology based on the knowledge available at the time [ 27 ]. In this model, direct injury to the bone initially triggers the local release of proinflammatory mediators, such as TNF, IL-1, IL-6, substance P, and calcitonin gene-related peptide. This is followed by changes in capillary permeability, resulting in edema, hypoxia, and acidosis [ 27 , 28 ]. Another noteworthy finding of this study is that bone turnover markers, specifically B-ALP and β-CTX, remained within normal limits, even though most of our patients were postmenopausal women. These results support the conclusions of recent studies that challenge the notion of accelerated bone turnover with osteoclastic hyperactivity in the early stages of CRPS-I [ 28 , 29 ]. Instead, these studies suggest that the rapid loss of BMD during these phases may be due to the chemical dissolution of hydroxyapatite, caused by significant acidosis and a localized drop in pH [ 28 , 29 ]. In our study, we did not find reduced levels of vitamin D or elevated PTH levels in the entire population or within the three groups (CRPS-I, hip BMEs and knee BMEs) when analyzed separately. These findings appear to contrast with what has been reported in several other studies [ 30 , 31 ]. In particular, a recent scoping review of the literature highlighted that over 60% of studies on patients with BMEs reported vitamin D levels indicative of deficiency or insufficiency [ 32 ]. This discrepancy may be explained by the fact that most postmenopausal women in our area regularly take vitamin D supplements. In this study, the percentage of patients with hip BMEs who had osteoporosis was nearly identical to that of patients with CRPS-I and markedly higher with respect to that of patients with knee BMEs. This finding is an interesting result of the study, as it suggests the identification of certain characteristics that may distinguish hip BMEs from knee BMEs. It aligns with the majority of studies on individuals with primary hip BMEs, which have identified osteopenia or osteoporosis as the most significant risk factors for the onset of the disease [ 15 ]. In fact, a large case series conducted by the Mayo Clinic, as well as an Italian study, found that over 50% of patients with transient osteoporosis of the hip had BMD values from DXA indicative of osteoporosis or osteopenia [ 14 , 16 ]. In another study on patients with transient osteoporosis of the hip, lumbar densitometry evaluations were performed on 31 patients, with 15 classified as osteopenic and 15 as osteoporotic [ 33 ]. Additionally, it has been hypothesized that patients with osteogenesis imperfecta are more likely to develop the disorder [ 15 , 16 ]. However, it is important to note that in these studies, unlike ours, BMD by DXA was assessed in only a small subgroup of patients, and it is unclear whether the affected limb was excluded from the analysis. Patients with knee BMEs have significantly higher levels of bone turnover markers compared to those with CRPS-I or hip BMEs. However, it is important to note that both B-ALP and β-CTX values remain within normal limits. It has been hypothesized that in patients with hip and knee BMEs, similar to those with CRPS-1, the rapid loss of bone mass in the proximal or distal femur is not due to osteoclastic hyperactivity but rather to the chemical dissolution of hydroxyapatite caused by low pH levels [ 29 ]. The increase in B-ALP levels could reflect heightened osteoblastic activity, which may also be responsible for elevated osteoprotegerin levels [ 34 , 35 ]. Our study has some limitations. First, its retrospective nature limits our ability to investigate the relationship between the type and number of risk factors, the intensity or duration of symptoms, and the response to therapy. Second, the diagnosis of primary BMEs involving the hip and knee is one of exclusion, which introduces the risk of including patients with other confounding conditions. However, the study also has several strengths. First, it is a single-center study that collected a large case series using uniform and predefined diagnostic criteria. Second, to our knowledge, it is one of the very few studies that assessed BMD using DXA in all patients with BMEs before starting therapy. Finally, it is certainly the first study to evaluate TBS in patients with BMEs. Conclusion This study reveals that patients with BMEs, particularly those with CRPS-I and hip BME, have a higher prevalence of osteoporosis and a notable reduction in TBS compared to age- and sex-matched healthy controls. This common risk factor, along with similarities in pathophysiological mechanisms, MRI imaging features, and a comparable response to bisphosphonates, confirms the pivotal role of bone tissue in the pathogenesis of these diseases and supports the hypothesis that these conditions fall under the broader category of "Bone Marrow Edema Syndromes." Declarations Acknoledgements None Authorship contribution statement C.C., S.G., A.A., Conceptualization, Methodology, Formal analysis, Writing – review & editing. C.M., S.G., Resources, Writing. A.V., G.C., L.T., Resources. L.G., B.F., Supervision. Funding This study was supported by the Bando 2022 Prot. 2022YSN898 Data availability Data will be made available upon reasonable request Disclosure None. Competing intersts The Authors declare no competing interests. References Korompilias AV, Karantanas AH, Lykissas MG, Beris AE (2009) Bone marrow edema syndrome. Skeletal Radiol 38:425–432. https://doi:10.1007/s00256-008-0529-1 Wilson AJ, Murphy WA, Hardy DC, Totty WG (1988) Transient osteoporosis: transient bone marrow edema? Radiology 167:757–760. https://doi:10.1148/radiology.167.3.3363136 Hofmann S, Kramer J, Vakil-Adli A, Aigner N, Breitenseher M (2004) Painful bone marrow edema of the knee: differential diagnosis and therapeutic concepts. Orthop Clin North Am 35:321–333. https://doi:10.1016/j.ocl.2004.04.005 Grøvle L, Julsrud Haugen A, Johansen M, Hasvik E (2024) The terminologies of transient, migratory, or localized osteoporosis, and bone marrow edema syndrome: a scoping review. Osteoporos Int 35:217–226. https://doi:10.1007/s00198-023-06929-x Hasvik E, Haugen AJ, Grøvle L (2025) Clinical characteristics of patients with bone marrow edema syndrome, transient osteoporosis or migratory osteoporosis: a scoping review. Bone. https://doi.org/10.1016/j.bone.2025.117535. 198,117535 Manara M, Varenna M (2014) A clinical overview of bone marrow edema. Reumatismo 66:184–196. https://doi:10.4081/reumatismo.2014.790 Molfetta L, Florian A, Saviola G, Frediani B (2022) Bone Marrow Edema: pathogenetic features. Clin Ter 173:434–439. https://doi:10.7417/CT.2022.2459 Marinus J, Moseley GL, Birklein F, Baron R, Maihofner C, Kingery WS, van Hilten JJ (2011) Clinical features and patho physiology of complex regional pain syndrome. Lancet Neurol 10:637–648. https://doi:10.1080/0963828021000007950 Ferraro MC, O'Connell NE, Sommer C, Goebel A, Bultitude JH, Cashin AG et al (2024) Complex regional pain syndrome: advances in epidemiology, pathophysiology, diagnosis, and treatment. Lancet Neurol 23:522–533. https://doi:10.1016/S1474-4422(24)00076-0 Sudeck P (1900) Über die acute entzündliche knochenatrophie. Archiv Klin Chir 62:147–156 Harden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, Swan M et al (2013) Complex regional pain syndrome: practi cal diagnostic and treatment guidelines, 4th edition. Pain Med. ;14:180–229. https://doi:10.1111/pme.12033 Kollmann G, Wertli MM, Dudli S, Distler O, Brunner F (2023) The role of the bone in complex regional pain syndrome 1-A systematic review. Eur J Pain 27:794–804. https://doi:10.1002/ejp.2116 Patel S (2014) Primary bone marrow oedema syndromes. Rheumatology 53:785–792. https://doi.org/10.1093/rheumatology/ ket324 Trevisan C, Klumpp R, Compagnoni R (2016) Risk factors in transient osteoporosis: a retrospective study on 23 cases. Clin Rheumatogy 35:2517–2522. https://doi:10.1007/s10067-016-3228-7 Di Martino A, Brunello M, Villari E, Cataldi P, D'Agostino C, Faldini C (2023) Bone marrow edema of the hip: a narrative review. Arch Orthop Trauma Surg 143:6901–6917. https://doi:10.1007/s00402-023-04961-4 Kotwal A, Hurtado MD, Sfeir JG, Wermers RA (2019) TRANSIENT OSTEOPOROSIS: CLINICAL SPECTRUM IN ADULTS AND ASSOCIATED RISK FACTORS. Endocr Pract 25:648–656. https://doi:10.4158/EP-2018-0626 Roemer FW, Frobel R, Hunter DJ, Crema MD, Fischer W, Bohndorf K et al (2009) MRI-detected subchondral bone marrow signal alterations of the knee joint: terminology, imaging appearance, relevance and radiological differential diagnosis. Osteoarthritis Cartilage 7:1115–1131. https://doi:10.1016/j.joca.2009.03.012 Komnos GA, Paridis DI, Banios KT, Karachalios TS, Dailiana ZH, Luceri F (2023) Randelli PS Regional migratory osteoporosis of the knee: a literature overview. Musculoskelet Surg 107:159–164. https://doi:10.1007/s12306-023-00774-1 Korompilias AV, Karantanas AH, Lykissas MG, Beris A (2009) Bone marrow edema syndrome. Skeletal Radiol 38:425–436. https://doi:10.1007/s00256-008-0529-1 Geith T, Stellwag AC, Müller E, Reiser P, Baur-Melnyk M (2020) Is bone marrow edema syndrome a precursor of hip or knee osteonecrosis? Results of 49 patients and review of the literature. Diagn Interv Radiol 26:355–362. https://doi:10.5152/dir.2020.19188 Gonnelli S, Caffarelli C, Cappelli S, Rossi S, Giordano N, Nuti R (2014) Gender-specific associations of appendicular muscle mass with BMD in elderly Italian subjects. Calcif Tissue Int 95:340–348. https://doi:10.1007/s00223-014-9902-3 Arriagada M, Arinoviche R (1994) X-ray bone densitometry in the diagnosis and followup of reflex sympathetic dystrophy syndrome. J Rheumatol 21:498–500 Cepollaro C, Gonnelli S, Pondrelli C, Martini S, Montagnani A, Rossi B, Gennari C (1998) Usefulness of ultrasound in Sudeck’s atrophy of the foot. Calcif Tissue Int 62:538–541. https://doi:10.1007/s002239900475 de Mos M, Huygen F, Dieleman JP, Koopman J, Stricker CBH, Sturkenboom M (2008) Medical history and the onset of complex regional pain syndrome (CRPS). Pain 139:458–466. https://doi:10.1016/j.pain.2008.07.002 Oehler N, Rolvien T, Schmidt T, Butscheidt S, Oheim R, Barvencik F, Mussawy H (2019) Bone microstructure is significantly altered in CRPS-affected distal tibiae as detected by HR-pQCT: a retrospective cross-sectional study. Bone Min Metab 37:741–748. https://doi:10.1007/s00774-018-0976-2 Bouvier M, Colson F, Noel E, Tebib JG, Felman C (1997) Two new case-reports of reflex sympathetic dystrophy syndrome in patients with osteogenesis imperfecta. Review of the literature. Rev Rhum Engl Ed 64:202–204 Varenna M, Crotti C (2018) Bisphosphonates in the treatment of complex regional pain syndrome: Is bone the main player at early stage of the disease? Rheumatol Int 38:1959–1962. https://doi:10.1007/s00296-018-4101-6 Kollmann G, Wertli MM, Dudli S, Distler O, Brunner F (2023) The role of the bone in complex regional pain syndrome 1-A systematic review. Eur J Pain 27:794–804. https://doi:10.1002/ejp.2116 Varenna M, Orsini F, Di Taranto R, Zucchi F, Adami G, Gatti D, Crotti C (2924) Bone Turnover Markers and Wnt Signaling Modulators in Early Complex Regional Pain Syndrome. A Pre-specified Observational Study. Calcif Tissue Int 115:251–259. https://doi:10.1007/s00223-024-01251-y Oehler N, Mussawy H, Schmidt T, Rolvien T, Barvencik F (2018) Identification of vitamin D and other bone metabolism parameters as risk factors for primary bone marrow oedema syndrome. BMC Musculoskelet Disord 19:451. https://doi.org/10.1186/s12891-018-2379 Lee S-U, Na K-T, Lee Y-M, Park JH, Joo SY (2020) Low vitamin D levels in post-menopausal women are associated with complex regional pain syndrome type I in surgically treated distal radius fractures. Orthop Surg Res 15:328. https://doi:10.1186/s13018-020-01859-4 Eidmann A, Eisert M, Rudert M, Stratos I (2022) Influence of Vitamin D and C on Bone Marrow Edema Syndrome-A Scoping Review of the Literature. J Clin Med 11:6820. https://doi.org/10.3390/jcm11226820 Klontzas ME, Vassalou EE, Zibis AH, Bintoudi AS, Karantanas AH (2015) MR imaging of transient osteoporosis of the hip: an update on 155 hip joints. Eur J Radiol. 2015;84:431-6. https://doi Asadipooya K, Graves L, Greene LW (2017) Transient osteoporosis of the hip: review of the literature. Osteoporos Int 28:1805–1816. https://doi:10.1016/j.ejrad.2014.11.022 Kramer HH, Hofbauer LC, Szalay G, Breimhorst M, Eberle T, Zieschang K et al (2014) Osteoprotegerin: a new biomarker for impaired bone metabolism in complex regional pain syndrome? Pain 155:889–895. https://doi:10.1016/j.pain.2014.01.014 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 14 Feb, 2026 Reviewers agreed at journal 21 Jan, 2026 Reviewers invited by journal 14 Oct, 2025 Editor assigned by journal 01 Sep, 2025 Submission checks completed at journal 01 Sep, 2025 First submitted to journal 30 Aug, 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7495683","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":534638751,"identity":"260adf5c-65a5-415b-befb-aeff3f7a30a0","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":534638752,"identity":"978abddf-c21b-4319-ae10-d71554f03052","order_by":1,"name":"Caterina Mondillo","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Caterina","middleName":"","lastName":"Mondillo","suffix":""},{"id":534638753,"identity":"527178e1-b826-4dbc-85ab-e90e5dc0914c","order_by":2,"name":"Alessandro Versienti","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Versienti","suffix":""},{"id":534638754,"identity":"a967664d-c41d-4bfa-9a54-d7771f2f2d7d","order_by":3,"name":"Guido Cavati","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Guido","middleName":"","lastName":"Cavati","suffix":""},{"id":534638755,"identity":"19e4eeb5-f2e0-4d68-a7c4-6ef79756a80b","order_by":4,"name":"Lisa Taddeo","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Taddeo","suffix":""},{"id":534638756,"identity":"b74656cf-cf2e-4ee0-83b1-f2a3d4afa637","order_by":5,"name":"Sara Gonnelli","email":"","orcid":"","institution":"University Hospital of Nice","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Gonnelli","suffix":""},{"id":534638757,"identity":"9c3f5b03-d2eb-442b-941a-969b38d05078","order_by":6,"name":"Stefano Gonnelli","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Gonnelli","suffix":""},{"id":534638758,"identity":"ddf5f60b-36da-4d68-9b41-3be2d6fb2d0b","order_by":7,"name":"Luigi Gennari","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Luigi","middleName":"","lastName":"Gennari","suffix":""},{"id":534638759,"identity":"4aa88ef2-49a4-4d9a-8e6d-d7e472ff0f43","order_by":8,"name":"Bruno Frediani","email":"","orcid":"","institution":"University of Siena","correspondingAuthor":false,"prefix":"","firstName":"Bruno","middleName":"","lastName":"Frediani","suffix":""},{"id":534638760,"identity":"3d946438-df29-48c3-bbdc-2064351aca40","order_by":9,"name":"Antonella Al Refaie","email":"","orcid":"","institution":"San Giuseppe Hospital","correspondingAuthor":false,"prefix":"","firstName":"Antonella","middleName":"Al","lastName":"Refaie","suffix":""}],"badges":[],"createdAt":"2025-08-30 13:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7495683/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7495683/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94640784,"identity":"94f2c6eb-af3f-4991-8ae3-97c9b52a79b9","added_by":"auto","created_at":"2025-10-29 07:50:13","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":58108,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscriptanonimysed.docx","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/559fa64ec510b04856896798.docx"},{"id":94638370,"identity":"e12e63b1-aaa1-4d8d-82c2-6716acbf080d","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":63344,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/246fa389d1da5c06ac2ce099.tif"},{"id":94638376,"identity":"8e088efc-b3f2-40df-8382-b1e63fd128c0","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":559106,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/6c7ef802ae88b99f5aa9c673.tif"},{"id":94640690,"identity":"676ece3c-5316-4c6b-a6c8-a493c9b42cb5","added_by":"auto","created_at":"2025-10-29 07:50:05","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12875,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/9ab6cb891e47f1fe48a1205d.docx"},{"id":94640802,"identity":"07e3bf2a-570b-474f-a54b-a7e8c250074d","added_by":"auto","created_at":"2025-10-29 07:50:16","extension":"tif","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":149474,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/d8cc25ade5dcb2df62c353ab.tif"},{"id":94641053,"identity":"2835814e-01b0-4a91-9304-1eedbd90608d","added_by":"auto","created_at":"2025-10-29 07:50:32","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":13652,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/44ca9561d631efe458fb22f3.docx"},{"id":94640961,"identity":"6708a92f-cd3d-445d-9dbc-42dfc192847d","added_by":"auto","created_at":"2025-10-29 07:50:24","extension":"tif","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80968,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/d766d470ff208d99211671ae.tif"},{"id":94640701,"identity":"fd487783-a96d-4658-9184-068bdbd38dc1","added_by":"auto","created_at":"2025-10-29 07:50:07","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12456,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/178d3f92795fa3c9318daa59.docx"},{"id":94638395,"identity":"61070383-1850-4293-a5b1-363df5483c9e","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"tif","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":77972,"visible":true,"origin":"","legend":"","description":"","filename":"Figure5.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/d548e43bf28f5baf113a2ad5.tif"},{"id":94638382,"identity":"8bab8a5b-ecab-42ee-8182-0952f2f7ccc0","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"tif","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80640,"visible":true,"origin":"","legend":"","description":"","filename":"Figure6.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/d6d8baee963c6dd8a6a8d820.tif"},{"id":94640144,"identity":"a0944c12-7b8c-4582-8fc3-b4bb0cd18338","added_by":"auto","created_at":"2025-10-29 07:48:29","extension":"json","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10148,"visible":true,"origin":"","legend":"","description":"","filename":"755db42e6ead486993d243ee6f07e463.json","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/48336ba90e256e0e5446dcb9.json"},{"id":94638386,"identity":"d70a44a7-2b93-4062-bf20-b2fa9c6cbe1d","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":103807,"visible":true,"origin":"","legend":"","description":"","filename":"755db42e6ead486993d243ee6f07e4631enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/4da103117b4909e11488964e.xml"},{"id":94638391,"identity":"ab697be9-81e7-447a-a55c-1088b61317bf","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"tif","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":63344,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/ee3aea400b1e7e761bb32f57.tif"},{"id":94638397,"identity":"6dc19633-8cec-42c6-b0ce-fab54688adc9","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"tif","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":559106,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/0f4a1dca5e62a4032c77cdbf.tif"},{"id":94640124,"identity":"da34e4b2-13cf-4ea4-bf6f-c9c8c94f1e90","added_by":"auto","created_at":"2025-10-29 07:48:22","extension":"tif","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":149474,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/3221f53564d9bf9fea1a467e.tif"},{"id":94640401,"identity":"8811dbfb-92e8-4752-b803-24dbc2dec867","added_by":"auto","created_at":"2025-10-29 07:49:23","extension":"tif","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80968,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/a6198c577ce5199c5973f824.tif"},{"id":94638384,"identity":"56bcd534-19d1-4272-bd32-559edab708b1","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"tif","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":77972,"visible":true,"origin":"","legend":"","description":"","filename":"Figure5.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/4c5fd3f0acd5b5adec563d5f.tif"},{"id":94638392,"identity":"9b30bf2e-dc37-4a02-b0b8-58f675057bb1","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"tif","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80640,"visible":true,"origin":"","legend":"","description":"","filename":"Figure6.tif","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/c2d47f7d8ed37c57b807356b.tif"},{"id":94640958,"identity":"87245541-bd5c-46bc-b3ce-d8e46b7d5f1f","added_by":"auto","created_at":"2025-10-29 07:50:24","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11170,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/b40f507701e583a44b1daea3.png"},{"id":94638389,"identity":"8c7877cd-f5ae-4ebc-ad6f-478099715dab","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":72890,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/94bbb833bbf4cea30ce19826.png"},{"id":94638378,"identity":"d14f28ba-7c10-4a84-8dcf-9c089f9a3868","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7271,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/61d5d1d2cc550b27bb47a4d4.png"},{"id":94640707,"identity":"dc95bb5f-3298-4299-be19-f21aa1b71ccd","added_by":"auto","created_at":"2025-10-29 07:50:07","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6948,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/e675b051f1cb13ec0fc8c2a7.png"},{"id":94640781,"identity":"2e5e08db-c7c6-49f4-862d-13ba37b160de","added_by":"auto","created_at":"2025-10-29 07:50:13","extension":"png","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9702,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/5a8e04726f28c01e54acd5a5.png"},{"id":94641052,"identity":"fd1a6335-1c29-43ba-8441-53192ffabd72","added_by":"auto","created_at":"2025-10-29 07:50:32","extension":"png","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10665,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure6.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/122c30da7bda409c7000b7f5.png"},{"id":94672254,"identity":"40131659-1767-4255-9102-e385c612ab29","added_by":"auto","created_at":"2025-10-29 13:40:01","extension":"xml","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":101675,"visible":true,"origin":"","legend":"","description":"","filename":"755db42e6ead486993d243ee6f07e4631structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/8956d2aa887c787ec12c8399.xml"},{"id":94640968,"identity":"55af87f6-dc0d-4d29-9eac-d2900bfeb04e","added_by":"auto","created_at":"2025-10-29 07:50:24","extension":"html","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":109319,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/61ef84560252962785c504b7.html"},{"id":94640108,"identity":"1423137f-8614-4a4b-a9ff-49dd36126a6a","added_by":"auto","created_at":"2025-10-29 07:48:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95840,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart showing the distribution of patients with BMEs\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/2ddbafeefda104f45251a748.png"},{"id":94640970,"identity":"55e5fe09-8fc8-4a95-8f3c-8cf07437974d","added_by":"auto","created_at":"2025-10-29 07:50:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":503547,"visible":true,"origin":"","legend":"\u003cp\u003eCharacteristic MRI findings from the three patient cohorts studied are illustrated: (A) A coronal STIR sequence of the hand reveals numerous patchy foci of BMEs; (B) A sagittal T2 STIR image of the right knee clearly demonstrates bone marrow edema within the medial femoral condyle; (C) A coronal T2-weighted axial image displays prominent bone marrow edema in the right femoral head. All images are highlighted by white arrows.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/90d8a19c094b3018e2a2f475.png"},{"id":94638369,"identity":"c1e03bcf-0392-4ef9-8bf2-75d847e15da3","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56499,"visible":true,"origin":"","legend":"\u003cp\u003eCharacteristic MRI findings from the three patient cohorts studied are illustrated: (A) A coronal STIR sequence of the hand reveals numerous patchy foci of BMEs; (B) A sagittal T2 STIR image of the right knee clearly demonstrates bone marrow edema within the medial femoral condyle; (C) A coronal T2-weighted axial image displays prominent bone marrow edema in the right femoral head. All images are highlighted by white arrows.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/d68daa63f69c5ed6c6d4fb99.png"},{"id":94638377,"identity":"18bd5fcd-673c-4a79-98d7-8325c9a8a35a","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":84032,"visible":true,"origin":"","legend":"\u003cp\u003ePercentage of “osteoporosis”, “osteopenic” or “normal BMD” in study population\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/61a70af8b6574451a361b046.png"},{"id":94640104,"identity":"9985fc4a-2a97-48dc-a6ab-ad37e2d790c6","added_by":"auto","created_at":"2025-10-29 07:48:18","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":62950,"visible":true,"origin":"","legend":"\u003cp\u003eBMD-LS (A) and TBS (B) in patients with CPRS-I, knee BMEs and hip BMEs\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/34d8ccd398806988d6a71634.png"},{"id":94638374,"identity":"b14e395b-a019-4999-a8d8-cbd4e3ff24eb","added_by":"auto","created_at":"2025-10-29 07:29:16","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":72281,"visible":true,"origin":"","legend":"\u003cp\u003eBMD-FN (A) and BMD-TH (B) in patients with CRPS-I, knee BMEs and hip BMEs\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/974dcb46192fdde7cefcda6a.png"},{"id":94674028,"identity":"b0fd4141-edf5-47d1-b9d5-dd94360b45e9","added_by":"auto","created_at":"2025-10-29 13:42:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1666842,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7495683/v1/d0094eba-275f-4c61-9a90-27844e7fa18e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Is Bone Marrow Edema syndrome (BMEs) associated with Osteoporosis? a single-center study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBone marrow edema (BME) is a radiological term used to describe an area that appears with low signal intensity on T1-weighted magnetic resonance imaging (MRI) but shows high signal intensity on T2-weighted MRI or short tau inversion recovery (STIR) sequences [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The term was first introduced in 1988 by Wilson et al. to describe increased water content in the bone among a small group of patients experiencing significant hip or knee pain [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In 2004, Hofmann et al. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] introduced the term \"bone marrow edema syndrome\" (BMEs) as a general term to describe a diagnosis of exclusion for clinical conditions marked by pain and increased interstitial fluid in the bone marrow without a clear cause. The advent of MRI has led to the association of this condition with various terms, including \"transient osteoporosis\", \"transient demineralization\", \"regional migratory osteoporosis\". A recent scoping review by Gravle on this confusing terminology found that while many publications used osteoporosis-related terms, only a few of these studies measured Bone Mineral Density (BMD). This suggests that an overarching term should be linked to bone marrow edema rather than osteoporosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although the pathophysiology of BMEs is still under discussion, past studies have suggested that even minor trauma may be a significant risk factor [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Emerging evidence now suggests that bone metabolic damage may be the primary driver of BMEs, affecting its clinical characteristics, diagnostic process, and treatment strategy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Recently, Molfetta et al. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], in an paper on the pathogenesis of bone edema, concluded that even Complex Regional Pain Syndrome type 1(CRPS-I), despite its distinctly unique clinical presentation, can be included among BMEs because it shares similarities in imaging, pathophysiology, and therapeutic response to bisphosphonates [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A common feature of BMEs is the characteristic preservation of the articular surface and the presence of varying degrees of pain. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Complex regional pain syndrome type-1 is a rare clinical condition generally affecting a single limb that is more common in the female population, with a variable ratio between 2:1 and 4:1. It is characterized by intense pain that is disproportionate to the initial cause and is typically accompanied by sensorimotor, vasomotor, sudomotor, and trophic changes in the affected area [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Bone involvement played a key role in the early descriptions of the disease. In particular, Paul Sudeck identified a radiological picture of patchy osteoporosis as a pivotal element for the diagnosis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Despite the pivotal role of fractures, sprains and repeated skeletal microtraumas in the development of CRPS-I, in recent decades there has been little focus on bone involvement in the disease. In fact, the current diagnostic criteria from the International Association for the Study of pain (AISP), known as the Budapest criteria, rely solely on clinical symptoms and signs, without incorporating imaging [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Nevertheless, MRI and triphasic bone scintigraphy with technetium-labeled bisphosphonates are imaging techniques that are commonly used in clinical practice to confirm diagnostic suspicions and determine the stage of the disease.The lack of attention that has been paid over the years to the involvement of bone tissue in CRPS-I may explain why the literature contains limited and controversial data on bone turnover markers and axial BMD levels in patients with CRPS-I [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe femur is the skeletal segment most commonly affected by BMEs, a condition characterized by bone marrow edema without an identifiable cause, affecting both the proximal and distal regions. Transient osteoporosis of the hip (TOH) is the most common form of BMEs affecting the hip [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. TOH is an idiopathic, self-limiting condition characterized by unexplained hip pain and limping, primarily affecting middle-aged men and women in the third trimester of pregnancy or the immediate postpartum period. In TOH patients, pain intensifies with weight-bearing activities, lessens with rest, but worsens at night. MRI is the most effective method for detecting bone edema and can identify TOH within a few days of symptom onset [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A significant proportion of TOH patients exhibit low BMD, although bone densitometry evaluations are infrequent [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Primary BMEs involving the knee are either a form transient osteoporosis (TOP) similar to TOH or, more frequently, regional migratory osteoporosis (RMO). RMO manifests with arthralgia localized to a single joint, which then moves, after several months, to another, generally more distal location [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The pathogenetic features and imaging characteristics of RMO are identical to those of TOH. The term \"transient BMEs of the knee\" is clinically and radiologically indistinguishable from TOP on MRI. Therefore, transient BMEs is considered the same as TOP when detected clinically before the development of osteopenia [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] Moreover, the most recent studies consider it unlikely that TOH and RMO can directly evolve into hip or knee osteonecrosis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis single-center observational study aimed to evaluate axial BMD using DXA, Trabecular Bone Score (TBS), and bone turnover markers in all patients diagnosed with BMEs (including CRPS-I, hip BMEs and knee BMEs) at the time of initial diagnosis and prior to initiating pharmacological therapy .\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003eThe patients for this observational study were recruited from the outpatient clinic of the Internal Medicine Unit at the University Hospital of Siena (Italy) between January 2017 and December 2024. Patients had to meet the following criteria: 1) Diagnosis of CRPS-I or BMEs of the hip or knee confirmed by MRI, characterized by an abnormal signal or a well-defined area of hypointensity on T1-weighted sequences and hyperintensity on T2-weighted or STIR sequences ; 2) spontaneous pain in the affected limb of \u0026ge;\u0026thinsp;50 mm on a visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (maximum pain) during the previous week; 3) age between 18 and 70 years. Exclusion criteria were: 1) disease duration longer than 6 months; 2) clinical history of severe chronic diseases or the presence of another chronic pain syndrome that interferes with pain ratings; 3) prior treatment with bisphosphonates or other anti-osteoporosis drugs (excluding calcium and vitamin D supplements) or undergoing therapies that could impact bone metabolism (such as glitazones, glucocorticoids, anticonvulsants, etc.); 4) for patients with suspected diagnosis of CRPS-I the lack of IASP diagnostic criteria (Budapest criteria) or major nerve damage suggestive of CRPS-II [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A cohort of 175 patients was evaluated. From the initial group, an additional 25 patients were excluded: 12 patients with suspected CRPS-I who did not meet the IASP diagnostic criteria (Budapest criteria) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; 1 patient due to major nerve damage indicative of CRPS-II; 5 patients secondary BMEs diagnosis; and 7 patients with BMEs involving skeletal sites outside the hip and knee. The remaining 150 BMEs patients were then divided into three groups: CRPS-I (n\u0026thinsp;=\u0026thinsp;56 ), hip BMEs (n\u0026thinsp;=\u0026thinsp;37), and knee BMEs (n\u0026thinsp;=\u0026thinsp;57); the flow chart showing the distribution of study participants is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In addition, in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows three characteristic MRI scans from the three patient groups investigated. All MRI examinations were evaluated by an experienced radiologist before recruitment, especially to exclude conditions of bone edema due to osteoarthritis. Age- and sex-matched healthy controls were recruited from a subgroup of individuals living in the Siena area (Italy) who had been participating in a larger epidemiological study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], as well as from healthy volunteers enrolled from the hospital personnel. Female controls were also matched for menopausal status. All patients underwent measurement of weight, height and body mass index (BMI). The body mass index expresses the ratio between weight in kilograms divided by the square of height in meters. Vital parameters, such as blood pressure and heart rate, were evaluated. For all patients a detailed personal and familiar medical history was obtained. The study was conducted in accordance with the 1964 Helsinki Declaration and its later amendments, and the research protocol received approval from the Ethics Committee of Siena University Hospital (ID-21211). Informed written consent was obtained from all participants. Prior to statistical analysis, all collected data underwent anonymization procedures.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eLaboratory and densitometric assessments\u003c/h3\u003e\n\u003cp\u003eAfter fasting for at least 12 hours, patients underwent blood sampling for the evaluation of: glycemia, creatinine, calcium, phosphate, albumin, total alkaline phosphatase, C-terminal telopeptide of type 1 collagen (β-CTX), bone isoenzyme of alkaline phosphatase (B-ALP), parathyroid hormone (PTH), 25hydroxyvitaminD (25OHD). Serum β-CTX was measured by an ELISA method (Immunotopics INT, San Clemente, CA, USA) and the intra- and inter-assay precision was 2.5 and 3.5%, respectively. Serum B-ALP was measured by a chemiluminescence immunoassay method (LIAISON BAP Ostase, DiaSorin Inc., Stillwater, MN, USA); in our institution, the intra-and inter-assay coefficients of variation for B-ALP were 4.2% and 7.9%, respectively. Serum PTH was assessed by immunoradiometric assay (Total Intact PTH, Antibodies Lab. Inc.; Santee, CA, USA) and the intra- and inter-assay coefficients of variation were 3.6% and 4.9%, respectively. Serum 25OHD was determined by a chemi-luminescence immunoassay (LIAISON 25OHD Total Assay, DiaSorin Inc, Stillwater, MN, USA); in our institution, the intra- and inter-assay coefficients of variation were 6.8% and 9.2%, respectively.\u003c/p\u003e\u003cp\u003eIn all subjects we measured BMD at the lumbar spine (LS-BMD), at femoral neck (FN-BMD) and total hip (TH-BMD) using a dual-energy X-ray absorptiometry device (Discovery W, Hologic, Waltham, MA, USA). All DXA scans were performed according to the standard clinical routine procedures. Obviously, femoral BMD was measured on the limb contralateral to the one possibly affected by BMEs. Osteoporosis and osteopenia were diagnosed according to the World Health Organization (WHO) definition: a T value lower than \u0026minus;\u0026thinsp;2.5 was diagnosed as osteoporosis and a T value less than \u0026minus;\u0026thinsp;1.0 but higher than \u0026minus;\u0026thinsp;2.5 was diagnosed as osteopenia; sex-matched Italian reference data were used for the calculation of T-score. For a better estimate of bone tissue microarchitecture, we also calculated the Trabecular Bone Score (TBS). TBS was calculated by using TBS iNsight software (Version 2.1, Medimaps SA, Bordeaux, France) in an operator-independent automated manner. The TBS was calculated from the standard DXA scan of the antero-posterior lumbar spine. TBS values were calibrated to standard values using the TBS calibration phantom (17 cm thickness and 25% fat mass equivalent), and were adjusted for BMI to 21.78. In our centre the short-term, precision of TBS calculation was 1.5% (CV).\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThe values in the study are presented as \"mean\u0026rdquo; \u0026plusmn; standard deviation (SD). The normality of the distribution of outcome variables was assessed using the Kolmogorov\u0026ndash;Smirnov test. Clinical data and initial values of the measured variables in the study groups were compared using Student\u0026rsquo;s t-test and Mann\u0026ndash;Whitney U-test, depending on the appropriateness of the data distribution. Categorical variables were subjected to comparison using the Chi-square test or Fisher\u0026rsquo;s exact test, as deemed appropriate. Associations between different parameters were examined through Pearson\u0026rsquo;s correlation or Spearman\u0026rsquo;s correlation, as appropriate, or via partial correlation analysis. All statistical analyses were performed using the SPSS statistical package for Windows version 16.0 (SPSS Inc., Chicago).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the clinical and densitometric parameters of the study population and healthy controls. As expected, the two groups were similar not only in age and gender but also in BMI. However, patients with BMEs exhibited significantly lower BMD at all skeletal sites and lower TBS values compared to healthy controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). The clinical characteristics and biochemical parameters of patients grouped by the localization of BMEs are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Notably, BMI was significantly higher in patients with knee BMEs compared to those with CRPS-I or hip BMEs. The time since diagnosis was 3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0 weeks for hip BME, 4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 weeks for knee BME and 4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 for CRPS-I. Additionally, B-ALP and β-CTX values were significantly higher in patients with knee BMEs (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, no significant differences were observed among the three groups regarding blood count, calcium, phosphorus, total alkaline phosphatase, vitamin D, and parathyroid hormone levels.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u0026ndash; Clinical and densitometric characteristics of the patients with BMEs and controls\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBMEs (N\u0026thinsp;=\u0026thinsp;150)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003econtrols (N\u0026thinsp;=\u0026thinsp;150)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (F/M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88/62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88/62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003en.s.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (yrs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57.7\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55.7\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003en.s.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (Kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003en.s.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLS-BMD (g/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.949\u0026thinsp;\u0026plusmn;\u0026thinsp;0.192\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.098\u0026thinsp;\u0026plusmn;\u0026thinsp;0.145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLS T-score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-1.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.65\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.17\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTBS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.248 \u0026plusmn; 0.146\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.392 \u0026plusmn; 0.087\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFN-BMD (g/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.751\u0026thinsp;\u0026plusmn;\u0026thinsp;0.143\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.869\u0026thinsp;\u0026plusmn;\u0026thinsp;0.111\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFN T-score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-1.44\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTH-BMD (g/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.854\u0026thinsp;\u0026plusmn;\u0026thinsp;0.148\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.951\u0026thinsp;\u0026plusmn;\u0026thinsp;0.118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTH T-score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u0026ndash; Clinical and biochemical characteristics of the patients with BMEs\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCRPS-I (N\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKnee BMEs (N\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHip BMEs (N\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (F/M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38/18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28/29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22/15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (yrs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57.17\u0026thinsp;\u0026plusmn;\u0026thinsp;10.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58.88\u0026thinsp;\u0026plusmn;\u0026thinsp;12.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e57.51\u0026thinsp;\u0026plusmn;\u0026thinsp;14.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (Kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.47\u0026thinsp;\u0026plusmn;\u0026thinsp;4.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.25\u0026thinsp;\u0026plusmn;\u0026thinsp;4.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25.42\u0026thinsp;\u0026plusmn;\u0026thinsp;4.00*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCalcium (mg/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhosphate (mg/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine (mg/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlalkaline phosphatase (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e79.43\u0026thinsp;\u0026plusmn;\u0026thinsp;34.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e78.43\u0026thinsp;\u0026plusmn;\u0026thinsp;20.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82.47\u0026thinsp;\u0026plusmn;\u0026thinsp;31.68\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25OHD (ng/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.88 \u0026plusmn; 13.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25.39 \u0026plusmn; 13.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27.14\u0026thinsp;\u0026plusmn;\u0026thinsp;15.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePTH (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32.51\u0026thinsp;\u0026plusmn;\u0026thinsp;16.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32.99\u0026thinsp;\u0026plusmn;\u0026thinsp;17.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31.38\u0026thinsp;\u0026plusmn;\u0026thinsp;19.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB-ALP (\u0026micro;g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13.16 \u0026plusmn; 6.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.42\u0026thinsp;\u0026plusmn;\u0026thinsp;14.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13.72\u0026thinsp;\u0026plusmn;\u0026thinsp;7.15*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eβ-CTX (ng/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.469\u0026thinsp;\u0026plusmn;\u0026thinsp;0.411\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.516\u0026thinsp;\u0026plusmn;\u0026thinsp;0.252\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.455\u0026thinsp;\u0026plusmn;\u0026thinsp;0.244*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRed blood count (x109/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite blood count (x109/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.02\u0026thinsp;\u0026plusmn;\u0026thinsp;1.90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13.74\u0026thinsp;\u0026plusmn;\u0026thinsp;1.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14.45\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14.17\u0026thinsp;\u0026plusmn;\u0026thinsp;1.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean corpuscular volume (fL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88.55\u0026thinsp;\u0026plusmn;\u0026thinsp;10.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88.63\u0026thinsp;\u0026plusmn;\u0026thinsp;6.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e92.41\u0026thinsp;\u0026plusmn;\u0026thinsp;5.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRed cell distribution width (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.04\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThrombocyte count (x109/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e255.26\u0026thinsp;\u0026plusmn;\u0026thinsp;60.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e248.94\u0026thinsp;\u0026plusmn;\u0026thinsp;66.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e228.38\u0026thinsp;\u0026plusmn;\u0026thinsp;61.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e* p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the mean BMD values at the total hip in patients with BMEs and healthy controls, expressed as T-scores. It is evident that BMD T-scores were lower in patients with BMEs compared to healthy controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Additionally, based on the localization of BMEs, the total hip T-score was lower in patients with CRPS-I.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the percentages of BMEs patients and healthy controls who, based on WHO criteria, exhibit a pattern of \u0026ldquo;osteoporosis\u0026rdquo;, \u0026ldquo;osteopenia\u0026rdquo;, or \u0026ldquo;normal BMD\u0026rdquo;. All three groups of BMEs patients have significantly higher rates of osteoporosis compared to healthy controls. Additionally, the rate of osteoporosis is notably higher in patients with CRPS-I and hip BMEs than in those with knee BMEs.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e shows the LS-BMD and TBS values in patients with BMEs, categorized by the location of the disease. Patients with knee BMEs had higher LS-BMD values compared to those with CRPS-I or hip BMEs, although the difference was not statistically significant. In contrast, TBS values did not show significant differences among the three groups. Figure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e presents the FN-BMD and TH-BMD values in patients with BMEs, also categorized by the location of the disease. FN-BMD and TH-BMD values were lower in patients with CRPS-I or hip BMEs compared to those with knee BMEs, but the difference was statistically significant only for TH-BMD (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the age- and BMI-adjusted partial correlations of B-ALP and β-CTX values with BMD values at all skeletal sites according to BMEs localization. We observed that B-ALP and β-CTX were significantly correlated with BMD values at all skeletal sites in patients with hip BMEs (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, in patients with CRPS-I and hip BMEs, β-CTX values presented a significant inverse correlation (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) only with LS-BMD.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAge-adjusted partial correlation between β-CTX and B-ALP and BMD according to with BMEs localization\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLS-BMD (g/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFN-BMD (g/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTH-BMD (g/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRPS-I (N\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB-ALP (\u0026micro;g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.19\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.17\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eβ-CTX (ng/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.56**\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.23\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.24\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKnee BMEs (N\u0026thinsp;=\u0026thinsp;57)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB-ALP (\u0026micro;g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.53*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.52*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.56*\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eβ-CTX (ng/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.54*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.61*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.75**\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHip BMEs (N\u0026thinsp;=\u0026thinsp;37)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB-ALP (\u0026micro;g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eβ-CTX (ng/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.60**\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.46*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.48*\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e*p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, ** p\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main finding of this study is that patients with bone marrow edema syndromes, particularly those with CRPS-I and hip BMEs, have reduced BMD compared to healthy controls of the same age and sex. For over 20 years, several studies on patients with CRPS-I have observed reduced BMD values by DXA, not only in the limb affected but also in the contralateral limb [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and at the lumbar level [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Additionally, other studies have reported a prevalence of osteopenia or osteoporosis in these patients [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and, in particular, de Mos et al., in a large study of the Dutch population, found that menopause and osteoporosis were key risk factors for CRPS-I [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. To our knowledge, this is the first study reporting that the values of trabecular bone score, a densitometric parameter influenced by the structural and qualitative characteristics of the bone, are significantly reduced in patients with BMEs compared to healthy controls. Furthermore, Oehler et al. by using high-resolution peripheral quantitative computed tomography (HR-pQCT) revealed significant microstructural alterations in cortical and trabecular bone tissues in CRPS-1, offering new insights into the morphological and pathophysiological processes specific to bone changes caused by CRPS-I [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The potential link between CRPS-I and bone quantity/quality was further supported by the observation of several cases of Sudeck's algodystrophy in patients with osteogenesis imperfecta [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Despite these data and the undeniable importance of fractures and bone trauma in the development of CRPS-I, research and the taxonomic classification of the disease have, for many years, remained focused on the role of sympathetic system hyperactivation in its pathogenesis. More recently, Varenna and Crotti in their 2018 expert opinion, identified bone involvement as a key feature in the pathogenesis of CRPS-I and described the underlying pathophysiology based on the knowledge available at the time [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In this model, direct injury to the bone initially triggers the local release of proinflammatory mediators, such as TNF, IL-1, IL-6, substance P, and calcitonin gene-related peptide. This is followed by changes in capillary permeability, resulting in edema, hypoxia, and acidosis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Another noteworthy finding of this study is that bone turnover markers, specifically B-ALP and β-CTX, remained within normal limits, even though most of our patients were postmenopausal women. These results support the conclusions of recent studies that challenge the notion of accelerated bone turnover with osteoclastic hyperactivity in the early stages of CRPS-I [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Instead, these studies suggest that the rapid loss of BMD during these phases may be due to the chemical dissolution of hydroxyapatite, caused by significant acidosis and a localized drop in pH [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our study, we did not find reduced levels of vitamin D or elevated PTH levels in the entire population or within the three groups (CRPS-I, hip BMEs and knee BMEs) when analyzed separately. These findings appear to contrast with what has been reported in several other studies [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In particular, a recent scoping review of the literature highlighted that over 60% of studies on patients with BMEs reported vitamin D levels indicative of deficiency or insufficiency [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. This discrepancy may be explained by the fact that most postmenopausal women in our area regularly take vitamin D supplements.\u003c/p\u003e\u003cp\u003eIn this study, the percentage of patients with hip BMEs who had osteoporosis was nearly identical to that of patients with CRPS-I and markedly higher with respect to that of patients with knee BMEs. This finding is an interesting result of the study, as it suggests the identification of certain characteristics that may distinguish hip BMEs from knee BMEs. It aligns with the majority of studies on individuals with primary hip BMEs, which have identified osteopenia or osteoporosis as the most significant risk factors for the onset of the disease [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In fact, a large case series conducted by the Mayo Clinic, as well as an Italian study, found that over 50% of patients with transient osteoporosis of the hip had BMD values from DXA indicative of osteoporosis or osteopenia [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In another study on patients with transient osteoporosis of the hip, lumbar densitometry evaluations were performed on 31 patients, with 15 classified as osteopenic and 15 as osteoporotic [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Additionally, it has been hypothesized that patients with osteogenesis imperfecta are more likely to develop the disorder [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, it is important to note that in these studies, unlike ours, BMD by DXA was assessed in only a small subgroup of patients, and it is unclear whether the affected limb was excluded from the analysis.\u003c/p\u003e\u003cp\u003ePatients with knee BMEs have significantly higher levels of bone turnover markers compared to those with CRPS-I or hip BMEs. However, it is important to note that both B-ALP and β-CTX values remain within normal limits. It has been hypothesized that in patients with hip and knee BMEs, similar to those with CRPS-1, the rapid loss of bone mass in the proximal or distal femur is not due to osteoclastic hyperactivity but rather to the chemical dissolution of hydroxyapatite caused by low pH levels [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The increase in B-ALP levels could reflect heightened osteoblastic activity, which may also be responsible for elevated osteoprotegerin levels [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study has some limitations. First, its retrospective nature limits our ability to investigate the relationship between the type and number of risk factors, the intensity or duration of symptoms, and the response to therapy. Second, the diagnosis of primary BMEs involving the hip and knee is one of exclusion, which introduces the risk of including patients with other confounding conditions. However, the study also has several strengths. First, it is a single-center study that collected a large case series using uniform and predefined diagnostic criteria. Second, to our knowledge, it is one of the very few studies that assessed BMD using DXA in all patients with BMEs before starting therapy. Finally, it is certainly the first study to evaluate TBS in patients with BMEs.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study reveals that patients with BMEs, particularly those with CRPS-I and hip BME, have a higher prevalence of osteoporosis and a notable reduction in TBS compared to age- and sex-matched healthy controls. This common risk factor, along with similarities in pathophysiological mechanisms, MRI imaging features, and a comparable response to bisphosphonates, confirms the pivotal role of bone tissue in the pathogenesis of these diseases and supports the hypothesis that these conditions fall under the broader category of \"Bone Marrow Edema Syndromes.\"\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknoledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC.C., S.G., A.A., Conceptualization, Methodology, Formal analysis, Writing – review \u0026amp; editing. C.M., S.G., Resources, Writing. A.V., G.C., L.T., Resources. L.G., B.F., \u0026nbsp;Supervision.\u0026nbsp;\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\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be made available upon reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting intersts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKorompilias AV, Karantanas AH, Lykissas MG, Beris AE (2009) Bone marrow edema syndrome. Skeletal Radiol 38:425\u0026ndash;432. https://doi:10.1007/s00256-008-0529-1\u003c/li\u003e\n \u003cli\u003eWilson AJ, Murphy WA, Hardy DC, Totty WG (1988) Transient osteoporosis: transient bone marrow edema? Radiology 167:757\u0026ndash;760. https://doi:10.1148/radiology.167.3.3363136\u003c/li\u003e\n \u003cli\u003eHofmann S, Kramer J, Vakil-Adli A, Aigner N, Breitenseher M (2004) Painful bone marrow edema of the knee: differential diagnosis and therapeutic concepts. Orthop Clin North Am 35:321\u0026ndash;333. https://doi:10.1016/j.ocl.2004.04.005\u003c/li\u003e\n \u003cli\u003eGr\u0026oslash;vle L, Julsrud Haugen A, Johansen M, Hasvik E (2024) The terminologies of transient, migratory, or localized osteoporosis, and bone marrow edema syndrome: a scoping review. Osteoporos Int 35:217\u0026ndash;226. https://doi:10.1007/s00198-023-06929-x\u003c/li\u003e\n \u003cli\u003eHasvik E, Haugen AJ, Gr\u0026oslash;vle L (2025) Clinical characteristics of patients with bone marrow edema syndrome, transient osteoporosis or migratory osteoporosis: a scoping review. Bone. https://doi.org/10.1016/j.bone.2025.117535. 198,117535\u003c/li\u003e\n \u003cli\u003eManara M, Varenna M (2014) A clinical overview of bone marrow edema. Reumatismo 66:184\u0026ndash;196. https://doi:10.4081/reumatismo.2014.790\u003c/li\u003e\n \u003cli\u003eMolfetta L, Florian A, Saviola G, Frediani B (2022) Bone Marrow Edema: pathogenetic features. Clin Ter 173:434\u0026ndash;439. https://doi:10.7417/CT.2022.2459\u003c/li\u003e\n \u003cli\u003eMarinus J, Moseley GL, Birklein F, Baron R, Maihofner C, Kingery WS, van Hilten JJ (2011) Clinical features and patho physiology of complex regional pain syndrome. Lancet Neurol 10:637\u0026ndash;648. https://doi:10.1080/0963828021000007950\u003c/li\u003e\n \u003cli\u003eFerraro MC, O\u0026apos;Connell NE, Sommer C, Goebel A, Bultitude JH, Cashin AG et al (2024) Complex regional pain syndrome: advances in epidemiology, pathophysiology, diagnosis, and treatment. Lancet Neurol 23:522\u0026ndash;533. https://doi:10.1016/S1474-4422(24)00076-0\u003c/li\u003e\n \u003cli\u003eSudeck P (1900) \u0026Uuml;ber die acute entz\u0026uuml;ndliche knochenatrophie. Archiv Klin Chir 62:147\u0026ndash;156\u003c/li\u003e\n \u003cli\u003eHarden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, Swan M et al (2013) Complex regional pain syndrome: practi cal diagnostic and treatment guidelines, 4th edition. Pain Med. ;14:180\u0026ndash;229. https://doi:10.1111/pme.12033\u003c/li\u003e\n \u003cli\u003eKollmann G, Wertli MM, Dudli S, Distler O, Brunner F (2023) The role of the bone in complex regional pain syndrome 1-A systematic review. Eur J Pain 27:794\u0026ndash;804. https://doi:10.1002/ejp.2116\u003c/li\u003e\n \u003cli\u003ePatel S (2014) Primary bone marrow oedema syndromes. Rheumatology 53:785\u0026ndash;792. https://doi.org/10.1093/rheumatology/ ket324\u003c/li\u003e\n \u003cli\u003eTrevisan C, Klumpp R, Compagnoni R (2016) Risk factors in transient osteoporosis: a retrospective study on 23 cases. Clin Rheumatogy 35:2517\u0026ndash;2522. https://doi:10.1007/s10067-016-3228-7\u003c/li\u003e\n \u003cli\u003eDi Martino A, Brunello M, Villari E, Cataldi P, D\u0026apos;Agostino C, Faldini C (2023) Bone marrow edema of the hip: a narrative review. Arch Orthop Trauma Surg 143:6901\u0026ndash;6917. https://doi:10.1007/s00402-023-04961-4\u003c/li\u003e\n \u003cli\u003eKotwal A, Hurtado MD, Sfeir JG, Wermers RA (2019) TRANSIENT OSTEOPOROSIS: CLINICAL SPECTRUM IN ADULTS AND ASSOCIATED RISK FACTORS. Endocr Pract 25:648\u0026ndash;656. https://doi:10.4158/EP-2018-0626\u003c/li\u003e\n \u003cli\u003eRoemer FW, Frobel R, Hunter DJ, Crema MD, Fischer W, Bohndorf K et al (2009) MRI-detected subchondral bone marrow signal alterations of the knee joint: terminology, imaging appearance, relevance and radiological differential diagnosis. Osteoarthritis Cartilage 7:1115\u0026ndash;1131. https://doi:10.1016/j.joca.2009.03.012\u003c/li\u003e\n \u003cli\u003eKomnos GA, Paridis DI, Banios KT, Karachalios TS, Dailiana ZH, Luceri F (2023) Randelli PS Regional migratory osteoporosis of the knee: a literature overview. Musculoskelet Surg 107:159\u0026ndash;164. https://doi:10.1007/s12306-023-00774-1\u003c/li\u003e\n \u003cli\u003eKorompilias AV, Karantanas AH, Lykissas MG, Beris A (2009) Bone marrow edema syndrome. Skeletal Radiol 38:425\u0026ndash;436. https://doi:10.1007/s00256-008-0529-1\u003c/li\u003e\n \u003cli\u003eGeith T, Stellwag AC, M\u0026uuml;ller E, Reiser P, Baur-Melnyk M (2020) Is bone marrow edema syndrome a precursor of hip or knee osteonecrosis? Results of 49 patients and review of the literature. Diagn Interv Radiol 26:355\u0026ndash;362. https://doi:10.5152/dir.2020.19188\u003c/li\u003e\n \u003cli\u003eGonnelli S, Caffarelli C, Cappelli S, Rossi S, Giordano N, Nuti R (2014) Gender-specific associations of appendicular muscle mass with BMD in elderly Italian subjects. Calcif Tissue Int 95:340\u0026ndash;348. https://doi:10.1007/s00223-014-9902-3\u003c/li\u003e\n \u003cli\u003eArriagada M, Arinoviche R (1994) X-ray bone densitometry in the diagnosis and followup of reflex sympathetic dystrophy syndrome. J Rheumatol 21:498\u0026ndash;500\u003c/li\u003e\n \u003cli\u003eCepollaro C, Gonnelli S, Pondrelli C, Martini S, Montagnani A, Rossi B, Gennari C (1998) Usefulness of ultrasound in Sudeck\u0026rsquo;s atrophy of the foot. Calcif Tissue Int 62:538\u0026ndash;541. https://doi:10.1007/s002239900475\u003c/li\u003e\n \u003cli\u003ede Mos M, Huygen F, Dieleman JP, Koopman J, Stricker CBH, Sturkenboom M (2008) Medical history and the onset of complex regional pain syndrome (CRPS). Pain 139:458\u0026ndash;466. https://doi:10.1016/j.pain.2008.07.002\u003c/li\u003e\n \u003cli\u003eOehler N, Rolvien T, Schmidt T, Butscheidt S, Oheim R, Barvencik F, Mussawy H (2019) Bone microstructure is significantly altered in CRPS-affected distal tibiae as detected by HR-pQCT: a retrospective cross-sectional study. Bone Min Metab 37:741\u0026ndash;748. https://doi:10.1007/s00774-018-0976-2\u003c/li\u003e\n \u003cli\u003eBouvier M, Colson F, Noel E, Tebib JG, Felman C (1997) Two new case-reports of reflex sympathetic dystrophy syndrome in patients with osteogenesis imperfecta. Review of the literature. Rev Rhum Engl Ed 64:202\u0026ndash;204\u003c/li\u003e\n \u003cli\u003eVarenna M, Crotti C (2018) Bisphosphonates in the treatment of complex regional pain syndrome: Is bone the main player at early stage of the disease? Rheumatol Int 38:1959\u0026ndash;1962. https://doi:10.1007/s00296-018-4101-6\u003c/li\u003e\n \u003cli\u003eKollmann G, Wertli MM, Dudli S, Distler O, Brunner F (2023) The role of the bone in complex regional pain syndrome 1-A systematic review. Eur J Pain 27:794\u0026ndash;804. https://doi:10.1002/ejp.2116\u003c/li\u003e\n \u003cli\u003eVarenna M, Orsini F, Di Taranto R, Zucchi F, Adami G, Gatti D, Crotti C (2924) Bone Turnover Markers and Wnt Signaling Modulators in Early Complex Regional Pain Syndrome. A Pre-specified Observational Study. Calcif Tissue Int 115:251\u0026ndash;259. https://doi:10.1007/s00223-024-01251-y\u003c/li\u003e\n \u003cli\u003eOehler N, Mussawy H, Schmidt T, Rolvien T, Barvencik F (2018) Identification of vitamin D and other bone metabolism parameters as risk factors for primary bone marrow oedema syndrome. BMC Musculoskelet Disord 19:451. https://doi.org/10.1186/s12891-018-2379\u003c/li\u003e\n \u003cli\u003eLee S-U, Na K-T, Lee Y-M, Park JH, Joo SY (2020) Low vitamin D levels in post-menopausal women are associated with complex regional pain syndrome type I in surgically treated distal radius fractures. Orthop Surg Res 15:328. https://doi:10.1186/s13018-020-01859-4\u003c/li\u003e\n \u003cli\u003eEidmann A, Eisert M, Rudert M, Stratos I (2022) Influence of Vitamin D and C on Bone Marrow Edema Syndrome-A Scoping Review of the Literature. J Clin Med 11:6820. https://doi.org/10.3390/jcm11226820\u003c/li\u003e\n \u003cli\u003eKlontzas ME, Vassalou EE, Zibis AH, Bintoudi AS, Karantanas AH (2015) MR imaging of transient osteoporosis of the hip: an update on 155 hip joints. Eur J Radiol. 2015;84:431-6. https://doi\u003c/li\u003e\n \u003cli\u003eAsadipooya K, Graves L, Greene LW (2017) Transient osteoporosis of the hip: review of the literature. Osteoporos Int 28:1805\u0026ndash;1816. https://doi:10.1016/j.ejrad.2014.11.022\u003c/li\u003e\n \u003cli\u003eKramer HH, Hofbauer LC, Szalay G, Breimhorst M, Eberle T, Zieschang K et al (2014) Osteoprotegerin: a new biomarker for impaired bone metabolism in complex regional pain syndrome? Pain 155:889\u0026ndash;895. https://doi:10.1016/j.pain.2014.01.014\u003c/li\u003e\n\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":"archives-of-orthopaedic-and-trauma-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aots","sideBox":"Learn more about [Archives of Orthopaedic and Trauma Surgery](http://link.springer.com/journal/402)","snPcode":"402","submissionUrl":"https://submission.springernature.com/new-submission/402/3","title":"Archives of Orthopaedic and Trauma Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Bone marrow edema syndromes (BMEs), complex regional pain syndrome type-1, hip-BMEs, knee-BMEs, bone mineral density, trabecular bone score, bone markers","lastPublishedDoi":"10.21203/rs.3.rs-7495683/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7495683/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe term \"bone marrow edema syndrome\" (BMEs) refers to some primary clinical conditions characterized by a high signal on fluid-sensitive MRI sequences at the subchondral bone level, accompanied by pain. This study aimed to evaluate bone status and bone turnover in patients with BMEs compared to a control group.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e\u003cp\u003eA cohort of 150 patients with Complex Regional Pain Syndrome type 1(CRPS-I) (n\u0026thinsp;=\u0026thinsp;56), hip BMEs (n\u0026thinsp;=\u0026thinsp;37), and knee BMEs (n\u0026thinsp;=\u0026thinsp;57) and 150 age- and sex-matched healthy controls were recruited for this study. In all we measured bone turnover markers, vitamin D and Bone Mineral Density (BMD) at lumbar spine and at femur by DXA. For a better estimate of bone tissue microarchitecture, we also calculated the Trabecular Bone Score (TBS).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003epatients with BMEs exhibited significantly lower BMD at all skeletal sites and lower TBS values compared to healthy controls. The three groups of BMEs patients have significantly higher rates of osteoporosis compared to healthy controls and the rate of osteoporosis higher in patients with CRPS-I and hip BMEs than in those with knee BMEs. Vitamin D and markers of bone turnover show no significant differences among BEMs patients and controls.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study indicates that patients with CRPS-I, as well as those with hip and knee BMEs, exhibit a significantly higher prevalence of osteoporosis and a notable reduction in TBS compared to age- and sex-matched healthy controls, thus confirming the pivotal role of bone tissue in the pathogenesis of these diseases.\u003c/p\u003e","manuscriptTitle":"Is Bone Marrow Edema syndrome (BMEs) associated with Osteoporosis? a single-center study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-29 07:29:11","doi":"10.21203/rs.3.rs-7495683/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-14T22:14:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223523365094648451237368684160774361540","date":"2026-01-21T07:18:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-14T19:25:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-01T06:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-01T05:58:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Orthopaedic and Trauma Surgery","date":"2025-08-30T13:49:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-orthopaedic-and-trauma-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aots","sideBox":"Learn more about [Archives of Orthopaedic and Trauma Surgery](http://link.springer.com/journal/402)","snPcode":"402","submissionUrl":"https://submission.springernature.com/new-submission/402/3","title":"Archives of Orthopaedic and Trauma Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2651338a-7900-4310-b44b-0d08a412446c","owner":[],"postedDate":"October 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-29T07:29:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-29 07:29:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7495683","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7495683","identity":"rs-7495683","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}