Do Atypical Femoral Fractures Have Atypical Blood Tests? A Comparison of Atypical vs Typical Femoral Fractures

Do Atypical Femoral Fractures Have Atypical Blood Tests? 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A Comparison of Atypical vs Typical Femoral Fractures Aongus O Brolchain, Zander Engelbrecht, Richard Steer, Alfred Phillips, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5383801/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose : Atypical femoral fractures (AFFs) are a rare but important complication of anti-resorptive therapy (ART). The pathophysiology of these fractures remains poorly understood. AFFs are associated with low serum alkaline phosphatase (ALP) and other bone turnover markers, but the diagnosis is established on radiological grounds. This study investigated differences in serum biochemistry at time of hospitalisation AFFs and ‘typical’ femoral fractures (TFFs). Methods : : Retrospective observational study across two centers in Queensland, Australia between 2012 – 2022. All femoral shaft fractures presenting across two hospitals between 2012 – 2022 were screened for inclusion. Two groups comprising AFFs and TFFs were identified for comparison. Blood results at the time of hospital admission were reviewed from the electronic medical record. Results : 143 fractures were included, with 41 patients in the AFF group and 102 in the TFF group. Significant differences were observed between AFF and TFF groups in median serum ALP (56IU/L vs 83IU/L, p=<0.001 ), vitamin D level (86.8nmol/L vs 69.5nmol/L, p = 0.01 ), albumin (38g/L vs 36g/L, p = 0.015 ), globulin (27g/L vs 29g/, p = 0.02), creatinine (68 vs 77, p = 0.05 ) and B12 (360pg/ml vs 250pg/ml, p = 0.03). In the AFF group, 22.5% patients had a serum ALP <40IU/L compared with 3.9% in the TFF group. There was no significant difference observed in the remaining markers of liver function, electrolytes, blood group or coagulation profile. Conclusion : Most datapoints were similar between groups. These data demonstrate that AFFs are associated with low serum ALP levels. Lower creatinine levels in the AFF group may reflect reduced muscle mass and increased frailty in these patients. Atypical Fracture ALP Biochemistry Figures Figure 1 Contribution Statement AOB was responsible for conceptualization and wrote all drafts of the manuscript, as well as performed statistical analysis and creation of tables and figures. ZB was involved curation and collection of data. RS, AF and CL provided expert review of radiographs. All authors have reviewed and have approved this manuscript for submission. Summary The predominant osteoporosis treatments are strongly associated with ‘atypical’ femoral fractures. The radiological diagnostic criteria are qualitative. Many fractures are preventable and are underdiagnosed. In search of objective biochemical diagnostic clues, this is the first study to compare blood results between patients with typical and atypical fractures at time of hospitalization. Introduction Atypical femoral fractures (AFF) are a rare complication of anti-resorptive treatment (ART) for osteoporosis. Femoral shaft ‘fragility’ fractures are uncommon, and when encountered, typically originate at the weight-bearing medial cortex of the bone and are oblique or spiral in nature ( 1 ). In contrast, AFFs resemble ‘fatigue’ or ‘stress’ fractures observed in various materials in engineering and are associated with wear and age. Stress fractures are observed in the lower limbs of weight-bearing athletes, where tensional forces acting on the longitudinal axis of the bone cause significant mechanical stress. The resultant ‘material fatigue’ fracture lines run perpendicular to these forces, causing a transversely-oriented fracture ( 2 ). The pathophysiology of the simulacra ‘atypical’ fractures in elderly, osteoporotic patients and the role of ART is controversial, and the exact mechanisms underlying their genesis is not fully elucidated ( 3 ). It has been postulated that ‘micro’ stress fractures occur on the lateral cortex of the femur and that the spontaneous bone healing and repair that would ordinarily occur is inhibited by the suppression of bone turnover evinced by the use of ART ( 4 ). Several bone turnover markers exist, including serum C-terminal telopeptide of type I collagen and serum procollagen type I N-propeptide, but are specialized, and are not routinely used ( 5 ). ALP, ubiquitously conserved in almost all living organisms, catalyzes the dephosphorylation of pyrophosphate (which is structurally analogous to bisphosphonates ( 6 )) and pyridoxal-5′-phosphate in vivo ( 7 ) and is a marker of bone turnover. Low serum levels of ALP are associated with risk of AFF and lower levels are observed in AFF patients treated with ART. Furthermore, there is evidence that a serum ALP of < 40IU/L may be a risk factor for bilateral AFFs, and that these patients warrant close surveillance ( 8 ). Some monogenic skeletal dysplasias can cause fractures that are clinically indistinguishable from AFFs, most notably hypophosphatasia ( 9 ). Hypophosphatasia (HP) is a rare metabolic disorder caused by deficiency of ALP activity and results in defective bone mineralization ( 10 ). HP can cause unusual femoral fractures that meet the American Society of Bone and Mineral Research (ASBMR) criteria for AFF ( 11 ). Patients with HP are frequently misdiagnosed with osteoporosis and receive ART, which is contraindicated ( 12 ). In patients presenting with AFF, low serum ALP on serial sampling should prompt clinicians to consider the possibility of HP both with and without a history of ART ( 13 ). AFFs are rare, but the use of anti-resorptives is becoming more prevalent. In Australia, the number of people prescribed an osteoporosis medication between 2014 and 2018 increased by 50% ( 14 ). There are several established risk-factors for the development of both osteoporosis and AFFs, including rheumatological and chronic kidney disease, and use of medications such as statins, proton-pump-inhibitors (PPIs), corticosteroids ( 3 ). Despite this, there are few known biochemical signals available to distinguish AFFs from TFFs and the diagnosis remains a radiological one. Therefore, it is essential for all physicians prescribing anti-resorptives to be cognizant of both clinical (prodromal thigh pain) and radiological (periosteal thickening or incomplete fracture) features. This study sought to investigate for potential diagnostic biochemical clues by comparing admission bloods results of patients presenting with both typical and AFFs. Methods The study was conducted at the Gold Coast University and Robina Hospitals on the Gold Coast, Queensland, Australia (ethics approval (LNR) HREC/2022/QGC/84798). A waiver of consent was granted under the National Statement on Ethical Conduct in Human Research (2007) - Updated 2018. Femoral fractures presenting between January 2012 and March 2022 were identified from the electronic medical record using ICD codes (M80.45 – Drug induced osteoporosis with pathological fracture, pelvic region and thigh , Fracture of base of neck of femur S72.05, Fracture of shaft of femur S72.3, subtrochanteric fracture S72.2) (see Fig. 1 ). Radiographs were reviewed by a single reviewer, and all periprosthetic fractures and those proximal to the lesser trochanter and distal to the supracondylar flare (including neck of femur and intertrochanteric fractures) and were excluded. Following chart review, all patients with high-energy mechanism of injury along with patients with diseases of bone mineralization (e.g. Paget’s Disease) or active solid organ or haematological malignancy were excluded. In patients presenting with sequential fractures, only the index presentation was included. Using ASBMR criteria, two consultant orthopaedic surgeons and a consultant radiologist performed a blinded review of pelvic and femoral radiographs in random sequence with demographic data removed. Groups were then divided into AFFs and TFFs. Admission blood results were reviewed and relevant data included, lactate, blood group, coagulation profile, Alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALP, gamma-glutamyl transferase (GGT), ferritin, creatinine, urea, lactate dehydrogenase (LDH), albumin, TSH, free thyroxine (fT4) and electrolytes (sodium, magnesium, potassium, corrected and ionized calcium and phosphate) was recorded. Haemolysed samples and blood tests collected more than 24 hours following presentation were excluded. Serum B12, Folate, Vitamin D levels were also recorded, where available, provided this was done within 72 hours of admission. Statistical analysis was performed using Stata17 (College Station, Tx, USA). Means and standard deviations were used to summarize continuous variables. For continuous variables with normal distribution, the t-test was used. For non-normally distributed continuous variables, the Mann-Whitney U test was used to compare groups by AFF status. Normality of distribution by assessed using the Shapiro-Wilk test. For categorical variables, Chi-squared test was used. Results Eight-hundred and sixty-nine femoral shaft fractures were identified using ICD-10 codes. Fractures proximal to the lesser trochanter and distal to the supracondylar flare and periprosthetic fractures were excluded. Using ASBMR criteria, 81 possible candidates for AFF were identified. Following expert panel review, a cohort of 46 AFFs was identified, leaving 106 TFFs in the second group. Following chart review by a single reviewer and application of exclusion criteria (Fig. 1 ), 41 AFFs and 103 TFFs had at least one blood sample available for inclusion. The median age in years was 74 for the AFF group and 76 in the TFF group ( p = 0.06 ). Almost a quarter of patients (22.5%) in the AFF group had a serum ALP < 40IU/L compared with 3.9% in the TFF group. Significant differences were observed between AFF and TFF groups in mean serum ALP (63.3IU/L vs 92.1IU/L, p = < 0.001 ), vitamin D level (86.8nmol/L vs 69.5nmol/L, p = 0.006 ) (Fig. 1 ), albumin (38g/L vs 36g/L, p = 0.015 ) and B12 (360pg/ml vs 250pg/ml, p = 0.034 ). There was no significant difference observed in calcium, phosphate, magnesium or renal function or other biochemical and haematological parameters (Table 2 ). There was no significant difference in proportions of blood groups or sex between the two groups (Table 3 ). Clinical and fracture characteristics, along with medication history and demographic information of AFF patients are shown in Table 1 . Bone biopsy was performed intraoperatively in 7 patients (5 TFFs, 2 AFFs). None of the biopsies revealed malignancy or granulomatous disease. Discussion There are minimal data on serum biochemistry in general and ALP concentrations in particular with respect to AFF patients in the hospital setting ( 8 ), and this study is the first to compare biochemical and haematological data of patients hospitalized with AFF vs TFFs. Significantly lower levels of ALP were observed in patients presenting with AFF vs TFF. ALP levels can be transiently depressed for several reasons, including acute illness and recent ART, the latter of which reduces ALP by up to 40% ( 15 ). However, it may also reflect the longer duration of anti-resorptive exposure, and a low ALP is an indicator of anti-resorptive efficiency in the treatment of osteoporosis ( 16 ). It should be noted from the outset that ALP is non-specific and isoforms are synthesized in the biliary system. For this reason, Low levels of ALP in the serum may reflect occult metabolic bone disease (such as HP). In a Danish study that examined patients with low ALP presenting to an ambulatory endocrinology clinic over 12 years, more than half of the patients who underwent genetic testing were confirmed to have HP ( 17 ). In a recent Australian study, all patients presenting to osteoporosis clinic with persistently low ALP levels who underwent genetic testing were diagnosed with HP ( 13 ). A systematic review concluded that the rate of AFF in HP may be as high as 10%, with large numbers never being treated with anti-resorptives ( 18 ). ART is a known cause of low ALP ( 11 ) and prolonged use of ART is a known risk factor for AFF ( 19 ). Biomarkers, such as a high urinary phosphoethanolamine level and serum PLP (main circulating form of vitamin B6) can differentiate HP from other causes of low ALP ( 13 , 20 ). None of the patients in this study underwent genetic testing for HP, and it seems likely that there is an increased need for screening in this population. One previous small study with 8 outpatients with a history of AFF demonstrated normal ALP, phosphate and in-tact PTH in all patients ( 21 ). In a Canadian study, 5 patients were found to have an ALP level below the reference range – 4 of whom had bilateral AFFs ( 22 ). In another prospective study involving 100 outpatients (just 2 of whom had AFFs) there was no difference observed in serum calcium, albumin, 25-hydroxy vitamin D, intact parathyroid hormone, alkaline phosphatase, and serum C-telopeptide and urine N-telopeptide levels between TFFs and AFFs ( 23 ). Despite the differences in serum ALP, it is notable that there was no significant difference in the other hepatic indices observed between groups. There are no known studies comparing LFTs, electrolytes, coagulation profiles or blood group in patients with AFF vs TFF. Higher levels of vitamin D observed in this study may reflect higher secondary prevention in the established bisphosphonate group. Higher levels of vitamin B12 may also reflect higher level of surveillance. As a matter of conjecture, lower creatinine levels may reflect lower levels of muscle mass (a marker of frailty) in the AFF group, as long-term bisphosphonate use is associated with a significantly smaller cross-sectional muscle mass when compared to controls ( 24 ) and body composition assessment could be performed in future prospective studies. This study had limitations which must be considered. The retrospective nature of the study increases the risk of bias, uncontrolled variables and missing data. Similarly, ALP is affected by numerous other factors and it is not possible to infer causality. Use of ICD-10 codes is not an optimal means of identifying patients and there is a risk of missing data. Some of the studied parameters (B12, Folate, Vitamin D) are not routinely collected in all patients and a large minority of patients did not have these measured. Unfortunately, bone-specific ALP was not measured, and prospective studies could consider employing this assay, in addition to urinary phosphoethanolamine level and serum PLP (main circulating form of vitamin B6) where a diagnosis of HP is suspected (or where ALP is < 40IU/L). This study has a number of strengths, notably being the first of its kind in analyzing biochemistry of patients hospitalized with AFF and comparing them to TFF. A large proportion of patients in both groups had a large number of biochemical parameters available for examination. This study highlights the need to raise awareness not only of AFF but of other possible mimicks, and to be mindful that ‘atypical’ femoral fractures may actually be ‘typical’ fractures where there is an underlying metabolic bone disease. Selection bias was mitigated by inclusion of all patients presenting with femoral shaft fractures over a period of 10 years. Other strengths of this study include the use of a panel of experts in the adjudication of AFFs and a relatively large sample size given the low incidence of AFF. Table 1 Table 1 shows the clinical and fracture characteristics, medications and demographic information of patients with AFF. Frequencies are demonstrating using (%) and SD is illustrated alongside mean values AFF (n = 44) Frequency Number of available results Fracture characteristics Left-sided 36.3% (16/44) Right-sided 61.3% (27/44) Bilateral 2.3% (1/44) Prodrome 38.6% (17 ) Clinical Characteristics Age (years) 73.6 (10.9) LOS (days) 10.9 (8.80) Weight (kg) 64.8 (18.2) 34/44 Body mass index (BMI) [kg/m 2 ] 25.4 (5.9) 29/44 Previous minimal trauma fracture 38.6% (17/44) Second AFF 15.9% (7/44) Co-morbidities* Osteoporosis 43 (97.7%) Rheumatological disease 9 (20.5%) Rheumatoid arthritis 4 (9.1%) Polymyalgia rheumatica 2 (4.5%) Systemic lupus erythematosus 2 (4.5%) Paget’s Disease 1 (2.3%) Chronic obstructive pulmonary disease 8 (18.1%) Chronic kidney disease 3 (6.8%) Medications Bisphosphonates 77.3% (34/44) Average duration (years) 9.96 (5.9) 23/44 Denosumab 52.3% (19/44) Average duration (years) 3.33 years 18/44 None 1 (2.3%) PPI 47.7% (21/44) Statin 40.9% (18/44) Anti-depressant 27.3% (12/44) Thyroxine 4 (9.1%) Inhaled corticosteroids 6 (13.6%) Table 2 Table 2 depicts the comparison by univariate analysis of admission blood results between patients presenting with AFF vs TFF. Mean (SD), comparisons are by t-test; Median [(Q1, Q3) where Q1 is the 1st quartile and Q3 is the 3rd quartile], comparisons are by rank-sum test. Normal range AFF (n = 41) No. of readings TFF (n = 103) No. of readings P value ALP (U/L) (30–110 ) 41 56 (41, 75) 102 83 (63.3, 107) < 0.001 GGT (U/L) (< 55 U) 27 45 (16, 45) 101 24 (15, 45) 0.61 ALT (U/L (< 45) 40 20 (14,25) 99 16 (12, 25) 0.18 AST (U/L) (< 35) 39 22 (18,28) 98 22 (17 ,32) 0.79 Ferritin (ug/L) (45–17) 14 68 (36, 107) 40 124 (44, 244) 0.08 Creatinine (umol/L) (64–108) 37 68 (57, 75) 102 77 (61, 104) 0.05 Urea (mmol/L) (2.9–8.2) 40 7.3 (5.9, 8.8) 102 8.01 (5.1, 9.4) 0.33 LDH (unit/L) (120–250) 33 262 (226, 293) 81 269 (243, 318) 0.27 Albumin (g/L) (35–50) 40 38 (35, 41) 103 36 (35, 41) 0.02 Globulin (g/L) (25–45) 40 27 (25, 30) 102 29 (27, 32) 0.02 K (mmol/L) (3.5–5.2) 39 4.13 (3.9, 4.4) 101 4.27 (3.9, 4.6)) 0.41 Na (mmol/L) (135–145) 40 137 (135, 138) 103 137 (135, 139) 0.74 Mg (mmol/L) (0.70–1.10) 33 0.81 (0.75, 0.91) 94 0.81 (0.75, 0.87) 0.42 TSH (mU/L) (0.4–4) 29 1.5 (0.9, 3.0) 61 2.2 (0.9, 3.6) 0.72 FT4 (pmol/L) (11.5–22.7) 28 14 ( 13 , 17 ) 59 13 (11.8, 16.3) 0.11 B12 (pmol/L) (133–680) 25 360 (168, 403) 64 249.4 (143, 276) 0.18 Folate (nmol/L) (> 7) 23 36.1 (20, 51) 64 28.4 (20,35) 0.06 CCa2+ (mmol/L (2.10–2.60) 35 2.31 (2.24, 2.37) 98 2.32 (2.24, 2.38) 0.89 Ionized CA (1.15–1.32) 9 1.19 (0.06) 40 1.21 (0.07) 0.13 Lactate (0.5–2.2) 9 1.6 (1.3, 1.7) 40 1.6 (1.18, 2.72) 0.37 Phosphate (mmol/L) (0.75–1.50) 35 1.12 (0.91, 1.3) 98 1.17 (0.96, 1.3) 0.49 Vitamin D (nmol/L) (> 49) 29 86.79 (29.4) 70 69.45 (27.5) 0.01 INR (0.9–1.2) 27 1 (1.0, 1.05) 74 1.05 (1.0, 1.1) 0.02 PT ( 9 – 13 ) 27 12 ( 11 , 14 ) 74 12 ( 11 , 14 ) 0.26 aPTT (25–38) 24 27.6 (5.2) 70 28.5 (4.5) 0.43 Fibrinogen (1.7–4.5) 24 3.25 (3.25, 4.23) 70 3.75 (3.13, 4.4) 0.23 Platelets (140–400) 28 244 (72.8) 87 226 (75.3) 0.27 Table 3 Table 3 shows the blood group frequencies between TFFs and AFFs Blood Group TFF group Frequency (%) AFF group Frequency (%) N = 102 N = 42 A+ 38 37.255 19 45.238 A- 2 1.961 2 4.762 AB+ 1 0.980 2 4.762 B+ 10 9.804 2 4.762 B- 1 0.980 2 4.762 O+ 36 35.294 10 23.810 O- 9 8.824 3 7.143 (Missing) 5 4.902 2 4.762 Male 25 24.6% 4 9.5% Female 77 75.5% 38 90.5% *ICD-10 codes: M80.45 – Drug induced osteoporosis with pathological fracture, pelvic region and thigh , Fracture of base of neck of femur S72.05, Fracture of shaft of femur S72.3, subtrochanteric fracture S72.2 Declarations Data availability statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Funding declaration The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Ethics declaration Ethics approval was granted by the Human Research and Ethics Committee (LNR) HREC/2022/QGC/84798 and the protocol formulated in accordance with the the NHMRC National Statement on Ethical Conduct in Human Research (2023) References Medda S, Unger T, Halvorson J. Diaphyseal Femur Fracture. StatPearls. Treasure Island (FL)2024. Schilcher J, Koeppen V, Ranstam J, Skripitz R, Michaelsson K, Aspenberg P. Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone. 2013;52(1):389–92. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29(1):1–23. 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Atypical femoral fractures: epidemiology, etiology, and patient management. Curr Opin Support Palliat Care. 2012;6(3):348–54. Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233–46. Bhadada SK, Sridhar S, Muthukrishnan J, Mithal A, Sharma DC, Bhansali A, Dhiman V. Predictors of atypical femoral fractures during long term bisphosphonate therapy: a case series & review of literature. Indian J Med Res. 2014;140(1):46–54. Mahjoub Z, Jean S, Leclerc JT, Brown JP, Boulet D, Pelet S, et al. Incidence and Characteristics of Atypical Femoral Fractures: Clinical and Geometrical Data. J Bone Miner Res. 2016;31(4):767–76. La Rocca Vieira R, Rosenberg ZS, Allison MB, Im SA, Babb J, Peck V. Frequency of incomplete atypical femoral fractures in asymptomatic patients on long-term bisphosphonate therapy. AJR Am J Roentgenol. 2012;198(5):1144–51. Uchiyama S, Ikegami S, Kamimura M, Mukaiyama K, Nakamura Y, Nonaka K, Kato H. The skeletal muscle cross sectional area in long-term bisphosphonate users is smaller than that of bone mineral density-matched controls with increased serum pentosidine concentrations. Bone. 2015;75:84–7. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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-5383801","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":383267175,"identity":"be4a87d4-9009-4b4c-84ae-fce5d5e160fd","order_by":0,"name":"Aongus O Brolchain","email":"data:image/png;base64,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","orcid":"","institution":"Griffith University","correspondingAuthor":true,"prefix":"","firstName":"Aongus","middleName":"O","lastName":"Brolchain","suffix":""},{"id":383267176,"identity":"8e9bc5be-4960-4146-bc81-23488c148464","order_by":1,"name":"Zander Engelbrecht","email":"","orcid":"","institution":"Gold Coast Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zander","middleName":"","lastName":"Engelbrecht","suffix":""},{"id":383267177,"identity":"a3283c5f-5947-4503-a5c7-673089d00370","order_by":2,"name":"Richard Steer","email":"","orcid":"","institution":"Gold Coast Hospital","correspondingAuthor":false,"prefix":"","firstName":"Richard","middleName":"","lastName":"Steer","suffix":""},{"id":383267178,"identity":"0c1ba86b-0852-464d-92be-4c87a3855acc","order_by":3,"name":"Alfred Phillips","email":"","orcid":"","institution":"Gold Coast Hospital","correspondingAuthor":false,"prefix":"","firstName":"Alfred","middleName":"","lastName":"Phillips","suffix":""},{"id":383267179,"identity":"00ec46f4-d11e-4c1d-b792-b6e424003382","order_by":4,"name":"Chen-i Lin","email":"","orcid":"","institution":"Gold Coast Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chen-i","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2024-11-03 23:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5383801/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5383801/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71792086,"identity":"cff8237a-1f2b-4d93-bc15-c7ff995c452b","added_by":"auto","created_at":"2024-12-18 15:32:53","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":454277,"visible":true,"origin":"","legend":"\u003cp\u003edepicts the exclusion process during screening and division of groups by fracture type\u003c/p\u003e\n\u003cp\u003e*ICD-10 codes: M80.45 – \u003cem\u003eDrug induced osteoporosis with pathological fracture, pelvic region and thigh\u003c/em\u003e, \u003cem\u003eFracture of base of neck of femur\u003c/em\u003e S72.05, \u003cem\u003eFracture of shaft of femur\u003c/em\u003e S72.3, \u003cem\u003esubtrochanteric fracture\u003c/em\u003e S72.2\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5383801/v1/f96467fa3437b7f635ed3ef7.jpeg"},{"id":71793925,"identity":"27995eff-fbf9-4e5a-9e64-32d47969acb5","added_by":"auto","created_at":"2024-12-18 15:48:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1075942,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5383801/v1/24476dd8-e14e-4b47-bfb5-c2da28494002.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Do Atypical Femoral Fractures Have Atypical Blood Tests? A Comparison of Atypical vs Typical Femoral Fractures","fulltext":[{"header":"Contribution Statement","content":"\u003cp\u003eAOB was responsible for conceptualization and wrote all drafts of the manuscript, as well as performed statistical analysis and creation of tables and figures. ZB was involved curation and collection of data. RS, AF and CL provided expert review of radiographs. All authors have reviewed and have approved this manuscript for submission.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Summary","content":"\u003cp\u003eThe predominant osteoporosis treatments are strongly associated with \u0026lsquo;atypical\u0026rsquo; femoral fractures. The radiological diagnostic criteria are qualitative. Many fractures are preventable and are underdiagnosed. In search of objective biochemical diagnostic clues, this is the first study to compare blood results between patients with typical and atypical fractures at time of hospitalization.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAtypical femoral fractures (AFF) are a rare complication of anti-resorptive treatment (ART) for osteoporosis. Femoral shaft \u0026lsquo;fragility\u0026rsquo; fractures are uncommon, and when encountered, typically originate at the weight-bearing medial cortex of the bone and are oblique or spiral in nature (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In contrast, AFFs resemble \u0026lsquo;fatigue\u0026rsquo; or \u0026lsquo;stress\u0026rsquo; fractures observed in various materials in engineering and are associated with wear and age. Stress fractures are observed in the lower limbs of weight-bearing athletes, where tensional forces acting on the longitudinal axis of the bone cause significant mechanical stress. The resultant \u0026lsquo;material fatigue\u0026rsquo; fracture lines run perpendicular to these forces, causing a transversely-oriented fracture (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe pathophysiology of the simulacra \u0026lsquo;atypical\u0026rsquo; fractures in elderly, osteoporotic patients and the role of ART is controversial, and the exact mechanisms underlying their genesis is not fully elucidated (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It has been postulated that \u0026lsquo;micro\u0026rsquo; stress fractures occur on the lateral cortex of the femur and that the spontaneous bone healing and repair that would ordinarily occur is inhibited by the suppression of bone turnover evinced by the use of ART (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Several bone turnover markers exist, including serum C-terminal telopeptide of type I collagen and serum procollagen type I N-propeptide, but are specialized, and are not routinely used (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). ALP, ubiquitously conserved in almost all living organisms, catalyzes the dephosphorylation of pyrophosphate (which is structurally analogous to bisphosphonates (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)) and pyridoxal-5\u0026prime;-phosphate in vivo (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and is a marker of bone turnover. Low serum levels of ALP are associated with risk of AFF and lower levels are observed in AFF patients treated with ART. Furthermore, there is evidence that a serum ALP of \u0026lt;\u0026thinsp;40IU/L may be a risk factor for bilateral AFFs, and that these patients warrant close surveillance (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSome monogenic skeletal dysplasias can cause fractures that are clinically indistinguishable from AFFs, most notably hypophosphatasia (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Hypophosphatasia (HP) is a rare metabolic disorder caused by deficiency of ALP activity and results in defective bone mineralization (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). HP can cause unusual femoral fractures that meet the American Society of Bone and Mineral Research (ASBMR) criteria for AFF (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Patients with HP are frequently misdiagnosed with osteoporosis and receive ART, which is contraindicated (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In patients presenting with AFF, low serum ALP on serial sampling should prompt clinicians to consider the possibility of HP both with and without a history of ART (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAFFs are rare, but the use of anti-resorptives is becoming more prevalent. In Australia, the number of people prescribed an osteoporosis medication between 2014 and 2018 increased by 50% (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). There are several established risk-factors for the development of both osteoporosis and AFFs, including rheumatological and chronic kidney disease, and use of medications such as statins, proton-pump-inhibitors (PPIs), corticosteroids (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Despite this, there are few known biochemical signals available to distinguish AFFs from TFFs and the diagnosis remains a radiological one. Therefore, it is essential for all physicians prescribing anti-resorptives to be cognizant of both clinical (prodromal thigh pain) and radiological (periosteal thickening or incomplete fracture) features. This study sought to investigate for potential diagnostic biochemical clues by comparing admission bloods results of patients presenting with both typical and AFFs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e The study was conducted at the Gold Coast University and Robina Hospitals on the Gold Coast, Queensland, Australia (ethics approval (LNR) HREC/2022/QGC/84798). A waiver of consent was granted under the National Statement on Ethical Conduct in Human Research (2007) - Updated 2018. Femoral fractures presenting between January 2012 and March 2022 were identified from the electronic medical record using ICD codes (M80.45 \u0026ndash; \u003cem\u003eDrug induced osteoporosis with pathological fracture, pelvic region and thigh\u003c/em\u003e, \u003cem\u003eFracture of base of neck of femur\u003c/em\u003e S72.05, \u003cem\u003eFracture of shaft of femur\u003c/em\u003e S72.3, \u003cem\u003esubtrochanteric fracture\u003c/em\u003e S72.2) (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRadiographs were reviewed by a single reviewer, and all periprosthetic fractures and those proximal to the lesser trochanter and distal to the supracondylar flare (including neck of femur and intertrochanteric fractures) and were excluded. Following chart review, all patients with high-energy mechanism of injury along with patients with diseases of bone mineralization (e.g. Paget\u0026rsquo;s Disease) or active solid organ or haematological malignancy were excluded. In patients presenting with sequential fractures, only the index presentation was included. Using ASBMR criteria, two consultant orthopaedic surgeons and a consultant radiologist performed a blinded review of pelvic and femoral radiographs in random sequence with demographic data removed. Groups were then divided into AFFs and TFFs.\u003c/p\u003e \u003cp\u003eAdmission blood results were reviewed and relevant data included, lactate, blood group, coagulation profile, Alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALP, gamma-glutamyl transferase (GGT), ferritin, creatinine, urea, lactate dehydrogenase (LDH), albumin, TSH, free thyroxine (fT4) and electrolytes (sodium, magnesium, potassium, corrected and ionized calcium and phosphate) was recorded. Haemolysed samples and blood tests collected more than 24 hours following presentation were excluded. Serum B12, Folate, Vitamin D levels were also recorded, where available, provided this was done within 72 hours of admission.\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using Stata17 (College Station, Tx, USA). Means and standard deviations were used to summarize continuous variables. For continuous variables with normal distribution, the t-test was used. For non-normally distributed continuous variables, the Mann-Whitney U test was used to compare groups by AFF status. Normality of distribution by assessed using the Shapiro-Wilk test. For categorical variables, Chi-squared test was used.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eEight-hundred and sixty-nine femoral shaft fractures were identified using ICD-10 codes. Fractures proximal to the lesser trochanter and distal to the supracondylar flare and periprosthetic fractures were excluded. Using ASBMR criteria, 81 possible candidates for AFF were identified. Following expert panel review, a cohort of 46 AFFs was identified, leaving 106 TFFs in the second group. Following chart review by a single reviewer and application of exclusion criteria (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), 41 AFFs and 103 TFFs had at least one blood sample available for inclusion.\u003c/p\u003e \u003cp\u003eThe median age in years was 74 for the AFF group and 76 in the TFF group (\u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.06\u003c/em\u003e). Almost a quarter of patients (22.5%) in the AFF group had a serum ALP\u0026thinsp;\u0026lt;\u0026thinsp;40IU/L compared with 3.9% in the TFF group. Significant differences were observed between AFF and TFF groups in mean serum ALP (63.3IU/L vs 92.1IU/L, \u003cem\u003ep\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/em\u003e), vitamin D level (86.8nmol/L vs 69.5nmol/L, \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.006\u003c/em\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), albumin (38g/L vs 36g/L, \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.015\u003c/em\u003e) and B12 (360pg/ml vs 250pg/ml, \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.034\u003c/em\u003e). There was no significant difference observed in calcium, phosphate, magnesium or renal function or other biochemical and haematological parameters (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was no significant difference in proportions of blood groups or sex between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClinical and fracture characteristics, along with medication history and demographic information of AFF patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eBone biopsy was performed intraoperatively in 7 patients (5 TFFs, 2 AFFs). None of the biopsies revealed malignancy or granulomatous disease.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere are minimal data on serum biochemistry in general and ALP concentrations in particular with respect to AFF patients in the hospital setting (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), and this study is the first to compare biochemical and haematological data of patients hospitalized with AFF vs TFFs. Significantly lower levels of ALP were observed in patients presenting with AFF vs TFF. ALP levels can be transiently depressed for several reasons, including acute illness and recent ART, the latter of which reduces ALP by up to 40% (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, it may also reflect the longer duration of anti-resorptive exposure, and a low ALP is an indicator of anti-resorptive efficiency in the treatment of osteoporosis (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). It should be noted from the outset that ALP is non-specific and isoforms are synthesized in the biliary system. For this reason,\u003c/p\u003e \u003cp\u003eLow levels of ALP in the serum may reflect occult metabolic bone disease (such as HP). In a Danish study that examined patients with low ALP presenting to an ambulatory endocrinology clinic over 12 years, more than half of the patients who underwent genetic testing were confirmed to have HP (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In a recent Australian study, all patients presenting to osteoporosis clinic with persistently low ALP levels who underwent genetic testing were diagnosed with HP (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). A systematic review concluded that the rate of AFF in HP may be as high as 10%, with large numbers never being treated with anti-resorptives (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). ART is a known cause of low ALP (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) and prolonged use of ART is a known risk factor for AFF (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Biomarkers, such as a high urinary phosphoethanolamine level and serum PLP (main circulating form of vitamin B6) can differentiate HP from other causes of low ALP (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). None of the patients in this study underwent genetic testing for HP, and it seems likely that there is an increased need for screening in this population.\u003c/p\u003e \u003cp\u003eOne previous small study with 8 outpatients with a history of AFF demonstrated normal ALP, phosphate and in-tact PTH in all patients (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In a Canadian study, 5 patients were found to have an ALP level below the reference range \u0026ndash; 4 of whom had bilateral AFFs (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In another prospective study involving 100 outpatients (just 2 of whom had AFFs) there was no difference observed in serum calcium, albumin, 25-hydroxy vitamin D, intact parathyroid hormone, alkaline phosphatase, and serum C-telopeptide and urine N-telopeptide levels between TFFs and AFFs (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite the differences in serum ALP, it is notable that there was no significant difference in the other hepatic indices observed between groups. There are no known studies comparing LFTs, electrolytes, coagulation profiles or blood group in patients with AFF vs TFF.\u003c/p\u003e \u003cp\u003eHigher levels of vitamin D observed in this study may reflect higher secondary prevention in the established bisphosphonate group. Higher levels of vitamin B12 may also reflect higher level of surveillance. As a matter of conjecture, lower creatinine levels may reflect lower levels of muscle mass (a marker of frailty) in the AFF group, as long-term bisphosphonate use is associated with a significantly smaller cross-sectional muscle mass when compared to controls (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) and body composition assessment could be performed in future prospective studies.\u003c/p\u003e \u003cp\u003eThis study had limitations which must be considered. The retrospective nature of the study increases the risk of bias, uncontrolled variables and missing data. Similarly, ALP is affected by numerous other factors and it is not possible to infer causality. Use of ICD-10 codes is not an optimal means of identifying patients and there is a risk of missing data. Some of the studied parameters (B12, Folate, Vitamin D) are not routinely collected in all patients and a large minority of patients did not have these measured. Unfortunately, bone-specific ALP was not measured, and prospective studies could consider employing this assay, in addition to urinary phosphoethanolamine level and serum PLP (main circulating form of vitamin B6) where a diagnosis of HP is suspected (or where ALP is \u0026lt;\u0026thinsp;40IU/L).\u003c/p\u003e \u003cp\u003eThis study has a number of strengths, notably being the first of its kind in analyzing biochemistry of patients hospitalized with AFF and comparing them to TFF. A large proportion of patients in both groups had a large number of biochemical parameters available for examination. This study highlights the need to raise awareness not only of AFF but of other possible mimicks, and to be mindful that \u0026lsquo;atypical\u0026rsquo; femoral fractures may actually be \u0026lsquo;typical\u0026rsquo; fractures where there is an underlying metabolic bone disease. Selection bias was mitigated by inclusion of all patients presenting with femoral shaft fractures over a period of 10 years. Other strengths of this study include the use of a panel of experts in the adjudication of AFFs and a relatively large sample size given the low incidence of AFF.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\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\u003eshows the clinical and fracture characteristics, medications and demographic information of patients with AFF. Frequencies are demonstrating using (%) and SD is illustrated alongside mean values\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFF (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrequency\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNumber of available results\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eFracture characteristics\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.3% (16/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61.3% (27/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3% (1/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProdrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.6% (17 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical Characteristics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.6 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLOS (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.9 (8.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.8 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34/44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (BMI) [kg/m\u003csup\u003e2\u003c/sup\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.4 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29/44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious minimal trauma fracture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.6% (17/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecond AFF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.9% (7/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCo-morbidities*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOsteoporosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (97.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatological disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymyalgia rheumatica\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic lupus erythematosus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaget\u0026rsquo;s Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (18.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBisphosphonates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77.3% (34/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.96 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23/44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDenosumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52.3% (19/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.33 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18/44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47.7% (21/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.9% (18/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-depressant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.3% (12/44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroxine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInhaled corticosteroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (13.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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\u003edepicts the comparison by univariate analysis of admission blood results between patients presenting with AFF vs TFF. Mean (SD), comparisons are by t-test; Median [(Q1, Q3) where Q1 is the 1st quartile and Q3 is the 3rd quartile], comparisons are by rank-sum test.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\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\u003eNormal range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAFF (n\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e \u003cp\u003eNo. of readings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTFF (n\u0026thinsp;=\u0026thinsp;103)\u003c/p\u003e \u003cp\u003eNo. of readings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP\u003c/p\u003e \u003cp\u003e\u003cem\u003e(U/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(30\u0026ndash;110 )\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e41\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e56 (41, 75)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e102\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e83 (63.3, 107)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGGT\u003c/p\u003e \u003cp\u003e\u003cem\u003e(U/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026lt;\u0026thinsp;55 U)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (16, 45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24 (15, 45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003c/p\u003e \u003cp\u003e(U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026lt;\u0026thinsp;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (14,25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16 (12, 25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003cp\u003e(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026lt;\u0026thinsp;35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (18,28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22 (17 ,32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin\u003c/p\u003e \u003cp\u003e(ug/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(45\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68 (36, 107)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e124 (44, 244)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine\u003cem\u003e(umol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(64\u0026ndash;108)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e37\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e68 (57, 75)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e102\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e77 (61, 104)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrea\u003c/p\u003e \u003cp\u003e\u003cem\u003e(mmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(2.9\u0026ndash;8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.3 (5.9, 8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.01 (5.1, 9.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH\u003c/p\u003e \u003cp\u003e\u003cem\u003e(unit/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(120\u0026ndash;250)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e262 (226, 293)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e269 (243, 318)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin\u003c/p\u003e \u003cp\u003e\u003cem\u003e(g/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(35\u0026ndash;50)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e40\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e38 (35, 41)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e103\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e36 (35, 41)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlobulin\u003c/p\u003e \u003cp\u003e\u003cem\u003e(g/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(25\u0026ndash;45)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e40\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e27 (25, 30)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e102\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e29 (27, 32)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK\u003c/p\u003e \u003cp\u003e\u003cem\u003e(mmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(3.5\u0026ndash;5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.13 (3.9, 4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.27 (3.9, 4.6))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNa \u003cem\u003e(mmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(135\u0026ndash;145)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e137 (135, 138)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e137 (135, 139)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMg\u003c/p\u003e \u003cp\u003e\u003cem\u003e(mmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0.70\u0026ndash;1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81 (0.75, 0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.81 (0.75, 0.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH\u003c/p\u003e \u003cp\u003e\u003cem\u003e(mU/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0.4\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.5 (0.9, 3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.2 (0.9, 3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFT4\u003c/p\u003e \u003cp\u003e\u003cem\u003e(pmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(11.5\u0026ndash;22.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13 (11.8, 16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB12\u003c/p\u003e \u003cp\u003e\u003cem\u003e(pmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(133\u0026ndash;680)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e360 (168, 403)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e249.4 (143, 276)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolate\u003c/p\u003e \u003cp\u003e\u003cem\u003e(nmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026gt;\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.1 (20, 51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.4 (20,35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCa2+ \u003cem\u003e(mmol/L\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(2.10\u0026ndash;2.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.31 (2.24, 2.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.32 (2.24, 2.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIonized CA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1.15\u0026ndash;1.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19 (0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.21 (0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0.5\u0026ndash;2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.6 (1.3, 1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.6 (1.18, 2.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhosphate \u003cem\u003e(mmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0.75\u0026ndash;1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003cp\u003e(0.91, 1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.17 (0.96, 1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D\u003c/p\u003e \u003cp\u003e\u003cem\u003e(nmol/L)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(\u0026gt;\u0026thinsp;49)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e29\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e86.79 (29.4)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e70\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e69.45 (27.5)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0.9\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.0, 1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.05 (1.0, 1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaPTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(25\u0026ndash;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.6 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.5 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrinogen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1.7\u0026ndash;4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.25 (3.25, 4.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.75 (3.13, 4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(140\u0026ndash;400)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e244 (72.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e226 (75.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.27\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\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\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\u003eshows the blood group frequencies between TFFs and AFFs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTFF group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrequency (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAFF group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrequency (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37.255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e45.238\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.961\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAB+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.980\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.804\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.980\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35.294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e23.810\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.824\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.143\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(Missing)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.902\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e75.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e90.5%\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 \u003c/p\u003e \u003cp\u003e*ICD-10 codes: M80.45 \u0026ndash; \u003cem\u003eDrug induced osteoporosis with pathological fracture, pelvic region and thigh\u003c/em\u003e, \u003cem\u003eFracture of base of neck of femur\u003c/em\u003e S72.05, \u003cem\u003eFracture of shaft of femur\u003c/em\u003e S72.3, \u003cem\u003esubtrochanteric fracture\u003c/em\u003e S72.2\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was granted by the Human Research and Ethics Committee (LNR) HREC/2022/QGC/84798 and the protocol formulated in accordance with the the NHMRC National Statement on Ethical Conduct in Human Research (2023)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMedda S, Unger T, Halvorson J. Diaphyseal Femur Fracture. StatPearls. Treasure Island (FL)2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchilcher J, Koeppen V, Ranstam J, Skripitz R, Michaelsson K, Aspenberg P. Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone. 2013;52(1):389\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29(1):1\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTjhia CK, Odvina CV, Rao DS, Stover SM, Wang X, Fyhrie DP. Mechanical property and tissue mineral density differences among severely suppressed bone turnover (SSBT) patients, osteoporotic patients, and normal subjects. Bone. 2011;49(6):1279\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark SY, Ahn SH, Yoo JI, Chung YJ, Jeon YK, Yoon BH, et al. Position Statement on the Use of Bone Turnover Markers for Osteoporosis Treatment. J Bone Metab. 2019;26(4):213\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGanesan K, Goyal A, Roane D. Bisphosphonate. StatPearls. Treasure Island (FL)2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiedtke D, Hofmann C, Jakob F, Klopocki E, Graser S. Tissue-Nonspecific Alkaline Phosphatase-A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease. Biomolecules. 2020;10(12).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsiantouli E, Biver E, Chevalley T, Petrovic R, Hannouche D, Ferrari S. Prevalence of Low Serum Alkaline Phosphatase and Hypophosphatasia in Adult Patients with Atypical Femur Fractures. Calcif Tissue Int. 2022;110(6):703\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuncan EL. Atypical Femoral Fracture: A Fascinating Story in Evolution. J Bone Miner Res. 2018;33(12):2089\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarini F, Masi L, Giusti F, Cianferotti L, Cioppi F, Marcucci G, et al. ALPL Genotypes in Patients With Atypical Femur Fractures or Other Biochemical and Clinical Signs of Hypophosphatasia. J Clin Endocrinol Metab. 2022;107(5):e2087-e94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGenest F, Seefried L. Subtrochanteric and diaphyseal femoral fractures in hypophosphatasia-not atypical at all. Osteoporos Int. 2018;29(8):1815\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X, Ren N, Wang Z, Wang Y, Hu Y, Hu W, et al. Clinical and Genetic Characteristics of Hypophosphatasia in Chinese Adults. Genes (Basel). 2023;14(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNg E, Ashkar C, Seeman E, Schneider HG, Nguyen H, Ebeling PR, Sztal-Mazer S. A low serum alkaline phosphatase may signal hypophosphatasia in osteoporosis clinic patients. Osteoporos Int. 2023;34(2):327\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDenosumab for Osteoporosis 2020 [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.pbs.gov.au/info/industry/listing/participants/public-release-docs/2020-10/denosumab-for-osteoporosis-october-2020\u003c/span\u003e\u003cspan address=\"https://www.pbs.gov.au/info/industry/listing/participants/public-release-docs/2020-10/denosumab-for-osteoporosis-october-2020\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEastell R, Hannon RA. Biomarkers of bone health and osteoporosis risk. Proc Nutr Soc. 2008;67(2):157\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuo TR, Chen CH. Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives. Biomark Res. 2017;5:18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHepp N, Frederiksen AL, Duno M, Praest Holm J, Rye Jorgensen N, Beck Jensen JE. Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark. Bone Rep. 2021;15:101101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharoenngam N, Thongpiya J, Yingchoncharoen P, Ponvilawan B, Marangoz MS, Chenbhanich J, Ungprasert P. Atypical Femoral Fracture in Hypophosphatasia: A Systematic Review. Int J Endocrinol. 2023;2023:5544148.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonnelly E, Saleh A, Unnanuntana A, Lane JM. Atypical femoral fractures: epidemiology, etiology, and patient management. Curr Opin Support Palliat Care. 2012;6(3):348\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhadada SK, Sridhar S, Muthukrishnan J, Mithal A, Sharma DC, Bhansali A, Dhiman V. Predictors of atypical femoral fractures during long term bisphosphonate therapy: a case series \u0026amp; review of literature. Indian J Med Res. 2014;140(1):46\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahjoub Z, Jean S, Leclerc JT, Brown JP, Boulet D, Pelet S, et al. Incidence and Characteristics of Atypical Femoral Fractures: Clinical and Geometrical Data. J Bone Miner Res. 2016;31(4):767\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLa Rocca Vieira R, Rosenberg ZS, Allison MB, Im SA, Babb J, Peck V. Frequency of incomplete atypical femoral fractures in asymptomatic patients on long-term bisphosphonate therapy. AJR Am J Roentgenol. 2012;198(5):1144\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUchiyama S, Ikegami S, Kamimura M, Mukaiyama K, Nakamura Y, Nonaka K, Kato H. The skeletal muscle cross sectional area in long-term bisphosphonate users is smaller than that of bone mineral density-matched controls with increased serum pentosidine concentrations. Bone. 2015;75:84\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Atypical, Fracture, ALP, Biochemistry","lastPublishedDoi":"10.21203/rs.3.rs-5383801/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5383801/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: Atypical femoral fractures (AFFs) are a rare but important complication of anti-resorptive therapy (ART). The pathophysiology of these fractures remains poorly understood. AFFs are associated with low serum alkaline phosphatase (ALP) and other bone turnover markers, but the diagnosis is established on radiological grounds. This study investigated differences in serum biochemistry at time of hospitalisation AFFs and ‘typical’ femoral fractures (TFFs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: : Retrospective observational study across two centers in Queensland, Australia between 2012 – 2022. All femoral shaft fractures presenting across two hospitals between 2012 – 2022 were screened for inclusion. Two groups comprising AFFs and TFFs were identified for comparison. Blood results at the time of hospital admission were reviewed from the electronic medical record.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: 143 fractures were included, with 41 patients in the AFF group and 102 in the TFF group. Significant differences were observed between AFF and TFF groups in median serum ALP (56IU/L vs 83IU/L, \u003cem\u003ep=\u0026lt;0.001\u003c/em\u003e), vitamin D level (86.8nmol/L vs 69.5nmol/L, \u003cem\u003ep = 0.01\u003c/em\u003e), albumin (38g/L vs 36g/L, \u003cem\u003ep = 0.015\u003c/em\u003e), globulin (27g/L vs 29g/, p = 0.02), creatinine (68 vs 77, \u003cem\u003ep = 0.05\u003c/em\u003e) and B12 (360pg/ml vs 250pg/ml, p = 0.03). In the AFF group, 22.5% patients had a serum ALP \u0026lt;40IU/L compared with 3.9% in the TFF group. There was no significant difference observed in the remaining markers of liver function, electrolytes, blood group or coagulation profile.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Most datapoints were similar between groups. These data demonstrate that AFFs are associated with low serum ALP levels. Lower creatinine levels in the AFF group may reflect reduced muscle mass and increased frailty in these patients.\u003c/p\u003e","manuscriptTitle":"Do Atypical Femoral Fractures Have Atypical Blood Tests? A Comparison of Atypical vs Typical Femoral Fractures","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-18 15:32:48","doi":"10.21203/rs.3.rs-5383801/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"57e6e709-d64c-4664-b9a0-6f6af0e88ddc","owner":[],"postedDate":"December 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-18T15:32:51+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-18 15:32:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5383801","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5383801","identity":"rs-5383801","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}