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  • 1.
    Atanasova, Diana
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten.
    Mirgorodskaya, Ekaterina
    Proteomics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Moparthi, Lavanya
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Koch, Stefan
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Haarhaus, Mathias
    Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Narisawa, Sonoko
    Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States.
    Millán, José Luis
    Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States.
    Landberg, Eva
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Glycoproteomic profile of human tissue-nonspecific alkaline phosphatase expressed in osteoblasts2024Ingår i: JBMR Plus, E-ISSN 2473-4039, Vol. 8, nr 2, artikel-id ziae006Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tissue-nonspecific alkaline phosphatase (TNALP) is a glycoprotein expressed by osteoblasts that promotes bone mineralization. TNALP catalyzes the hydrolysis of the mineralization inhibitor inorganic pyrophosphate and ATP to provide inorganic phosphate, thus controlling the inorganic pyrophosphate/inorganic phosphate ratio to enable the growth of hydroxyapatite crystals. N-linked glycosylation of TNALP is essential for protein stability and enzymatic activity and is responsible for the presence of different bone isoforms of TNALP associated with functional and clinical differences. The site-specific glycosylation profiles of TNALP are, however, elusive. TNALP has 5 potential N-glycosylation sites located at the asparagine (N) residues 140, 230, 271, 303, and 430. The objective of this study was to reveal the presence and structure of site-specific glycosylation in TNALP expressed in osteoblasts. Calvarial osteoblasts derived from Alpl+/− expressing SV40 Large T antigen were transfected with soluble epitope-tagged human TNALP. Purified TNALP was analyzed with a lectin microarray, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, and liquid chromatography with tandem mass spectrometry. The results showed that all sites (n = 5) were fully occupied predominantly with complex-type N-glycans. High abundance of galactosylated biantennary N-glycans with various degrees of sialylation was observed on all sites, as well as glycans with no terminal galactose and sialic acid. Furthermore, all sites had core fucosylation except site N271. Modelling of TNALP, with the protein structure prediction software ColabFold, showed possible steric hindrance by the adjacent side chain of W270, which could explain the absence of core fucosylation at N271. These novel findings provide evidence for N-linked glycosylation on all 5 sites of TNALP, as well as core fucosylation on 4 out of 5 sites. We anticipate that this new knowledge can aid in the development of functional and clinical assays specific for the TNALP bone isoforms.

  • 2.
    Swolin-Eide, Diana
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Forsander, Gun
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Lycka, Auste Pundziute
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Novak, Daniel
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Grillari, Johannes
    Res Ctr Cooperat AUVA, Austria; Univ Nat Resources & Life Sci, Austria; Austrian Cluster Tissue Regenerat, Austria.
    Diendorfer, Andreas B.
    TAmiRNA GmbH, Austria.
    Hackl, Matthias
    TAmiRNA GmbH, Austria.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Circulating microRNAs in young individuals with long-duration type 1 diabetes in comparison with healthy controls2023Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 13, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    MicroRNAs (miRNAs) are short non-coding RNAs that are involved in post-transcriptional control of gene expression and might be used as biomarkers for diabetes-related complications. The aim of this case-control study was to explore potential differences in circulating miRNAs in young individuals with long-duration type 1 diabetes (T1D) compared to healthy controls, and how identified miRNAs are expressed across different tissues. Twelve adolescents, age 15.0-17.9 years, with T1D duration of more than 8 years (mean 11.1 years), were enrolled from the Swedish diabetes quality registry. An age-matched control group was recruited. Circulating miRNAs (n = 187) were analyzed by quantitative PCR. We observed that 27 miRNAs were upregulated and one was downregulated in T1D. Six of these miRNAs were tissue-enriched (blood cells, gastrointestinal, nerve, and thyroid tissues). Six miRNAs with the largest difference in plasma, five up-regulated (hsa-miR-101-3p, hsa-miR-135a-5p, hsa-miR-143-3p, hsa-miR-223-3p and hsa-miR-410-3p (novel for T1D)) and one down-regulated (hsa-miR-495-3p), with P-values below 0.01, were selected for further in-silico analyses. AKT1, VEGFA and IGF-1 were identified as common targets. In conclusion, 28 of the investigated miRNAs were differently regulated in long-duration T1D in comparison with controls. Several associations with cancer were found for the six miRNAs with the largest difference in plasma.

  • 3.
    Jaiswal, Raju
    et al.
    Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg , 413 45 Gothenburg , Sweden.
    Johansson, Helena
    Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg , 413 45 Gothenburg , Sweden;Mary MacKillop Institute for Health Research, Australian Catholic University , Melbourne, VIC, 3000 , Australia.
    Axelsson, Kristian F
    Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg , 413 45 Gothenburg , Sweden;Region Västra Götaland, Närhälsan Norrmalm, Health Centre , 549 40 Skövde , Sweden.
    Magnusson, Per
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi.
    Harvey, Nicholas C
    MRC Lifecourse Epidemiology Centre, University of Southampton , Southampton , UK;NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust , Southampton , UK.
    Vandenput, Liesbeth
    Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg , 413 45 Gothenburg , Sweden;Mary MacKillop Institute for Health Research, Australian Catholic University , Melbourne, VIC, 3000 , Australia.
    McCloskey, Eugene
    Centre for Metabolic Bone Diseases, University of Sheffield Medical School , Sheffield , UK;MRC Versus Arthritis Centre for Integrated research in Musculoskeletal Ageing, Mellanby Centre for Musculoskeletal Research, University of Sheffield , Sheffield , UK.
    Kanis, John A
    Mary MacKillop Institute for Health Research, Australian Catholic University , Melbourne, VIC, 3000 , Australia;Centre for Metabolic Bone Diseases, University of Sheffield Medical School , Sheffield , UK.
    Litsne, Henrik
    Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg , 413 45 Gothenburg , Sweden.
    Johansson, Lisa
    Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg , 413 45 Gothenburg , Sweden;Region Västra Götaland, Department of Orthopedics, Sahlgrenska University Hospital , Mölndal , Sweden.
    Lorentzon, Mattias
    Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg , 413 45 Gothenburg , Sweden;Mary MacKillop Institute for Health Research, Australian Catholic University , Melbourne, VIC, 3000 , Australia;Region Västra Götaland, Department of Geriatric Medicine, Sahlgrenska University Hospital , Mölndal , Sweden.
    Hemoglobin Levels Improve Fracture Risk Prediction in Addition to FRAX Clinical Risk Factors and Bone Mineral Density2023Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 108, nr 12, s. e1479-e1488Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ontext: Anemia and decreasing levels of hemoglobin (Hb) have previously been linked to increased fracture risk, but the added value to FRAX, the most utilized fracture prediction tool worldwide, is unknown.

    Objective: To investigate the association between anemia, Hb levels, bone microstructure, and risk of incident fracture and to evaluate whether Hb levels improve fracture risk prediction in addition to FRAX clinical risk factors (CRFs).

    Methods: A total of 2778 community-dwelling women, aged 75-80 years, and part of a prospective population-based cohort study in Sweden were included. At baseline, information on anthropometrics, CRFs, and falls was gathered, blood samples were collected, and skeletal characteristics were investigated using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. At the end of follow-up, incident fractures were retrieved from a regional x-ray archive.

    Results: The median follow-up time was 6.4 years. Low Hb was associated with worse total hip and femoral neck bone mineral density (BMD), and lower tibia cortical and total volumetric BMD, and anemia was associated with increased risk of major osteoporotic fracture (MOF; hazard ratio 2.04; 95% CI 1.58-2.64). Similar results were obtained for hip fracture and any fracture, also when adjusting for CRFs. The ratio between 10-year fracture probabilities of MOF assessed in models with Hb levels included and not included ranged from 1.2 to 0.7 at the 10th and 90th percentile of Hb, respectively.

    Conclusion: Anemia and decreasing levels of Hb are associated with lower cortical BMD and incident fracture in older women. Considering Hb levels may improve the clinical evaluation of patients with osteoporosis and the assessment of fracture risk.

  • 4.
    Kroksmark, Anna-Karin
    et al.
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Alberg, Lars
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden.
    Tulinius, Mar
    Univ Gothenburg, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Soderpalm, Ann-Charlott
    Univ Gothenburg, Sweden.
    Low bone mineral density and reduced bone-specific alkaline phosphatase in 5q spinal muscular atrophy type 2 and type 3: A 2-year prospective study of bone health2023Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 112, nr 12, s. 2589-2600Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AimIndividuals with spinal muscular atrophy (SMA) are at risk of developing skeletal problems. This study investigated bone mineral density (BMD), bone turnover markers and motor function in children and adolescents with SMA type 2 and type 3 over a two-year period. The effect of nusinersen was studied in a subgroup.MethodsSingle-centre study, including 20 patients, 2-18 years, of whom ten patients received nusinersen treatment. BMD was measured by dual-energy X-ray absorptiometry.ResultsAll patients had low BMD levels at baseline; mean Z-score -2.3 for total body less head (TBLH) and -2.9 for total hip left (THL). Significant correlations were found both at baseline and for the follow-up change for motor function and Z-scores (TBLH and THL). For the whole study group, reduced bone formation and unchanged bone resorption, assessed by bone-specific alkaline phosphatase (BALP) (p = 0.0006, ES = -0.83) and C-terminal cross-linking telopeptide of type I collagen (CTX), respectively, were found over the study period. However, BALP decreased less in the nusinersen treatment group, which suggests a positive development on bone mass in these patients.ConclusionBone health evaluation is important in follow-up programmes for SMA patients. Further investigations are warranted for individuals on survival motor neuron-targeted treatments.

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  • 5.
    Haarhaus, Mathias
    et al.
    Karolinska Univ Hosp, Sweden; Diaverum Sweden AB, Sweden.
    Cianciolo, Giuseppe
    Univ Bologna, Italy.
    Barbuto, Simona
    Univ Bologna, Italy.
    La Manna, Gaetano
    Univ Bologna, Italy.
    Gasperoni, Lorenzo
    AUSL Romagna Infermi Hosp, Italy.
    Tripepi, Giovanni
    CNR, Italy.
    Plebani, Mario
    Univ Padua, Italy.
    Fusaro, Maria
    Natl Res Council CNR, Italy; Univ Padua, Italy.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease2022Ingår i: Nutrients, E-ISSN 2072-6643, Vol. 14, nr 10, artikel-id 2124Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Alkaline phosphatase (ALP) is an evolutionary conserved enzyme and widely used biomarker in clinical practice. Tissue-nonspecific alkaline phosphatase (TNALP) is one of four human isozymes that are expressed as distinct TNALP isoforms after posttranslational modifications, mainly in bone, liver, and kidney tissues. Beyond the well-known effects on bone mineralization, the bone ALP (BALP) isoforms (B/I, B1, B1x, and B2) are also involved in the pathogenesis of ectopic calcification. This narrative review summarizes the recent clinical investigations and mechanisms that link ALP and BALP to inflammation, metabolic syndrome, vascular calcification, endothelial dysfunction, fibrosis, cardiovascular disease, and mortality. The association between ALP, vitamin K, bone metabolism, and fracture risk in patients with chronic kidney disease (CKD) is also discussed. Recent advances in different pharmacological strategies are highlighted, with the potential to modulate the expression of ALP directly and indirectly in CKD-mineral and bone disorder (CKD-MBD), e.g., epigenetic modulation, phosphate binders, calcimimetics, vitamin D, and other anti-fracture treatments. We conclude that the significant evidence for ALP as a pathogenic factor and risk marker in CKD-MBD supports the inclusion of concrete treatment targets for ALP in clinical guidelines. While a target value below 120 U/L is associated with improved survival, further experimental and clinical research should explore interventional strategies with optimal risk-benefit profiles. The future holds great promise for novel drug therapies modulating ALP.

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  • 6.
    Svedlund, Anna
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Pettersson, Cecilia
    Univ Gothenburg, Sweden.
    Tubic, Bojan
    Univ Gothenburg, Sweden.
    Ellegard, Lars
    Univ Gothenburg, Sweden.
    Elfvin, Anders
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Swolin-Eide, Diana
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Bone mass and biomarkers in young women with anorexia nervosa: a prospective 3-year follow-up study2022Ingår i: Journal of Bone and Mineral Metabolism, ISSN 0914-8779, E-ISSN 1435-5604, Vol. 40, nr 6, s. 974-989Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction Anorexia nervosa (AN) increases the risk of impaired bone health, low areal bone mineral density (aBMD), and subsequent fractures. This prospective study investigated the long-term effects of bone and mineral metabolism on bone and biomarkers in 22 women with AN. Materials and methods Body composition and aBMD were measured by dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography. Total and free 25-hydroxyvitamin D (25OHD), C-terminal collagen cross-links (CTX), osteocalcin, bone-specific alkaline phosphatase (BALP), leptin, sclerostin, and oxidized/non-oxidized parathyroid hormone (PTH) were analyzed before and after 12 weeks of intensive nutrition therapy and again 3 years later. An age-matched comparison group of 17 healthy women was recruited for the 3-year follow-up. Results Body mass index (BMI) and fat mass increased from baseline to 3 years in women with AN. Sclerostin decreased during nutrition therapy and further over 3 years, indicating reduced bone loss. CTX was elevated at baseline and after 12 weeks but decreased over 3 years. BALP increased during nutrition therapy and stabilized over 3 years. Free 25OHD was stable during treatment but decreased over 3 years. Non-oxidized PTH was stable during treatment but increased over 3 years. Trabecular volumetric BMD in AN patients decreased during the first 12 weeks and over 3 years despite stable BMI and bone biomarkers implying increased BMD. Conclusion Our findings highlight the importance of early detection and organized long-term follow-up of bone health in young women with a history of AN.

  • 7.
    Rojvall, Annika Svanstrom
    et al.
    Karolinska Inst, Sweden; Capio S T Gorans Hosp, Sweden.
    Buchli, Christian
    Karolinska Inst, Sweden; Dept Pelv Canc, Sweden.
    Saaf, Maria
    Karolinska Inst, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Radestad, Angelique Floter
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Martling, Anna
    Karolinska Inst, Sweden; Dept Pelv Canc, Sweden.
    Segelman, Josefin
    Karolinska Inst, Sweden; Ersta Hosp, Sweden.
    Impact of radiotherapy on bone health in women with rectal cancer- A prospective cohort study2022Ingår i: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 48, nr 12, s. 2509-2517Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Pelvic radiotherapy (RT) increases the risk of pelvic insufficiency fractures. The aim was to investigate if RT is associated with changes in serum bone biomarkers in women with rectal cancer, and to examine the incidence of radiation-induced bone injuries and the association with bone biomarkers.Material and methods: Women diagnosed with rectal cancer stage I-III, planned for abdominal surgery +/- preoperative (chemo) RT, were prospectively included and followed one year. Serum bone biomarkers comprised sclerostin (regulatory of bone formation), CTX (resorption), BALP and PINP (for-mation). A subgroup was investigated with annual pelvic magnetic resonance imaging (MRI). The as-sociation between RT and bone biomarkers was explored in regression models.Results: Of 134 included women, 104 had surgery with preoperative RT. The formation markers BALP and PINP increased from baseline to one year in the RT-exposed group (p < 0.001, longitudinal comparison). In the adjusted regression analysis, the mean increase in PINP was higher in the RT-exposed than the unexposed group (17.6 (3.6-31.5) mg/L, p = 0.013). Sclerostin and CTX did not change within groups nor differed between groups. Radiation-induced injuries were detected in 16 (42%) of 38 women with available MRI. At one year, BALP was higher among women with than without bone injuries (p = 0.018, cross-sectional comparison).Conclusions: Preoperative RT was associated with an increase in the formation marker PINP, which could represent bone recovery following RT-induced injuries, commonly observed in participants evaluated with MRI. These findings should be further explored in larger prospective studies on bone health in rectal cancer patients.(c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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  • 8.
    Skogastierna, Carin
    et al.
    Univ Gothenburg, Sweden.
    Elfvin, Anders
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Hansson, Sverker
    Univ Gothenburg, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Swolin-Eide, Diana
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Impaired renal clearance among Swedish adolescents born preterm2022Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 111, nr 9, s. 1722-1728Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim To determine whether adolescents born before 28 gestational weeks have an increased risk for renal impairment. Methods Swedish infants, born before 28 gestational weeks in 2001 and 2002, were identified from a local register. A total of 16 children, 12 females and 4 males, were examined at 16-17 years of age with Cr-51-EDTA clearance. A comparison group (n = 26) was used. Results Most study participants (n = 13) had normal blood pressure; one individual had hypertension stage 1. All study participants had results within the reference interval for ionised calcium, parathyroid hormone, intact fibroblast growth factor-23 and for urinary albumin-to-creatinine ratio. Four out of 16 participants (25%) had a Cr-51-EDTA clearance less than 90 ml/min/1.73 m(2), indicating a reduced kidney function. Measured Cr-51-EDTA clearance values were significantly lower in the study group than in the comparison group (p = 0.0012). Five study participants (31%) were referred for further investigations. Conclusion Swedish children born before 28 gestational weeks have an increased risk of renal impairment later in life, suggesting that the kidney function in these individuals should be assessed, at least once, during adolescence.

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  • 9.
    Loid, Petra
    et al.
    Folkhalsan Res Ctr, Finland; Univ Helsinki, Finland; Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Hauta-Alus, Helena
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland; Univ Helsinki, Finland; Finnish Inst Hlth & Welf THL, Finland; Oulu Univ Hosp, Finland; Univ Oulu, Finland.
    Makitie, Outi
    Folkhalsan Res Ctr, Finland; Univ Helsinki, Finland; Helsinki Univ Hosp, Finland; Univ Helsinki, Finland; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Makitie, Riikka E.
    Folkhalsan Res Ctr, Finland; Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Lipocalin-2 is associated with FGF23 in WNT1 and PLS3 osteoporosis2022Ingår i: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 13, artikel-id 954730Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundThe pathogenic mechanisms of early-onset osteoporosis caused by WNT1 and PLS3 mutations are incompletely understood and diagnostic biomarkers of these disorders are limited. Recently, lipocalin-2 has been recognized as an osteokine involved in bone development and homeostasis. However, the role of lipocalin-2 in WNT1 and PLS3 osteoporosis is unknown. ObjectiveWe aimed to investigate if plasma lipocalin-2 could be utilized as a biomarker for WNT1 and PLS3 osteoporosis and to evaluate the association between lipocalin-2 and other parameters of bone metabolism. MethodsWe measured plasma lipocalin-2 in 17 WNT1 and 14 PLS3 mutation-positive patients and compared them to those of 34 mutation-negative (MN) healthy subjects. We investigated possible associations between lipocalin-2 and several bone biomarkers including collagen type I cross-linked C-telopeptide (CTX), alkaline phosphatase (ALP), type I procollagen intact N-terminal propeptide (PINP), intact and C-terminal fibroblast growth factor 23 (FGF23), dickkopf-1 (DKK1) and sclerostin as well as parameters of iron metabolism (iron, transferrin, transferrin saturation, soluble transferrin receptor and ferritin). ResultsWe found no differences in plasma lipocalin-2 levels in WNT1 or PLS3 patients compared with MN subjects. However, lipocalin-2 was associated with C-terminal FGF23 in WNT1 patients (r=0.62; p=0.008) and PLS3 patients (r=0.63, p=0.017), and with intact FGF23 in PLS3 patients (r=0.80; p<0.001). In addition, lipocalin-2 correlated with serum transferrin in WNT1 patients (r=0.72; p=0.001). ConclusionWe conclude that plasma lipocalin-2 is not altered in WNT1 or PLS3 mutation-positive subjects but is associated with FGF23 in abnormal WNT1 or PLS3 signaling and with iron status in abnormal WNT1 signaling.

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  • 10.
    Omran, Ahmed
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Atanasova, Diana
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Landgren, Filip
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Sclerostin: From Molecule to Clinical Biomarker2022Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, nr 9, artikel-id 4751Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Sclerostin, a glycoprotein encoded by the SOST gene, is mainly produced by mature osteocytes and is a critical regulator of bone formation through its inhibitory effect on Wnt signaling. Osteocytes are differentiated osteoblasts that form a vast and highly complex communication network and orchestrate osteogenesis in response to both mechanical and hormonal cues. The three most commonly described pathways of SOST gene regulation are mechanotransduction, Wnt/beta-catenin, and steroid signaling. Downregulation of SOST and thereby upregulation of local Wnt signaling is required for the osteogenic response to mechanical loading. This review covers recent findings concerning the identification of SOST, in vitro regulation of SOST gene expression, structural and functional properties of sclerostin, pathophysiology, biological variability, and recent assay developments for measuring circulating sclerostin. The three-dimensional structure of human sclerostin was generated with the AlphaFold Protein Structure Database applying a novel deep learning algorithm based on the amino acid sequence. The functional properties of the 3-loop conformation within the tertiary structure of sclerostin and molecular interaction with low-density lipoprotein receptor-related protein 6 (LRP6) are also reviewed. Second-generation immunoassays for intact/biointact sclerostin have recently been developed, which might overcome some of the reported methodological obstacles. Sclerostin assay standardization would be a long-term objective to overcome some of the problems with assay discrepancies. Besides the use of age- and sex-specific reference intervals for sclerostin, it is also pivotal to use assay-specific reference intervals since available immunoassays vary widely in their methodological characteristics.

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  • 11.
    Svedlund, Anna
    et al.
    Univ Gothenburg, Sweden; Queen Silvia Childrens Hosp, Sweden.
    Tubic, Bojan
    Univ Gothenburg, Sweden.
    Elfvin, Anders
    Univ Gothenburg, Sweden; Queen Silvia Childrens Hosp, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Swolin-Eide, Diana
    Univ Gothenburg, Sweden; Queen Silvia Childrens Hosp, Sweden.
    The Significance of the FTO Gene for Weight and Body Composition in Swedish Women With Severe Anorexia Nervosa During Intensive Nutrition Therapy2022Ingår i: Journal of the American College of Nutrition (Print), ISSN 0731-5724, E-ISSN 1541-1087, Vol. 41, nr 6, s. 594-599Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The aim of this prospective study was to investigate the potential influence of the fat mass and obesity-associated gene (FTO), SNP rs9939609, on body mass index (BMI) and body composition in women with anorexia nervosa (AN) undergoing intensive nutrition therapy. Method: Twenty-five female patients with AN (20.1 +/- 2.3 years; BMI, 15.5 +/- 0.9 kg/m(2)) were included for 12 weeks of treatment with a high-energy diet. FTO was genotyped and body composition parameters were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography at baseline and after 12 weeks. Results: The distribution of the different FTO genotypes were as follows: AA, 24%; TA, 48%; and TT, 28%. Patients gained a median of 9.8 kg (range, 5.5-17.0 kg) and BMI increased to 19.0 +/- 0.9 kg/m(2). The increase in BMI, fat mass, and the quotient fat/muscle area was significant for the TT and TA genotype groups. Total lean mass was stable in all genotype groups. We could not demonstrate any difference among the 3 FTO genotypes related to the increases in BMI during nutrition therapy when the additive, dominant, and recessive models of inheritance were applied. Conclusions: Irrespective of the FTO genotype, there was no difference in weight response during nutrition therapy. Hence, in this small study there was limited support for individualized nutrition therapy for AN based on FTO genotype.

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  • 12.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Njurmedicinska kliniken US. Karolinska Inst, Sweden; Diaverum Sweden AB, Sweden.
    Fernström, Anders
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Njurmedicinska kliniken US.
    Qureshi, Abdul Rashid
    Karolinska Inst, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    The Novel Bone Alkaline Phosphatase Isoform B1x Is Associated with Improved 5-Year Survival in Chronic Kidney Disease2021Ingår i: Nutrients, E-ISSN 2072-6643, Vol. 13, nr 12, artikel-id 4402Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Circulating alkaline phosphatase (ALP) is an independent cardiovascular risk marker. Serum bone ALP (BALP) isoforms indicate bone turnover and comprise approximately 50% of total circulating ALP. In chronic kidney disease (CKD), mortality is highest in patients with increased ALP and BALP and low bone turnover. However, not all low bone turnover states are associated with increased mortality. Chronic inflammation and oxidative stress, features of protein energy wasting syndrome, induce cardiovascular BALP activity and fibro-calcification, while bone turnover is suppressed. Circulating BALP isoform B1x is associated with low ALP and low bone turnover and has been exclusively detected in CKD. We investigated the association of serum B1x with survival, abdominal aortic calcification (AAC) score, and aortic pulse wave velocity (PWV) in CKD. Serum ALP, BALP isoforms, parathyroid hormone (PTH), PWV, and AAC were measured repeatedly over 2 years in 68 prevalent dialysis patients. Mortality was assessed after 5 years. B1x was detected in 53 patients. A competing risk analysis revealed an association of B1x with improved 5-year survival; whereas, baseline PWV, but not AAC score, predicted mortality. However, PWV improved in 26 patients (53%), and B1x was associated with variation of PWV over time (p = 0.03). Patients with B1x had lower PTH and total ALP, suggesting an association with lower bone turnover. In conclusion, B1x is associated with time-varying PWV, lower circulating ALP, and improved survival in CKD, and thus may be an indicator of a reduced cardiovascular risk profile among patients with low bone turnover.

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  • 13.
    Larsson, B. A. M.
    et al.
    Univ Gothenburg, Sweden.
    Johansson, L.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Johansson, H.
    Univ Gothenburg, Sweden; Australian Catholic Univ, Australia.
    Axelsson, K. F.
    Univ Gothenburg, Sweden; Skaraborg Hosp, Sweden.
    Harvey, N.
    Univ Southampton, England; Univ Hosp Southampton NHS Fdn Trust, England.
    Vandenput, L.
    Australian Catholic Univ, Australia; Univ Gothenburg, Sweden.
    Magnusson, Per
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi.
    McCloskey, E.
    Univ Sheffield, England.
    Liu, E.
    Australian Catholic Univ, Australia.
    Kanis, J. A.
    Australian Catholic Univ, Australia; Univ Sheffield, England.
    Sundh, D.
    Univ Gothenburg, Sweden.
    Lorentzon, M.
    Univ Gothenburg, Sweden; Australian Catholic Univ, Australia; Sahlgrens Univ Hosp, Sweden.
    The timed up and go test predicts fracture risk in older women independently of clinical risk factors and bone mineral density2021Ingår i: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 32, s. 75-84Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The timed up and go (TUG) test measures physical performance and predicts falls in the elderly. In older women, TUG time predicts the risk of major osteoporotic fracture and hip fracture independently of clinical risk factors and bone mineral density, and has a substantial impact on fracture probabilities. Introduction The timed up and go (TUG) test measures physical performance and predicts falls in the elderly. A slow TUG has been associated with an increased fracture risk, but it is unclear whether the association is independent of clinical risk factors and bone mineral density (BMD). The aim of this study was to investigate if TUG time was associated with fracture risk independently of clinical risk factors and BMD and to determine its impact on fracture probabilities in older women. Methods A standardized questionnaire was used to assess information regarding clinical risk factors in the large population-based SUPERB study of 3028 older women (75-80 years). At baseline, the TUG test was performed and BMD measured with DXA. The association between TUG time and the risk of hip fracture and major osteoporotic fracture (MOF) was examined using an extension of Poisson regression. Results Fracture incidence increased steeply with increasing TUG time up to 12 s and subsequently started to level off. A slow TUG time was therefore defined as TUG > 12 s, a cutoff level then used in Cox models to study the association between slow TUG and fracture risk. A slow TUG time was associated with an increased risk of fracture (MOF 2.39 [1.80-3.18] and hip fracture 2.96 [1.62-5.40]). These associations were slightly attenuated but remained significant after adjustment for clinical risk factors and femoral neck BMD. Depending on BMD, the 4-year fracture probability of MOF increased by a factor of 1.5-1.9 in a 75-year-old woman with slow TUG (> 12 s). Conclusion The TUG time predicts the risk of MOF and hip fracture independently of clinical risk factors and BMD and has a substantial impact on fracture probabilities, indicating that inclusion of the TUG test in patient evaluation should be considered in order to improve fracture prediction in older women.

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  • 14.
    Novak, Daniel
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Forsander, Gun
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Kristiansen, Eva
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Svedlund, Anna
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Swolin-Eide, Diana
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Altered cortical bone strength and lean mass in young women with long-duration (19 years) type 1 diabetes2020Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikel-id 22367Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To investigate bone health and body composition in young women with long-duration type 1 diabetes (T1D) in relation to matched controls. Twenty-three Swedish women, age 19.2-27.9 years, with a T1D duration of 10 years or more were recruited from the Swedish National Diabetes Registry (NDR). An age-, gender- and geography-matched control group was recruited. Bone mass and body composition were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Data was retrieved from the NDR and SWEDIABKIDS registries. T1D individuals had a mean diabetes duration of 19 years. T1D individuals had reduced lean mass (40.0 +/- 6.1 kg vs. 43.9 +/- 4.9 kg) and were shorter (1.66 +/- 0.06 m vs. 1.71 +/- 0.06 m) although comparable BMI. Subjects with T1D had lower muscle area (P=0.0045). No differences were observed for fractures; physical activity; total, lumbar spine or femur areal bone mineral density. The cortical bone strength strain index was lower for TD1 patients (1875 +/- 399 mm(3) vs. 2277 +/- 332 mm(3)). In conclusion, young women with long-term diabetes duration showed reduced cortical bone strength, decreased periosteal circumference, endosteal circumference and altered body composition. These factors contribute to the health burden of TD1, which warrants further attention for advancing bone health in women with T1D.

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  • 15.
    Johansson, Lisa
    et al.
    Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Orthopaedics, Sahlgrenska University Hospital, Mölndal, Sweden.
    Sundh, Daniel
    Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Rukmangatharajan, Komagal
    Kungälvs Hospital, Kungälv, Sweden.
    Mellström, Dan
    Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Geriatric Medicine Clinic, Sahlgrenska University Hospital, Mölndal, Sweden.
    Nilsson, Anna G.
    Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Endocrinology, Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lorentzon, Mattias
    Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Geriatric Medicine Clinic, Sahlgrenska University Hospital, Mölndal, Sweden; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.
    Because prevalent vertebral fracture (VF) is a strong predictor of future fractures, they are important to identify in clinical practice as osteoporosis medications are effective and can be used to reduce fracture risk in postmenopausal women with VF. Lateral spine imaging (LSI) with dual-energy X-ray absorptiometry (DXA) can be used to diagnose VFs accurately but is not widespread in clinical practice. The prognostic value of grade 1 (20% to 25% compression) VFs diagnosed by LSI with DXA has been insufficiently studied. The aim of this study was to determine if grade 1 VF is associated with incident fracture in older women. Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures (SUPERB) is a population-based study of 3028 older women from Gothenburg, Sweden. Included women were 75 to 80 years of age at baseline, answered questionnaires, and were scanned with DXA (Discovery A, Hologic, Waltham, MA, USA). LSI was used to diagnose VFs, which were classified using the Genant semiquantitative method. Cox regression models were used to estimate the association between VFs at baseline and X-ray-verified incident fractures, with adjustment for confounders. Women with a grade 1 VF (n= 264) or a grade 2-3 VF (n= 349) were compared with women without any fracture (n= 1482). During 3.6 years (median, interquartile range [IQR] 1.5 years) of follow-up, 260 women had any incident fracture and 213 a major osteoporotic fracture (MOF). Women with only grade 1 VF had increased risk of any fracture (hazard ratio [HR] = 1.67; 95% confidence interval [CI] 1.18-2.36) and MOF (HR = 1.86; 95% CI 1.28-2.72). For MOF, this association remained after adjustment for clinical risk factors and femoral neck bone mineral density (BMD). In conclusion, grade 1 VFs were associated with incident MOF, also after adjustment for clinical risk factors and BMD, indicating that all VF identified by DXA should be considered in the evaluation of fracture risk in older women. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by American Society for Bone and Mineral Research.2020Ingår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 35, nr 10, s. 1942-1951Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Because prevalent vertebral fracture (VF) is a strong predictor of future fractures, they are important to identify in clinical practice as osteoporosis medications are effective and can be used to reduce fracture risk in postmenopausal women with VF. Lateral spine imaging (LSI) with dual-energy X-ray absorptiometry (DXA) can be used to diagnose VFs accurately but is not widespread in clinical practice. The prognostic value of grade 1 (20% to 25% compression) VFs diagnosed by LSI with DXA has been insufficiently studied. The aim of this study was to determine if grade 1 VF is associated with incident fracture in older women. Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures (SUPERB) is a population-based study of 3028 older women from Gothenburg, Sweden. Included women were 75 to 80 years of age at baseline, answered questionnaires, and were scanned with DXA (Discovery A, Hologic, Waltham, MA, USA). LSI was used to diagnose VFs, which were classified using the Genant semiquantitative method. Cox regression models were used to estimate the association between VFs at baseline and X-ray-verified incident fractures, with adjustment for confounders. Women with a grade 1 VF (n = 264) or a grade 2-3 VF (n = 349) were compared with women without any fracture (n = 1482). During 3.6 years (median, interquartile range [IQR] 1.5 years) of follow-up, 260 women had any incident fracture and 213 a major osteoporotic fracture (MOF). Women with only grade 1 VF had increased risk of any fracture (hazard ratio [HR] = 1.67; 95% confidence interval [CI] 1.18-2.36) and MOF (HR = 1.86; 95% CI 1.28-2.72). For MOF, this association remained after adjustment for clinical risk factors and femoral neck bone mineral density (BMD). In conclusion, grade 1 VFs were associated with incident MOF, also after adjustment for clinical risk factors and BMD, indicating that all VF identified by DXA should be considered in the evaluation of fracture risk in older women. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

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  • 16.
    Makitie, Riikka E.
    et al.
    Univ Helsinki, Finland; Imperial Coll London, England.
    Kampe, Anders
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Costantini, Alice
    Karolinska Inst, Sweden.
    Alm, Jessica J.
    Karolinska Inst, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Makitie, Outi
    Univ Helsinki, Finland; Karolinska Inst, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Helsinki, Finland; Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF232020Ingår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 35, nr 5, s. 901-912Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent advancements in genetic research have uncovered new forms of monogenic osteoporosis, expanding our understanding of the molecular pathways regulating bone health. Despite active research, knowledge on the pathomechanisms, disease-specific biomarkers, and optimal treatment in these disorders is still limited. Mutations in WNT1, encoding a WNT/beta-catenin pathway ligand WNT1, and PLS3, encoding X chromosomally inherited plastin 3 (PLS3), both result in early-onset osteoporosis with prevalent fractures and disrupted bone metabolism. However, despite marked skeletal pathology, conventional bone markers are usually normal in both diseases. Our study aimed to identify novel bone markers in PLS3 and WNT1 osteoporosis that could offer diagnostic potential and shed light on the mechanisms behind these skeletal pathologies. We measured several parameters of bone metabolism, including serum dickkopf-1 (DKK1), sclerostin, and intact and C-terminal fibroblast growth factor 23 (FGF23) concentrations in 17 WNT1 and 14 PLS3 mutation-positive subjects. Findings were compared with 34 healthy mutation-negative subjects from the same families. Results confirmed normal concentrations of conventional metabolic bone markers in both groups. DKK1 concentrations were significantly elevated in PLS3 mutation-positive subjects compared with WNT1 mutation-positive subjects (p amp;lt; .001) or the mutation-negative subjects (p = .002). Similar differences were not seen in WNT1 subjects. Sclerostin concentrations did not differ between any groups. Both intact and C-terminal FGF23 were significantly elevated in WNT1 mutation-positive subjects (p = .039 and p = .027, respectively) and normal in PLS3 subjects. Our results indicate a link between PLS3 and DKK1 and WNT1 and FGF23 in bone metabolism. The normal sclerostin and DKK1 levels in patients with impaired WNT signaling suggest another parallel regulatory mechanism. These findings provide novel information on the molecular networks in bone. Extended studies are needed to investigate whether these biomarkers offer diagnostic value or potential as treatment targets in osteoporosis. (c) 2020 American Society for Bone and Mineral Research.

  • 17.
    Nizet, Adrien
    et al.
    Univ Liege, Belgium.
    Cavalier, Etienne
    Univ Liege, Belgium.
    Stenvinkel, Peter
    Karolinska Inst, Sweden.
    Haarhaus, Mathias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Karolinska Inst, Sweden; Diaverum Sweden, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Bone alkaline phosphatase: An important biomarker in chronic kidney disease - mineral and bone disorder2020Ingår i: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 501, s. 198-206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Increased cardiovascular morbidity and mortality in chronic kidney disease (CKD) represents an emerging major health problem. Indeed, disturbances in mineral and bone metabolism occur frequently in CKD and are termed chronic kidney disease - mineral and bone disorder (CKD-MBD). These can lead to cardiovascular pathology, resulting in an increased cardiovascular risk. Bone alkaline phosphatase (BALP) is essential for biomineralization. Recent findings demonstrate a crucial role for BALP in the pathogenesis of vascular calcification and identified it as a promising predictor of mortality in CKD. In conjunction with parathyroid hormone (PTH), serum BALP has been suggested as a biomarker of bone turnover in CKD-MBD. In contrast to PTH, serum BALP demonstrates a lower variability and may thus be better suited for the diagnosis and longitudinal follow-up of bone turnover. The linear association with mortality, compared to the U-shaped curve for PTH, is an additional advantage, making BALP more suitable than PTH as a treatment target in CKD. Here we review the main characteristics of alkaline phosphatase isozymes/isoforms and the various assays currently used in clinical routine laboratories. We also discuss the role of BALP in both physiological and pathological mineralization, and the clinical benefit of BALP determination in CKD.

  • 18.
    Swolin-Eide, Diana
    et al.
    Univ Gothenburg, Sweden; Queen Silvia Childrens Hosp, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Does Whole-Body Vibration Treatment Make Childrens Bones Stronger?2020Ingår i: CURRENT OSTEOPOROSIS REPORTS, ISSN 1544-1873, Vol. 18, s. 471-479Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Purpose of Review To summarize the last 10 years of literature regarding the effects of whole-body vibration (WBV) on bone in children, and if WBV results in increased bone acquisition. Recent Findings WBV intervention appears to be a safe intervention with beneficial effects on bone mass in some diseases and syndromes, but there is still low evidence for WBV in clinical practice. The positive effects on muscle strength, balance, and walking speed are more conclusive. One of the takeaways of this review is that well-trained individuals may not further improve bone mass with WBV; thus, interventions are more beneficial in pediatric individuals with Down syndrome or severe motor disabilities with low bone mass and reduced activity levels. WBV appears to be a safe non-pharmacological anabolic approach to increase bone mass in some pediatric populations; however, longer (> 6 months) and larger prospective studies are needed to elucidate the efficacy of WBV on bone health in young individuals.

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  • 19.
    Patlaka, Christina
    et al.
    Karolinska Inst, Sweden.
    Tubic, Bojan
    Univ Gothenburg, Sweden.
    Lang, Pernilla
    Karolinska Inst, Sweden.
    Paulie, Staffan
    Mabtech AB, Sweden.
    Swolin-Eide, Diana
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Andersson, Goran
    Karolinska Inst, Sweden.
    Intensive weight gain therapy in patients with anorexia nervosa results in improved serum tartrate-resistant acid phosphatase (TRAP) 5a and 5b isoform protein levels2020Ingår i: Eating and Weight Disorders, ISSN 1124-4909, E-ISSN 1590-1262, Vol. 25, nr 5, s. 1387-1397Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim Tartrate-resistant acid phosphatase (TRAP) exists as isoforms 5a and 5b. TRAP 5a is a biomarker of chronic inflammation and influences adipose tissue and 5b associates with bone metabolism/pathologies. The aim was to investigate the association of serum TRAP 5a/5b isoforms with fat and bone markers and anthropometric parameters in patients with anorexia nervosa (AN) during weight gain therapy. Methods Twenty-five Swedish female AN patients, age 16-24 years, were treated for 12 weeks with a high-energy diet with six meals daily. Serum TRAP 5a/5b, markers of fat/glucose metabolism, markers of bone resorption and formation were measured. Parameters of bone and body composition were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Results BMI increased from median 15.4 kg/m(2)to 19.0 kg/m(2),p < 0.0001. TRAP 5a and 5a/5b ratio increased but TRAP 5b decreased during the study. TRAP Delta 5a and Delta 5b correlated with Delta insulin and Delta adiponectin, respectively. TRAP 5b correlated with trabecular density at start but not at week 12. At 12 weeks, TRAP 5b correlated with CTX, and Delta decrease in TRAP 5b correlated to Delta increase in bone-specific alkaline phosphatase. Conclusions This clinical interventional study resulted in increased BMI in patients with AN. The decreased TRAP 5b protein levels confirm a role for TRAP 5b as a marker of bone resorption, whereas increased TRAP 5a seemed to derive from systemic changes in bone as well as metabolic changes. The combined detection of TRAP 5a and TRAP 5b in serum could be an indicator of improved bone metabolism.

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  • 20.
    Whyte, Michael P.
    et al.
    Shriners Hosp Children, MO 63110 USA; Washington Univ, MO 63110 USA.
    Ma, Nina S.
    Harvard Med Sch, MA 02115 USA; Univ Colorado, CO 80045 USA.
    Mumm, Steven
    Shriners Hosp Children, MO 63110 USA; Washington Univ, MO 63110 USA.
    Gottesman, Gary S.
    Shriners Hosp Children, MO 63110 USA.
    McAlister, William H.
    Washington Univ, MO 63110 USA.
    Nenninger, Angela R.
    Shriners Hosp Children, MO 63110 USA.
    Bijanki, Vinieth N.
    Shriners Hosp Children, MO 63110 USA.
    Ericson, Karen L.
    Purdue Univ Ft Wayne, IN 46805 USA.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Persistent idiopathic hyperphosphatasemia from bone alkaline phosphatase in a healthy boy2020Ingår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 138, artikel-id 115459Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alkaline phosphatase (ALP) in humans comprises a family of four cell-surface phosphomonoester phosphohydrolase isozymes. Three genes separately encode the "tissue-specific" ALPs whereas the fourth gene encodes ubiquitous homodimeric "tissue-nonspecific" ALP (TNSALP) richly expressed in bone, liver, kidney, and developing teeth. TNSALP monomers have five putative N-linked glycosylation sites where different post-translational modifications account for this isozymes distinctive physicochemical properties in different organs. Three bone-derived TNSALP (BALP) isoforms (B/I, B1, and B2) are present in healthy serum, whereas a fourth BALP isoform (Blx) can circulate in chronic kidney disease. Herein, we report a healthy boy with persistent hyperphosphatasemia due to BALP levels two- to threefold higher than age-appropriate reference values. Highperformance liquid chromatography, electrophoresis, heat inactivation, catalysis inhibition, and polyethylene glycol precipitation revealed increased serum B/I, B1, and B2 differing from patterns found in skeletal diseases. BA was similar to 23-fold elevated. Absence of mental retardation and physical stigmata excluded Mabry syndrome, the ALP-anchoring disorder causing hyperphosphatasemia. Routine biochemical studies indicated intact mineral homeostasis. Serum N-terminal propeptide of type I procollagen (P1NP) level was normal, but C-terminal crosslinking telopeptide of type I collagen (CTX) level was elevated. However, radiological studies showed no evidence for a generalized skeletal disturbance. Circulating pyridoxal 5-phosphate, a TNSALP natural substrate, was not low despite the laboratory hyperphosphatasemia, thereby suggesting BALP phosphohydrolase activity was not elevated endogenously. Mutation analysis of the ALPL gene encoding TNSALP revealed no defect. His non-consanguineous healthy parents had serum total ALP activity and BALP protein levels that were normal. Our patients sporadic idiopathic hyperphosphatasemia could reflect altered post-translational modification together with increased expression and/or impaired degradation of BALP.

  • 21.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, Stockholm; Diaverum Sweden AB, Stockholm, Sweden.
    Gilham, Dean
    Resverlogix Corp. Research and Development, Calgary, Alberta, Canada.
    Kulikowski, Ewelina
    Resverlogix Corp. Research and Development, Calgary, Alberta, Canada.
    Magnusson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Kalantar-Zadeh, Kamyar
    Division of Nephrology and Hypertension, Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California Irvine, Orange; Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach; Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA.
    Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease2020Ingår i: Current opinion in nephrology and hypertension, ISSN 1062-4821, E-ISSN 1473-6543, Vol. 29, nr 1, s. 4-15Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    PURPOSE OF REVIEW: In chronic kidney disease (CKD), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (CVD), and mortality. Single-target interventions have repeatedly failed to improve the prognosis for CKD patients. Epigenetic interventions have the potential to modulate several pathogenetic processes simultaneously. Alkaline phosphatase (ALP) is a robust predictor of CVD and all-cause mortality and implicated in pathogenic processes associated with CVD in CKD.

    RECENT FINDINGS: In experimental studies, epigenetic modulation of ALP by microRNAs or bromodomain and extraterminal (BET) protein inhibition has shown promising results for the treatment of CVD and other chronic metabolic diseases. The BET inhibitor apabetalone is currently being evaluated for cardiovascular risk reduction in a phase III clinical study in high-risk CVD patients, including patients with CKD (ClinicalTrials.gov Identifier: NCT02586155). Phase II studies demonstrate an ALP-lowering potential of apabetalone, which was associated with improved cardiovascular and renal outcomes.

    SUMMARY: ALP is a predictor of CVD and mortality in CKD. Epigenetic modulation of ALP has the potential to affect several pathogenetic processes in CKD and thereby improve cardiovascular outcome.

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  • 22.
    Magnusson, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Nilsen, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten.
    Schedvin, Göran
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för hälso- och sjukvårdsanalys. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    D-vitaminanalyser i primärvård måste användas ändamålsenligt [Appropriate use of vitamin D assessments in primary health care]: Ny strategi i Östergötland för införande och uppföljning av analyser gav bra resultat [Impact of new strategies for the introduction and follow-up of analyses in Östergötland]2019Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116, s. 1-4Artikel i tidskrift (Refereegranskat)
    Abstract [sv]

    Hälso- och sjukvårdslagen föranstaltar om en kostnadseffektiv och jämlik diagnostik inom den svenska hälso- och sjukvården. Samtidigt ökar efterfrågan på laboratorietest mer än annan medicinsk aktivitet, och utvecklingen leder även till att utbudet av laboratorietest ökar [1]. Vårdens generella resursbrist har lett till ökad betoning på värdeskapande testanvändning globalt [2] med fokus på såväl underanvändning av test (försenar korrekt diagnos och adekvat behandling) som överanvändning (medför överdiagnostik och resursslöseri) [3].Som en följd av denna utveckling har laboratorieverksamheten inom Region Östergötland initierat strategier med syfte att åstadkomma en mer rationell användning av laboratoriemedicinska analyser. Detta har skett genom en aktivare uppföljning av beställningsmönster åtföljd av information och feedback i relation till observerade beställningsmönster. År 2016 initierades s k KRAMA-strategier (KRAMA = Kompetensgruppen för rationell användning av medicinsk diagnostik i alla delar av vårdkedjan) (Figur 1). En viktig ambition var att överge ett passivt testinförande till förmån för ett mer effektivt införande i kombination med aktiv uppföljning av beställningsmönster.

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    D-vitaminanalyser i primärvårdmåste användas ändamålsenligt [Appropriate use of vitamin D assessments in primary health care]: Ny strategi i Östergötland för införande och uppföljning av analyser gav bra resultat [Impact of new strategies for the introduction and follow-up of analyses in Östergötland]
  • 23.
    Uhlin, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Tallinn Univ Technol, Estonia.
    Fernström, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Knapen, Marjo H. J.
    Maastricht Univ, Netherlands.
    Vermeer, Cees
    Maastricht Univ, Netherlands.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Long-term follow-up of biomarkers of vascular calcification after switch from traditional hemodialysis to online hemodiafiltration2019Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, nr 3, s. 174-181Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rapid progression of vascular calcification (VC) in hemodialysis (HD) patients is caused by several factors including inflammation and an imbalance between active inducers and inhibitors of VC. Growing evidence shows that online hemodiafiltration (ol-HDF), a combination of diffusive and convective solute transport, has positive effects on the uremic environment that affects patients on dialysis. However, we recently reported that serum 25-hydroxyvitamin D (25(OH)D) decreased after a switch from HD to ol-HDF. As a consequence of this finding, the present study was undertaken to investigate if inducers and inhibitors of VC (i.e. the inactive matrix Gla protein fractions dp-ucMGP and t-ucMGP, fetuin-A, Gla-rich protein (GRP), osteopontin (OPN), bone-specific alkaline phosphatase (BALP), and osteoprotegerin (OPG)) also are affected by ol-HDF. This non-comparative prospective study comprised 35 prevalent patients who were investigated 6, 12, and 24 months after their switch from HD to ol-HDF. Most patients had increased levels of the calcification inhibitors OPN and OPG; and of the inactive calcification inhibitor dp-ucMGP during the study period irrespective of the dialysis modality. BALP and t-ucMGP were mostly within the reference interval, but fetuin-A was mostly below the reference interval during the study period. OPN was significantly associated with BALP and parathyroid hormone, r = 0.62 and r = 0.65 (p amp;lt; .001), respectively. In conclusion, in contrast to decreased 25(OH)D levels, no differences were found for any of the measured biomarkers of VC following the switch from HD to ol-HDF. Further studies are needed to elucidate how these biomarkers can contribute to calcification risk assessment.

  • 24.
    Svedlund, A.
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Hallbook, T.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Dahlgren, J.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Swolin-Eide, D.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Prospective study of growth and bone mass in Swedish children treated with the modified Atkins diet2019Ingår i: European journal of paediatric neurology, ISSN 1090-3798, E-ISSN 1532-2130, Vol. 23, nr 4, s. 629-638Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: The modified Atkins diet (MAD) is a less restrictive treatment option than the ketogenic diet (KD) for intractable epilepsy and some metabolic conditions. Prolonged KD treatment may decrease bone mineralization and affect linear growth; however, long-term studies of MAD treatment are lacking. This study was designed to assess growth, body composition, and bone mass in children on MAD treatment for 24 months. Methods: Thirty-eight patients, mean age (SD) 6.1 years (4.8 years), 21 girls, with intractable epilepsy (n = 22), glucose transporter type 1 deficiency syndrome (n = 7), or pyruvate dehydrogenase complex deficiency (n = 9) were included. Body weight, height, body mass index (BMI), bone mass, and laboratory tests (calcium, phosphorus, magnesium, alkaline phosphatase, cholesterol, 25-hydroxyvitamin D, insulin-like growth factor-I and insulin-like growth factor binding protein 3) were assessed at baseline and after 24 months of MAD treatment. Results: Approximately 50% of the patients responded with more than 50% seizure reduction. Weight and height standard deviation score (SDS) were stable over 24 months, whereas median (minimum maximum) BMI SDS increased from 0.2 (-3.3 to 4.5) to 0.7 (-0.9 to 2.6), p amp;lt; 0.005. No effects were observed for bone mass (total body, lumbar spine and hip) or fat mass. Conclusions: The MAD was efficient in reducing seizures, and no negative effect was observed on longitudinal growth or bone mass after MAD treatment for 24 months. (C) 2019 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.

  • 25.
    Tubic, Bojan
    et al.
    Gothenburg Univ, Sweden.
    Zeijlon, Rickard
    Sahlgrens Univ Hosp, Sweden.
    Wennergren, Goeran
    Gothenburg Univ, Sweden.
    Obermayer-Pietsch, Barbara
    Med Univ Graz, Austria.
    Marild, Staffan
    Gothenburg Univ, Sweden.
    Dahlgren, Jovanna
    Gothenburg Univ, Sweden.
    Magnusson, Per
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi.
    Swolin-Eide, Diana
    Gothenburg Univ, Sweden.
    Randomised study of children with obesity showed that whole body vibration reduced sclerostin2019Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 108, nr 3, s. 502-513Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim New strategies are required to increase physical activity and improve metabolic profiles in children with obesity. We studied the effect of whole body vibration (WBV) on children with obesity on biochemical markers of energy and bone metabolism, anthropometric measurements, muscle parameters and calcaneal bone mineral density (BMD). Methods This was a randomised, prospective, controlled study of 30 children with a median age of 13 years (range 7-17) at Queen Silvia Children s Hospital, Gothenburg, Sweden, from 2013 to 2015. The target for the intervention group was to perform WBV three times a week for 12 weeks, and the study parameters were assessed at baseline and 12 weeks. Results The 16 in the WBV group achieved 51% of the planned activity, mainly at home, and were compared with 14 controls. Sclerostin, bone-specific alkaline phosphatase and carboxy-terminal collagen cross-links decreased in the WBV group (p amp;lt; 0.05) and balance improved (p amp;lt; 0.006), but osteocalcin and insulin remained unchanged. Anthropometric data, muscle strength and calcaneal BMD did not differ between the groups. Conclusion WBV did not affect most of the clinical parameters in children with obesity, but the reduction in sclerostin implies that it had direct effects on osteocytes, which are key players in bone mechanotransduction.

  • 26.
    Swolin-Eide, Diana
    et al.
    Gothenburg Univ, Sweden.
    Hansson, Sverker
    Gothenburg Univ, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    A 3-year longitudinal study of skeletal effects and growth in children after kidney transplantation2018Ingår i: Pediatric Transplantation, ISSN 1397-3142, E-ISSN 1399-3046, Vol. 22, nr 6, artikel-id e13253Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This prospective study investigated growth and skeletal development for 3years after kidney transplantation in pediatric patients, 3.4-15.0years of age. Growth, BMD, bone resorption markers (CTX and TRACP5b), bone formation markers (PINP, ALP, and osteocalcin), PTH, and vitamin D were assessed at start, 3, 12, and 36months after transplantation. Median GFR was 63 (range 37-96) mL/min/1.73m(2) after 3years. The median height SDS increased from -1.7 to -1.1, and median BMI SDS increased from -0.1 to 0.6 over 3years, which shows that transplantation had a favorable outcome on growth. Fat mass increased after transplantation at all time points, whereas lean mass increased after 1year and 3years. Total BMC increased at all time points. No changes were observed for total BMD. Bone resorption markers decreased initially after 3months and remained stable throughout the study, whereas the bone formation markers decreased initially, but successively increased over the study period. In conclusion, this study demonstrates that height SDS and BMI SDS increased, along with the increased formation markers that reveal a positive bone acquisition after kidney transplantation, which was reflected by the significant increase in total body BMC.

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  • 27.
    Swolin-Eide, Diana
    et al.
    Univ Gothenburg, Sweden.
    Andersson, Bjorn
    Univ Gothenburg, Sweden.
    Hellgren, Gunnel
    Univ Gothenburg, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Albertsson-Wikland, Kerstin
    Univ Gothenburg, Sweden.
    Variation of bone acquisition during growth hormone treatment in children can be explained by proteomic biomarkers, bone formation markers, body composition and nutritional factors2018Ingår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 116, s. 144-153Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Growth hormone (GH) regulates both longitudinal growth and bone acquisition in children, and has profound metabolic effects. The aim was to investigate the association between proteomic biomarkers, body fat, nutrition and bone formation markers, and longitudinal growth in response to GH during the first year of treatment. The degree to which changes in these factors could explain variations in GH-dependent longitudinal growth and bone mineralization was also assessed. Methods: The individualized GH dose trial included 128 short prepubertal children with either normal (non-GHdeficient) or reduced levels of GH secretion (GH-deficient) (mean age +/- SD, 8.6 +/- 2.6 years; 90 boys), i.e., with a broad range of GH-secretion and GH-responsiveness, receiving GH treatment (mean 43 mu g/kg/day). Blood samples were taken and dual-energy X-ray absorptiometry (DXA) measured at baseline and 1 year of treatment. Step-wise multiple regression models were constructed including three steps with different independent variables added at each step to explain the variance in outcome variables (height(SDS), bone mineral content (BMC) and bone mineral density (BMD). Independent variables included in Step I were previously identified proteomic markers related to GH treatment response, bone formation markers (intact PINP, bone -specific alkaline phosphatase and osteocalcin), variables at treatment start (GH dose mU/kg/clay, GH maximum secretion, and difference between childs current and mid-parental height(SDS)). Step II explored the added influence of body composition data (body mass index or DXA). Step HI explored the added influence of serum nutritional markers and hormones. Results: Step I variables explained 71% of the variation in first year heightsDs gain, median (minimum-maximum) 0.8 (0.24-1.67); and the proportion explained rose to 73% following inclusion of step H variables and 75% following step III. Corresponding values for total body BMC were 58%, 78%, and 80%, respectively. Proportions fell by approximately 20% when BMC was adjusted for height; 33%, 57%, and 57% for steps I, II, and III, respectively. Corresponding values for total body BMD were 29%, 39%, and 45%, respectively. Conclusion: For total BMC, as much as 80% of the variation during the first year of GH treatment could be explained by proteomic biomarkers, body fat, nutrition and bone formation markers, whereas for height -adjusted BMC 57% could be explained. The inclusion of information about either body composition (fat/lean mass) or nutritional markers contributed with approximately 20%. The variation in heightsps gain could be explained to 75%. Hence, information of fat or nutrition markers was needed for explaining the variation in bone acquisition to the same magnitude as explaining the variation in height response.

  • 28.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Karolinska Institute, Sweden.
    Brandenburg, Vincent
    RWTH University Hospital Aachen, Germany.
    Kalantar-Zadeh, Kamyar
    University of Calif Irvine, CA 92868 USA; University of Calif Los Angeles, CA 90502 USA.
    Stenvinkel, Peter
    Karolinska Institute, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD2017Ingår i: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 13, nr 7, s. 429-442Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Cardiovascular disease is the main cause of early death in the settings of chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and ageing. Cardiovascular events can be caused by an imbalance between promoters and inhibitors of mineralization, which leads to vascular calcification. This process is akin to skeletal mineralization, which is carefully regulated and in which isozymes of alkaline phosphatase (ALP) have a crucial role. Four genes encode ALP isozymes in humans. Intestinal, placental and germ cell ALPs are tissue-specific, whereas the tissue-nonspecific isozyme of ALP (TNALP) is present in several tissues, including bone, liver and kidney. TNALP has a pivotal role in bone calcification. Experimental overexpression of TNALP in the vasculature is sufficient to induce vascular calcification, cardiac hypertrophy and premature death, mimicking the cardiovascular phenotype often found in CKD and T2DM. Intestinal ALP contributes to the gut mucosal defence and intestinal and liver ALPs might contribute to the acute inflammatory response to endogenous or pathogenic stimuli. Here we review novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases. We also discuss new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.

  • 29.
    Halling Linder, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Ek-Rylander, Barbro
    Karolinska Institute, Sweden.
    Krumpel, Michael
    Karolinska Institute, Sweden.
    Norgard, Maria
    Karolinska Institute, Sweden.
    Narisawa, Sonoko
    Sanford Childrens Health Research Centre, CA 92037 USA.
    Luis Millan, Jose
    Sanford Childrens Health Research Centre, CA 92037 USA.
    Andersson, Göran
    Karolinska Institute, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Bone Alkaline Phosphatase and Tartrate-Resistant Acid Phosphatase: Potential Co-regulators of Bone Mineralization2017Ingår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 101, nr 1, s. 92-101Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Phosphorylated osteopontin (OPN) inhibits hydroxyapatite crystal formation and growth, and bone alkaline phosphatase (BALP) promotes extracellular mineralization via the release of inorganic phosphate from the mineralization inhibitor inorganic pyrophosphate (PPi). Tartrate-resistant acid phosphatase (TRAP), produced by osteoclasts, osteoblasts, and osteocytes, exhibits potent phosphatase activity towards OPN; however, its potential capacity as a regulator of mineralization has not previously been addressed. We compared the efficiency of BALP and TRAP towards the endogenous substrates for BALP, i.e., PPi and pyridoxal 5-phosphate (PLP), and their impact on mineralization in vitro via dephosphorylation of bovine milk OPN. TRAP showed higher phosphatase activity towards phosphorylated OPN and PPi compared to BALP, whereas the activity of TRAP and BALP towards PLP was comparable. Bovine milk OPN could be completely dephosphorylated by TRAP, liberating all its 28 phosphates, whereas BALP dephosphorylated at most 10 phosphates. OPN, dephosphorylated by either BALP or TRAP, showed a partially or completely attenuated phosphorylation-dependent inhibitory capacity, respectively, compared to native OPN on the formation of mineralized nodules. Thus, there are phosphorylations in OPN important for inhibition of mineralization that are removed by TRAP but not by BALP. In conclusion, our data indicate that both BALP and TRAP can alleviate the inhibitory effect of OPN on mineralization, suggesting a potential role for TRAP in skeletal mineralization. Further studies are warranted to explore the possible physiological relevance of TRAP in bone mineralization.

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  • 30.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Tillförlitliga referensintervall krävs för värdering av P-ALP: Nya pediatriska referensintervall för alkaliskt fosfatas har klinisk betydelse för att hitta rätt till diagnosen2017Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, nr 42, s. 1750-1751, artikel-id ETTHArtikel i tidskrift (Refereegranskat)
    Abstract [sv]

    Age- and gender-specific reference intervals are pivotal to ensure appropriate interpretation of plasma alkaline phosphatase activities in the lower range Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function mutations of the ALPL gene that mainly express alkaline phosphatase (ALP) in bone and liver. The clinical expression of HPP is highly variable and is classified into six different forms mainly affecting bone and tooth mineralization. The prognosis for each of these HPP forms depends upon the severity of the skeletal disease which reflects the age at presentation. The biochemical hallmark of HPP is low plasma ALP activity (hypophosphatasemia); however, HPP is often misdiagnosed because of low awareness and sometimes absence of age- and gender-specific ALP reference intervals. Children and adolescents have higher ALP levels in comparison with adults. Reliable reference intervals are pivotal for any clinical laboratory test. Harmonized age- and gender-specific plasma ALP reference intervals ought to be used to ensure appropriate interpretation of plasma ALP activities in the lower range.

  • 31.
    Svedlund, Anna
    et al.
    Gothenburg University, Sweden.
    Pettersson, Cecilia
    Gothenburg University, Sweden.
    Tubic, Bojan
    Gothenburg University, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Swolin-Eide, Diana
    Gothenburg University, Sweden.
    Vitamin D status in young Swedish women with anorexia nervosa during intensive weight gain therapy2017Ingår i: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 56, nr 6, s. 2061-2067Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose Anorexia nervosa (AN) is associated with reduced bone mass and an increased fracture risk. The aim was to evaluate the vitamin D status and the association with body mass index (BMI), fat mass and bone mineral density (BMD) in patients with severe AN during a prospective intervention study of intensive nutrition therapy. Methods This study comprised 25 Swedish female AN patients (20.1 +/- 2.3 years), who were treated as inpatients for 12 weeks with a high-energy diet. Serum 25-hydroxy-vitamin D (25(OH) D), calcium, phosphate and parathyroid hormone (PTH) were measured. BMD and body composition were assessed by dual-energy X-ray absorptiometry at study start and after 12 weeks. Results Twenty-two patients completed the study. The mean weight gain was 9.9 kg and BMI (mean +/- SD) increased from 15.5 +/- 0.9 to 19.0 +/- 0.9 kg/m(2), P amp;lt; 0.0001. Fat mass increased from median 12 to 27 %. The median serum 25(OH) D level was 84 nmol/L at baseline, which decreased to 76 nmol/L, P amp;lt; 0.05. PTH increased from median 21.9 to 30.0 ng/L, P amp;lt; 0.0001. BMC increased during the study period, P amp;lt; 0.001. Conclusions Serum 25(OH) D levels were adequate both at study start and completion, however, nominally decreased after the 12-week nutritional intervention. PTH increased subsequently, which coincide with the decreased 25(OH) D levels. The reduction in 25(OH) D could be due to an increased storage of vitamin D related to the increase in fat mass since vitamin D is sequestered in adipose tissue.

  • 32.
    Pettersson, Cecilia
    et al.
    Sahlgrens University Hospital, Sweden.
    Tubic, Bojan
    Gothenburg University, Sweden.
    Svedlund, Anna
    Gothenburg University, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Ellegard, Lars
    Gothenburg University, Sweden.
    Swolin-Eide, Diana
    Gothenburg University, Sweden.
    Berteus Forslund, Helene
    Gothenburg University, Sweden.
    Description of an intensive nutrition therapy in hospitalized adolescents with anorexia nervosa2016Ingår i: Eating Behaviors, ISSN 1471-0153, E-ISSN 1873-7358, Vol. 21, s. 172-178Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To describe an intensive nutrition therapy for hospitalized adolescents and young adults with anorexia nervosa (AN) in terms of body weight, body composition, energy balance and food related anxiety. Method: Twenty-six young females, 16-24 years of age, with AN were invited to participate at admission to a specialized eating disorder unit in Goteborg, Sweden. Intensive nutrition therapy comprised 12 weeks on a structured meal plan. Six meals were served daily, in combination with high-energy liquid nutritional supplements from start. Energy and nutrient intakes, energy expenditure, body composition and food related anxiety were measured during the study. A 3-month follow-up of body weight and food related anxiety was conducted. Results: Twenty-one patients participated. The total daily energy intake was, during the first week of treatment, (mean +/- SD) 3264 +/- 196 kcal (74 kcal/kg), and decreased gradually during treatment to 2622 +/- 331 kcal (49 kcal/kg). Total daily energy expenditure was initially 1568 +/- 149 kcal and increased gradually to 2034 +/- 194 kcal. Patients gained on average 9.8 +/- 2.1 kg and body mass index increased from 15.5 +/- 0.9 to 19.0 +/- 0.9 kg/m(2). Body fat increased from 13 +/- 6% to 26 +/- 6%. Fat free mass remained unchanged, but skeletal muscle mass increased from 16.7 +/- 2.0 to 17.6 +/- 2.4 kg, p = 0.009. Patients food related anxiety decreased significantly during treatment and was still unchanged 3 months later. Conclusion: The presented intensive nutrition therapy with initially high energy and nutrient intakes produced substantial weight gain, increased fat and muscle mass and decreased food related anxiety in AN patients, without any clinical side effects. (C) 2016 Elsevier Ltd. All rights reserved.

  • 33.
    Tubic, Bojan
    et al.
    University of Gothenburg, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Marild, Staffan
    University of Gothenburg, Sweden.
    Leu, Monica
    University of Gothenburg, Sweden.
    Schwetz, Verena
    Medical University of Graz, Austria.
    Sioen, Isabelle
    University of Ghent, Belgium; Flanders, Belgium.
    Herrmann, Diana
    BIPS, Germany.
    Obermayer-Pietsch, Barbara
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, A-8036, Graz, Austria.
    Lissner, Lauren
    University of Gothenburg, Sweden.
    Swolin-Eide, Diana
    University of Gothenburg, Sweden.
    Different osteocalcin forms, markers of metabolic syndrome and anthropometric measures in children within the IDEFICS cohort2016Ingår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 84, s. 230-236Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Osteocalcin (OC), an aboundant non-collagenous bone protein, is inversely associated with parameters of glucose metabolism. Interactions between bone tissue and energy metabolism have not been thoroughly investigated during childhood. This study investigated OC, metabolic parameters and anthropometric characteristics in normal weight and overweight/obese children. Methods: This study comprised 108 (46 normal weight/62 overweight/obese) Swedish 2-9 year old children. Anthropometric data, insulin, glucose, glycosylated haemoglobin (HbA1c), HOMA index, vitamin D, adiponectin, total OC, carboxylated OC (cOC) and undercarboxylated OC (ucOC) were analysed. Results: No difference was found for total OC between the normal and overweight/obese groups, with a mean (+/- SD) value of 82.6 ( +/- 2.8) ng/mL and 77.0 ( +/- 2.4) ng/mL, (P = 0.11), respectively. Overweight children had lower cOC levels, mean 69.1 ( +/- 2.2) ng/mL, vs. normal weight children, mean 75.6 ( +/- 2.5) ng/mL (P = 0.03). The mean ucOC levels of 7.9 ( +/- 0.4) ng/mL in overweight children did not differ vs. normal weight children, mean level 7.0 (+/- 0.4) ng/mL, (P = 0.067). None of the three OC forms correlated with any of the measured parameters. Conclusions: The cOC levels were lower in overweight children. There was no correlation between the three OC forms and any of the measured anthropometric or metabolic parameters. OC has been suggested to have a possible metabolic role, but in general the current study in prepubertal children does not support the hypothesis of an association between OC and a positive metabolic profile. (C) 2016 Elsevier Inc. All rights reserved.

  • 34.
    Halling Linder, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Enander, Karin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Glycation Contributes to Interaction Between Human Bone Alkaline Phosphatase and Collagen Type I2016Ingår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 98, nr 3, s. 284-293Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bone is a biological composite material comprised primarily of collagen type I and mineral crystals of calcium and phosphate in the form of hydroxyapatite (HA), which together provide its mechanical properties. Bone alkaline phosphatase (ALP), produced by osteoblasts, plays a pivotal role in the mineralization process. Affinity contacts between collagen, mainly type II, and the crown domain of various ALP isozymes were reported in a few in vitro studies in the 1980s and 1990s, but have not attracted much attention since, although such interactions may have important implications for the bone mineralization process. The objective of this study was to investigate the binding properties of human collagen type I to human bone ALP, including the two bone ALP isoforms B1 and B2. ALP from human liver, human placenta and E. coli were also studied. A surface plasmon resonance-based analysis, supported by electrophoresis and blotting, showed that bone ALP binds stronger to collagen type I in comparison with ALPs expressed in non-mineralizing tissues. Further, the B2 isoform binds significantly stronger to collagen type I in comparison with the B1 isoform. Human bone and liver ALP (with identical amino acid composition) displayed pronounced differences in binding, revealing that post-translational glycosylation properties govern these interactions to a large extent. In conclusion, this study presents the first evidence that glycosylation differences in human ALPs are of crucial importance for protein–protein interactions with collagen type I, although the presence of the ALP crown domain may also be necessary. Different binding affinities among the bone ALP isoforms may influence the mineral-collagen interface, mineralization kinetics, and degree of bone matrix mineralization, which are important factors determining the material properties of bone.

  • 35.
    Sharp, Christopher
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Increased bone alkaline phosphatase levels do not necessarily cause hypermineralization per se2016Ingår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 89, s. 83-84Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Diminished bone health and increased risk of fracture is increasingly recognised as a complication of diabetes mellitus and even as a consequence of its management. We read with interest the recently published review by Starup-Linde and Vestergaard [1] about bone turnover markers (BTMs) in patients with types 1 and 2 diabetes mellitus and their value in assessing bone health in diabetic patients. In brief, 611 eligible studies were identified of which 47 were included: 1 meta-analysis, 29 cross-sectional, 13 randomized controlled trials and 4 longitudinal studies.

    Ladda ner fulltext (pdf)
    fulltext
  • 36.
    Tubic, B.
    et al.
    Gothenburg University, Sweden.
    Pettersson, C.
    Gothenburg University, Sweden.
    Svedlund, A.
    Gothenburg University, Sweden.
    Berteus Forslund, H.
    Gothenburg University, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Swolin-Eide, D.
    Gothenburg University, Sweden.
    Increased Bone Mineral Content During Rapid Weight Gain Therapy in Anorexia Nervosa2016Ingår i: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 48, nr 10, s. 664-672Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with anorexia nervosa (AN) are at high risk of reduced bone mass. Osteocalcin (OC), a bone formation marker, has been proposed to act as a link between bone and energy metabolism. We investigated how the 3 forms of OC respond during a 12-week intensive nutrition therapy in AN patients, in whom large changes in energy metabolism are expected. Twenty-two female AN patients, mean 20.9 years of age, with a starting mean body mass index (BMI) 15.5kg/m(2) (minimum-maximum) (13.4-17.3kg/m(2)) completed the study. Biochemical markers, body composition, bone mass by DXA, and pQCT were assessed. Subjects gained in median 9.9kg (5.5-17.0kg), and BMI increased from median 15.4kg/m(2) (13.4-17.3kg/m(2)) to 19.0kg/m(2) (16.2-20.6kg/m(2)), pamp;lt;0.0001. Fat mass increased from median 11.4% (4.4-24.8%) to 26.7% (16.9-39.8%). Total OC, carboxylated OC (cOC), undercarboxylated OC (ucOC), and bone-specific alkaline phosphatase (BALP) increased during the study period. No change was observed for the resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX). Total body bone mineral content (BMC) increased, but no changes were found for whole body or lumbar spine bone mineral density. Tibial trabecular density measured by pQCT decreased. Total OC, cOC, and ucOC were not associated with BMI, insulin or body composition parameters. This prospective study demonstrates that all 3 forms of OC (total OC, cOC, ucOC) increase during rapid weight gain. BALP increased while the resorption marker CTX was unchanged, which corroborate with the increased total body BMC.

  • 37.
    Andersson, Björn
    et al.
    Institution of Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Swolin-Eide, Diana
    Göteborg Pediatric Growth Research Center (GP-GRC), Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Albertsson-Wikland, Kerstin
    Department of Physiology/Division of Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
    Vitamin D status in children over three decades – do children get enough vitamin D?2016Ingår i: Bone Reports, ISSN 2352-1872, Vol. 5, s. 150-152Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vitamin D is a key player in the endocrine regulation of calcium and phosphate metabolism and plays a pivotal role in the acquisition of bone mass during childhood. This study investigated long-term data of vitamin D levels in children and adolescents between 1 and 18 years of age. Serum 25-hydroxyvitamin D (25(OH)D) was analyzed between 1982 and 2013 in 2048 Swedish Caucasian children (mean age ± SD, 8.59 ± 3.68 years; 1197 boys). Overall, 704 (34%) children had below recommended levels of 50 nmol/L; however, only 63 (3%) had levels below 25 nmol/L, i.e., vitamin D deficiency. No trend for decreased vitamin D levels over time was found in this population, with median 25(OH)D levels of 58.4 nmol/L, minimum–maximum 5.0–159.3 nmol/L. Younger children, independent of gender, had significantly higher levels 25(OH)D.

    Ladda ner fulltext (pdf)
    Vitamin D status in children over three decades – do children get enough vitamin D?
  • 38.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Karolinska University Hospital, Sweden.
    Monier-Faugere, Marie-Claude
    University of Kentucky, KY 40536 USA.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Malluche, Hartmut H.
    University of Kentucky, KY 40536 USA.
    Bone Alkaline Phosphatase Isoforms in Hemodialysis Patients With Low Versus Non-Low Bone Turnover: A Diagnostic Test Study2015Ingår i: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 66, nr 1, s. 99-105Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (bALP) isoform B1x is exclusively found in serum of some patients with CKD. Study Design: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum bALP isoform activity and histomorphometric parameters of bone in patients with CKD receiving maintenance hemodialysis. Settings and Participants: Anterior iliac crest bone biopsy samples from 40 patients with CKD were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover. Index Test: In serum, bALP, bALP isoforms (B/I, B1x, B1, and B2), and parathyroid hormone (PTH) were measured. Reference Test: Low bone turnover was defined by mineral apposition rate, 0.36 mu m/d. Non-low bone turnover was defined by mineral apposition rate greater than= 0.36 mu m/d. Other Measurements: PTH. Results: B1x was found in 21 patients (53%) who had lower median levels of bALP, 18.6 versus 46.9 U/L; B/I, 0.10 versus 0.22 mu kat/L; B1, 0.40 versus 0.88 mu kat/L; B2, 1.21 versus 2.66 mu kat/L; and PTH, 49 versus 287 pg/mL, compared with patients without B1x (P less than 0.001). 13 patients (65%) with low bone turnover and 8 patients (40%) with non-low bone turnover (P less than 0.2) had detectable B1x. B1x correlated inversely with histomorphometric parameters of bone turnover. Receiver operating characteristic curves showed that B1x can be used for the diagnosis of low bone turnover (area under the curve [AUC], 0.83), whereas bALP (AUC, 0.89) and PTH (AUC, 0.85) are useful for the diagnosis of non-low bone turnover. Limitations: Small number of study participants. Requirement of high-performance liquid chromatography methods for measurement of B1x. Conclusions: B1x, PTH, and bALP have similar diagnostic accuracy in distinguishing low from non-low bone turnover. The presence of B1x is diagnostic of low bone turnover, whereas elevated bALP and PTH levels are useful for the diagnosis of non-low bone turnover.

  • 39.
    Sharp, Christopher
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Davie, Michael W. J.
    Robert Jones and Agnes Hunt Orthopaed Hospital, England.
    Oginni, Lawrence M.
    Obafemi Awolowo University, Nigeria.
    Editorial Material: We are what we eat - is it time to reconsider calcium-deficiency rickets in Nigeria? (FA)2015Ingår i: Tropical medicine & international health, ISSN 1360-2276, E-ISSN 1365-3156, Vol. 20, nr 4, s. 408-410Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 40.
    Uhlin, Fredrik
    et al.
    Region Östergötland, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Tallin University of Technology, Tallin, Estonia.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Larsson, Tobias E
    Karolinska Instituet, Karolinska University Hospital, Stockholm.
    Fernström, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Region Östergötland, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Linköpings universitet, Medicinska fakulteten.
    In the backwater of convective dialysis: decreased 25-hydroxyvitamin D levels following the switch to online hemodiafiltration.2015Ingår i: Clinical Nephrology, ISSN 0301-0430, Vol. 83, nr 6, s. 315-21Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND/AIMS: Vitamin D deficiency and elevated serum fibroblast growth factor-23 (FGF23) levels are hallmark features and surrogate markers of adverse clinical outcomes in patients with chronic kidney disease (CKD). Convection of molecules over the dialysis membrane during online hemodiafiltration (ol-HDF) increases the removal of larger waste molecules compared with traditional high-flux hemodialysis (HD). The primary aim of this study was to explore the long-term impact of ol-HDF on serum 25(OH)D and FGF23.

    METHOD: An observational, prospective, noncomparator study including 35 patients who were switched from HD to ol-HDF. Serum 25(OH)D and FGF23 were measured at baseline (i.e., time of switch to ol-HDF) and at 6, 12, and 24 months.

    RESULTS: At follow-up time points, there was a significant reduction in serum 25(OH)D compared with baseline (p < 0.0001) whereas FGF23 was unaltered (p > 0.05). The decrease in 25(OH)D was more prominent in individuals with higher baseline 25(OH)D levels.

    CONCLUSION: Ol-HDF may lower systemic 25(OH)D levels by convective mechanisms although the clinical significance remains unknown. Further controlled studies are warranted to replicate these findings in larger patient cohorts.

  • 41.
    Andersson, B.
    et al.
    University of Gothenburg, Sweden.
    Swolin-Eide, D.
    University of Gothenburg, Sweden.
    Kristroem, B.
    Umeå University, Sweden.
    Gelander, L.
    University of Gothenburg, Sweden; Angered Hospital, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Medicinska fakulteten.
    Albertsson-Wikland, K.
    University of Gothenburg, Sweden.
    Seasonal variations in vitamin D in relation to growth in short prepubertal children before and during first year growth hormone treatment2015Ingår i: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 38, nr 12, s. 1309-1317Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose This study investigated the relationship between seasonal variations in 25-hydroxyvitamin D (25(OH) D) levels and growth in prepubertal children during both the pretreatment year and the first year of GH treatment. Methods The study included 249 short prepubertal children with a broad range of GH secretion, GH(max) during a 24 h profile median 23; range 1-127 mU/L, 191 boys (mean age +/- SD, 8.6 +/- 2.6 years), 58 girls (7.5 +/- 1.9 years) receiving GH treatment (mean 43 mu g/kg/day; range 17-99 mu g/kg/day). Serum 25(OH) D was measured using an automated IDS-iSYS immunoassay. Results 25(OH) D levels showed seasonal variation, and decreased significantly during GH treatment. 25(OH) D levels at start and first year reduction in 25(OH) D, correlated (-) with the first year growth response during treatment. The degree of GH secretion capacity within our study population of mainly non-GH deficient children and 25(OH) D sufficient (67 +/- 29 nmol/L) had no influence on 25(OH) D levels. Growth during GH treatment were independent of seasonal variations in 25(OH) D. Multiple regression analysis showed that 25(OH) D levels at treatment start, together with auxological data and IGF-binding protein-3(SDS), explained 61 % of the variation in first year gain in height(SDS). Conclusion 25(OH) D levels were associated with first year growth response to GH and may be a useful contribution to future growth prediction models.

  • 42.
    Andersson, Bjorn
    et al.
    University of Gothenburg, Sweden.
    Swolin-Eide, Diana
    University of Gothenburg, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Albertsson-Wikland, Kerstin
    University of Gothenburg, Sweden.
    Short-term changes in bone formation markers following growth hormone (GH) treatment in short prepubertal children with a broad range of GH secretion2015Ingår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 82, nr 1, s. 91-99Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ObjectivesGrowth hormone (GH) promotes longitudinal growth and bone modelling/remodelling. This study investigated the relationship between levels of bone formation markers and growth during GH treatment in prepubertal children with widely ranging GH secretion levels. MethodsThe study group comprised 113 short prepubertal children (mean ageSD, 937213years; 99 boys) on GH treatment (330 +/- 006g/kg/day) for 1year. Blood samples were taken at baseline and 1 and 2weeks, 1 and 3months, and 1year after treatment start. Intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BALP) and osteocalcin were measured using an automated IDS-iSYS immunoassay system. ResultsIntact amino-terminal propeptide of type I procollagen (PINP), BALP and osteocalcin, increased in the short-term during GH treatment. PINP after 1week (P=000077), and BALP and osteocalcin after 1month (Pless than00001 and P=00043, respectively). PINP levels at 1 and 3months correlated positively, and osteocalcin levels at 1week and percentage change after 1month correlated negatively, with first year growth response. No significant correlations were found between BALP and first year growth. Multiple regression analysis showed that bone marker levels together with auxological data and insulin-like growth factor binding protein-3 explained the variation in first year growth response to 36% at start, 32% after 2weeks and 48% at 3months. ConclusionShort-term increases in levels of the bone formation markers PINP, BALP and osteocalcin showed different temporal patterns, but all correlated with first year growth response during GH treatment. These markers may be a useful addition to existing prediction models for growth response.

  • 43.
    Kilebrant, Sophie
    et al.
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Braathen, Gunnar
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Emilsson, Roger
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Glansen, Ulla
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Soderpalm, Ann-Charlott
    University of Gothenburg, Sweden.
    Zetterlund, Bo
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Westerberg, Barbro
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Swolin-Eide, Diana
    University of Gothenburg, Sweden.
    WHOLE-BODY VIBRATION THERAPY IN CHILDREN WITH SEVERE MOTOR DISABILITIES2015Ingår i: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 47, nr 3, s. 223-228Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To study the effect of whole-body vibration therapy on bone mass, bone turnover and body composition in severely disabled children. Methods: Nineteen non-ambulatory children aged 5.1-16.3 years (6 males, 13 females) with severe motor disabilities participated in an intervention programme with standing exercise on a self-controlled dynamic platform, which included whole-body vibration therapy (vibration, jump and rotation movements). Whole-body vibration therapy was performed at 40-42 Hz, with an oscillation amplitude of 0.2 mm, 5-15 min/treatment, twice/week for 6 months. Bone mass parameters and bone markers were measured at the study start, and after 6 and 12 months. Results: Whole-body vibration therapy was appreciated by the children. Total-body bone mineral density increased during the study period (p less than0.05). Z-scores for total-body bone mineral density ranged from -5.10 to -0.60 at study start and remained unchanged throughout. Approximately 50% of the subjects had increased levels of carboxy-terminal telopeptides of type I collagen and decreased levels of osteocalcin at the start. Body mass index did not change during the intervention period, but had increased by the 12-month follow-up (pless than 0.05). Conclusion: Whole-body vibration therapy appeared to be well tolerated by children with severe motor disabilities. Total-body bone mineral density increased after 6 months of whole-body vibration therapy. Higher carboxy-terminal telopeptides of type I collagen and lower osteocalcin values indicated that severely disabled children have a reduced capacity for bone acquisition.

  • 44.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden.
    Fernström, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    A multicenter prospective study of bone alkaline phosphatase isoforms and arterial calcification in chronic kidney disease patients on dialysis2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Chronic kidney disease – mineral and bone disorder (CKD-MBD) is associated with high morbidity and mortality due to frequent cardiovascular (CV) complications. Accelerated arterial stiffening and calcification are associated with serum alkaline phosphatase (ALP) in advanced CKD. We have previously described three bone ALP (BALP) isoforms in healthy individuals and detected a novel isoform, B1x, exclusively in serum from some CKD patients, in bone and in calcifying vascular smooth muscle cells. We investigated the association of these BALP isoforms, abdominal aortic calcification (AAC) score and carotid – femoral pulse wave velocity (PWV), with outcome in a 2-year prospective multicenter study of 68 prevalent dialysis patients participating in the Calcification Outcome in Renal Disease (CORD) study. Twenty-one patients experienced a combined event of all-cause mortality or a first nonfatal CV event during follow-up. PWV (hazard ratio 1.067, P = 0.03) was independently associated with the combined event. B1x was detected in 53 patients and was associated with baseline PWV (Kendall's tau 0.23, P = 0.007) and with variation of PWV over time (estimate 14.14, P = 0.03). Patients with B1x had lower levels of PTH and total ALP, indicating a possible association with low bone turnover. We found no association of BALP isoforms with AAC score. Cox regression revealed B1x as a positive predictor of event free survival (hazard ratio 0.98, P = 0.01). In conclusion, B1x is associated with vascular stiffness in CKD 5D. This finding is contrasted by the ability of B1x to predict longer event free survival in the current study.

  • 45.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden.
    Monier-Faugere, Marie-Claude
    Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    Malluche, Hartmut H.
    Bone alkaline phosphatase isoforms in CKD patients on hemodialysis with low and high bone turnover2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (BALP) isoform B1x is exclusively found in serum of some CKD patients.

    Study Design: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum BALP isoform activities and histomorphometric parameters of bone in patients with CKD on chronic hemodialysis.

    Setting & Participants: Anterior iliac crest bone biopsy samples from 40 CKD patients were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover.

    Index Test: In serum, BALP, BALP isoforms (B/I, B1x, B1 and B2), and parathyroid hormone (PTH) were measured.

    Reference Test or Outcome: Indices of osteoblastic activity and number.

    Other Measurements: Parathyroid hormone

    Results: B1x was found in 21 patients (53%) who had lower median levels of BALP, 18.6 versus 46.9 U/L; B/I, 0.10 versus 0.22 μkat/L; B1, 0.40 versus 0.88 μkat/L; B2, 1.21 versus 2.66 μkat/L; and PTH, 49 versus 287 pg/mL, compared to patients without B1x (p<0.001). B1x correlated inversely with osteoblast number and activity. ROC curves showed that B1x (AUC 0.83) can be used for diagnosis of low osteoblastic activity, while BALP (AUC 0.78) and PTH (AUC 0.77) are useful for diagnosis of high osteoblast number seen with high bone turnover.

    Limitations: Small number of study participants.

    Conclusions: The presence of B1x in serum may be a sign of perturbed osteoblast activity and it may be useful as a diagnostic parameter for low bone turnover rate.

  • 46.
    Stigson, Lennart
    et al.
    University of Gothenburg, Sweden .
    Kistner, Anna
    University of Gothenburg, Sweden .
    Sigurdsson, Jon
    University of Gothenburg, Sweden .
    Engstrom, Eva
    University of Gothenburg, Sweden .
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Hellstrom, Ann
    University of Gothenburg, Sweden .
    Swolin-Eide, Diana
    University of Gothenburg, Sweden .
    Bone and fat mass in relation to postnatal levels of insulin-like growth factors in prematurely born children at 4y of age2014Ingår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 75, nr 4, s. 544-550Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Children born prematurely may be at risk of developing osteopenia. This study investigated whether insulin-like growth factors (IGFs) in the early postnatal period influence bone mass and body composition in prematurely born children. METHODS: A total of 74 control (gestational age greater than36 wk; n = 37) and preterm (gestational age less than32 wk; n = 37) infants were investigated (mean age +/- SD: 4.59 +/- 0.31 y). Bone mineral density, body composition, and markers of bone and mineral metabolism were investigated in relation to postnatal IGF levels. RESULTS: After adjusting for confounders, we found no differences in bone mass, but significantly less lean mass, increased fat mass, and increased osteocalcin levels in ex-preterm infants. Forward stepwise multiple analysis revealed that higher late postnatal IGF-II levels predict lumbar spine bone mineral content (P less than 0.05) and lean mass (P less than 0.05). When the birth weight standard deviation score was included in the analysis, higher early postnatal IGF-I levels predicted both lumbar spine bone mineral density and bone mineral content (P less than 0.05). Higher early postnatal IGF binding protein-3 (P less than 0.01) predicted increased fat mass at 4-y follow-up. CONCLUSION: Ex-preterm children have normal bone mass but different body composition compared with full-term controls. Higher early IGF-I and late postnatal IGF-II concentrations are positive predictors of lumbar spine bone mass.

  • 47.
    Sardiwal, Sunita
    et al.
    East Kent Hospital University of NHS Fdn Trust, England .
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Goldsmith, David J A.
    Guys Hospital, England .
    Lamb, Edmund J.
    East Kent Hospital University of NHS Fdn Trust, England .
    Bone Alkaline Phosphatase in CKD-Mineral Bone Disorder2013Ingår i: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 62, nr 4, s. 810-822Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Overall and cardiovascular mortality in patients with chronic kidney disease (CKD) is greatly increased, without obvious current effective treatments. Mineral and bone disorder (MBD) is a common manifestation of CKD and contributes to the high risk of fracture and cardiovascular mortality in these patients. Traditionally, clinical management of CKD-MBD focused on attenuation of secondary hyperparathyroidism due to impaired renal activation of vitamin D and phosphate retention, although recently, adynamic forms of renal bone disease have become more prevalent. Definitive diagnosis was based on histologic (histomorphometric) analysis of bone biopsy material supported by radiologic changes and changes in levels of surrogate laboratory markers. Of these various markers, parathyroid hormone (PTH) has been considered to be the most sensitive and currently is the most frequently used; however, the many pitfalls of measuring PTH in patients with CKD increasingly are appreciated. We propose an alternative or complementary approach using bone alkaline phosphatase (ALP), which is directly related to bone turnover, reflects bone histomorphometry, and predicts outcomes in hemodialysis patients. Here, we consider the overall merits of bone ALP as a marker of bone turnover in adults with CKD-MBD, examine published bone histomorphometric data comparing bone ALP to PTH, and discuss possible pathogenic mechanisms by which bone ALP may be linked to outcomes in patients with CKD.

  • 48.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Njurmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Arnqvist, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrinmedicinska enheten.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform2013Ingår i: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 50, nr 2, s. 167-174Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Vascular calcification, causing cardiovascular morbidity and mortality, is associated with hyperphosphatemia in chronic kidney disease (CKD). In vitro, phosphate induces transdifferentiation of vascular smooth muscle cells to osteoblast-like cells that express alkaline phosphatase (ALP). In vivo, raised serum ALP activities are associated with increased mortality. A new bone ALP isoform (B1x) has been identified in serum from CKD patients. The present study investigated the different ALP isoforms in calcifying human aortic smooth muscle cells (HAoSMCs). Methods: HAoSMCs were cultured for 30 days in medium containing 5 or 10 mmol/l beta-glycerophosphate in the presence or absence of the ALP-specific inhibitor tetramisole. Results: All known bone-specific ALP (BALP) isoforms (B/I, B1x, B1 and B2) were identified in HAoSMCs. beta-Glycerophosphate stimulated calcification of HAoSMCs, which was associated with increased BALP isoforms B/I, B1x and B2. Tetramisole inhibited the beta-glycerophosphate-induced HAoSMC calcification, which was paralleled by the inhibition of the B1x and B/I, but not the other isoforms. Conclusions: HAoSMCs express the four known BALP isoforms. B/I, B1x and B2 could be essential for soft tissue calcification. B/I and B1x were more affected by tetramisole than the other isoforms, which suggests different biological functions during calcification of HAoSMCs.

  • 49.
    Jia, Ting
    et al.
    Karolinska Institute, Sweden .
    Rashid Qureshi, Abdul
    Karolinska Institute, Sweden .
    Brandenburg, Vincent
    Aachen University Hospital, Germany .
    Ketteler, Markus
    Klinikum Coburg, Germany .
    Barany, Peter
    Karolinska Institute, Sweden .
    Heimburger, Olof
    Karolinska Institute, Sweden .
    Uhlin, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Fernström, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Njurmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Lindholm, Bengt
    Karolinska Institute, Sweden .
    Stenvinkel, Peter
    Karolinska Institute, Sweden .
    Larsson, Tobias E.
    Karolinska Institute, Sweden .
    Determinants of Fibroblast Growth Factor-23 and Parathyroid Hormone Variability in Dialysis Patients2013Ingår i: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 37, nr 5, s. 462-471Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background/Aims: Treatment strategies for abnormal mineral metabolism in chronic kidney disease are largely based on achieving target ranges of biomarkers that vary considerably over time, yet determinants of their variability are poorly defined. Methods: Observational study including 162 patients of three dialysis cohorts (peritoneal dialysis, n = 78; hemodialysis, n = 49; hemodiafiltration, n = 35). Clinical and biochemical determinants of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) variability were analyzed in the peritoneal dialysis cohort. All cohorts were used for comparison of PTH and FGF23 intra-subject variability (intra-class correlation), and their intra-subject variability in different modes of dialysis was explored. Results: High PTH variability was independently associated with lower 25-hydroxyvitamin D concentration and factors of lipid and glucose metabolism, whereas high FGF23 variability was mainly associated with lower baseline serum phosphorous. These results were consistent in multivariate and sensitivity analyses. The intra-subject variability of FGF23 was lower than for PTH irrespective of dialysis mode. Conclusions: Baseline vitamin D status and serum phosphorous are independent determinants of the longitudinal variation in PTH and FGF23, respectively. The clinical utility of FGF23 measurement remains unknown, yet it appears favorable based on its greater temporal stability than PTH in dialysis patients.

  • 50.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Uhlin, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Frånlund, Ebba
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Fernström, Anders
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Linköpings universitet, Institutionen för medicin och hälsa, Njurmedicin. Linköpings universitet, Hälsouniversitetet.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Exon resequencing of the gene encoding UCMA/GRP reveals a common carboxy-terminal 138Thr > Ser Polymorphism2013Ingår i: Clinical Laboratory, ISSN 1433-6510, Vol. 59, nr 11-12, s. 1397-1401Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The upper zone of growth plate and cartilage matrix-associated protein (UCMA), also called Gla-rich protein (GRP), is a novel protein found at sites af-fected by pathological calcifications.Methods: We performed a full exon resequencing on DNA samples from 17 chronic kid-ney disease (CKD) patients (stage 5) and compared the results with 121 healthy con-trols in a Swedish population.Results: A novel non-synonymous single nucleotide polymorphism (SNP) causing a car-boxy-terminal amino acid exchange was found. This SNP involves an alteration of the last ACC codon for threonine in exon 5 (adjacent to the stop codon) to an AGC ser-ine codon (138Thr > Ser). Six controls and two CKD patients were heterozygous for the 138Thr > Ser polymorphism. Both patients had histories of vascular calcifica-tion; however, it is uncertain whether this SNP has any significance for the func-tional domains of the UCMA protein. In addition, a heterozygous transversion muta-tion was found in a patient at SNP rs4750328 (A/G) in intron 2, involving an ex-change of the ancestral A allele to a T base.Conclusions: The 138Thr > Ser polymorphism seems to be the only non-synonymous SNP found in the UCMA gene in a Swedish population.

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