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  • 101. Ohlsson, Claes
    et al.
    Wallaschofski, Henri
    Lunetta, Kathryn L.
    Stolk, Lisette
    Perry, John R. B.
    Koster, Annemarie
    Petersen, Ann-Kristin
    Eriksson, Joel
    Lehtimaki, Terho
    Huhtaniemi, Ilpo T.
    Hammond, Geoffrey L.
    Maggio, Marcello
    Coviello, Andrea D.
    Ferrucci, Luigi
    Heier, Margit
    Hofman, Albert
    Holliday, Kate L.
    Jansson, John-Olov
    Kahonen, Mika
    Karasik, David
    Karlsson, Magnus K.
    Kiel, Douglas P.
    Liu, Yongmei
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lorentzon, Mattias
    Lyytikainen, Leo-Pekka
    Meitinger, Thomas
    Mellstrom, Dan
    Melzer, David
    Miljkovic, Iva
    Nauck, Matthias
    Nilsson, Maria
    Penninx, Brenda
    Pye, Stephen R.
    Vasan, Ramachandran S.
    Reincke, Martin
    Rivadeneira, Fernando
    Tajar, Abdelouahid
    Teumer, Alexander
    Uitterlinden, Andre G.
    Ulloor, Jagadish
    Viikari, Jorma
    Voelker, Uwe
    Voelzke, Henry
    Wichmann, H. Erich
    Wu, Tsung-Sheng
    Zhuang, Wei Vivian
    Ziv, Elad
    Wu, Frederick C. W.
    Raitakari, Olli
    Eriksson, Anna
    Bidlingmaier, Martin
    Harris, Tamara B.
    Murray, Anna
    De Jong, Frank H.
    Murabito, Joanne M.
    Bhasin, Shalender
    Vandenput, Liesbeth
    Haring, Robin
    Genetic Determinants of Serum Testosterone Concentrations in Men2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 10, p. e1002313-Article in journal (Refereed)
    Abstract [en]

    Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as,300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2x10(-41) and rs6258, p = 2.3x10(-22)). Subjects with >= 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6610216). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.

  • 102. Omarsdottir, S
    et al.
    Ljunggren, O
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, H
    Department of Surgical Sciences.
    Olsson, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Prytz, H
    Lööf, L
    Interfaculty Units, Centre for Clinical Research.
    Longitudinal bone loss in postmenopausal women with primary biliary cirrhosis and well-preserved liver function.2002In: J Intern Med, ISSN 0954-6820, Vol. 252, no 6, p. 537-41Article in journal (Refereed)
  • 103. Omarsdottir, Sif
    et al.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Increased rate of bone loss at the femoral neck in patients with chronic liver disease2002In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 14, no 1, p. 43-8Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE : Patients with chronic liver disease (CLD) have an increased prevalence of osteoporosis. The aim of this study was to evaluate prospectively the rate of bone loss and potential predictors of increased bone loss in a cohort of patients with CLD. DESIGN : Bone mineral density (BMD) was measured at baseline and at follow-up by dual-energy X-ray absorptiometry at the lumbar spine and the femoral neck. RESULTS : Forty-three patients (31 female, 12 male) were available for a second measurement of BMD, with a median of 25 months (range 18-41) between the measurements. Mean annual bone loss at the lumbar spine and the femoral neck, respectively, was 0.6 +/- 2.0% and 1.5 +/- 2.4% in females and 0.8 +/- 1.9% and 2.9 +/- 2.0% in males. The BMD Z score decreased significantly over time at the femoral neck (P = 0.005 and P = 0.02 for females and males, respectively). Bone loss was increased significantly at the lumbar spine in patients classified as Child-Pugh B + C compared with those classified as Child-Pugh A (P = 0.04). Serum levels of bilirubin correlated independently and positively, and 25-hydroxy vitamin D3 levels negatively, with bone loss at the femoral neck. CONCLUSIONS : Patients with CLD have increased bone loss at the femoral neck. Advanced liver disease is associated with increased bone loss, and hyperbilirubinaemia and low levels of vitamin D3 are predictors of increased bone loss.

  • 104.
    Orwoll, Eric S.
    et al.
    Oregon Hlth & Sci Univ, Sch Med, Bone & Mineral Unit, Div Endocrinol Diabet & Clin Nutr, 3181 SW Sam Jackson Pk Rd CR 113, Portland, OR 97201 USA..
    Lapidus, Jodi
    Oregon Hlth & Sci Univ, Div Biostat, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA..
    Wang, Patty Y.
    Oregon Hlth & Sci Univ, Sch Med, Bone & Mineral Unit, Div Endocrinol Diabet & Clin Nutr, 3181 SW Sam Jackson Pk Rd CR 113, Portland, OR 97201 USA..
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Hoffman, Andrew
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Fink, Howard A.
    VA Med Ctr, Geriatr Res Educ & Clin Ctr, Minneapolis, MN USA.;Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA..
    Laughlin, Gail A.
    Univ Calif San Diego, Sch Med, Dept Family Med & Publ Hlth, Div Epidemiol, La Jolla, CA 92093 USA..
    Nethander, Maria
    Univ Gothenburg, Sahlgrenska Acad, Bioinformat Core Facil, Gothenburg, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Geriatr Med, Gothenburg, Sweden..
    Karlsson, Magnus K.
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Malmo Univ, Dept Orthopaed, Malmo, Sweden..
    Mellström, Dan
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Geriatr Med, Gothenburg, Sweden..
    Kwok, Anthony
    Chinese Univ Hong Kong, Dept Orthopaed & Traumatol, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Jockey Club Ctr Osteoporosis Care & Control, Hong Kong, Hong Kong, Peoples R China..
    Khosla, Sundeep
    Mayo Clin, Div Endocrinol, Rochester, MN USA..
    Kwok, Timothy
    Chinese Univ Hong Kong, Jockey Club Ctr Osteoporosis Care & Control, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    The Limited Clinical Utility of Testosterone, Estradiol, and Sex Hormone Binding Globulin Measurements in the Prediction of Fracture Risk and Bone Loss in Older Men2017In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 32, no 3, p. 633-640Article in journal (Refereed)
    Abstract [en]

    Measurement of serum testosterone (T) levels is recommended in the evaluation of osteoporosis in older men and estradiol (E2) and sex hormone binding globulin (SHBG) levels are associated with the rate of bone loss and fractures, but the clinical utility of sex steroid and SHBG measurements for the evaluation of osteoporosis in men has not been examined. To evaluate whether measurements of T, E2, and/or SHBG are useful for the prediction of fracture risk or the rate of bone loss in older men, we analyzed longitudinal data from 5487 community-based men participating in the Osteoporotic Fractures in Men (MrOS) study in the United States, Sweden, and Hong Kong. Serum T, E2, and SHBG levels were assessed at baseline; incident fractures were self-reported at 4-month intervals with radiographic verification (US), or ascertained via national health records (Sweden, Hong Kong). Rate of bone loss was assessed by serial measures of hip bone mineral density (BMD). We used receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to assess improvement in prediction. Mean age at baseline was 72 to 75 years and the prevalence of low T levels (<300 ng/dL) was 7.6% to 21.3% in the three cohorts. There were 619 incident major osteoporotic and 266 hip fractures during follow-up of approximately 10 years. Based on ROC curves, there were no improvements in fracture risk discrimination for any biochemical measure when added to models, including the Fracture Risk Assessment Tool (FRAX) with BMD. Although minor improvements in NRI were observed for the dichotomous parameters low bioavailable E2 (BioE2) (<11.4 pg/mL) and high SHBG(>59.1 nM), neither sex steroids nor SHBG provided clinically useful improvement in fracture risk discrimination. Similarly, they did not contribute to the prediction of BMD change. In conclusion, there is limited clinical utility of serum E2, T, and SHBG measures for the evaluation of osteoporosis risk in elderly men.

  • 105. Orwoll, Eric
    et al.
    Teglbjrg, Christence S.
    Langdahl, Bente L.
    Chapurlat, Roland
    Czerwinski, Edward
    Kendler, David L.
    Reginster, Jean-Yves
    Kivitz, Alan
    Lewiecki, E. Michael
    Miller, Paul D.
    Bolognese, Michael A.
    McClung, Michael R.
    Bone, Henry G.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Abrahamsen, Bo
    Gruntmanis, Ugis
    Yang, Yu-Ching
    Wagman, Rachel B.
    Siddhanti, Suresh
    Grauer, Andreas
    Hall, Jesse W.
    Boonen, Steven
    A Randomized, Placebo-Controlled Study of the Effects of Denosumab for the Treatment of Men with Low Bone Mineral Density2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 9, p. 3161-3169Article in journal (Refereed)
    Abstract [en]

    Context: Men with low bone mineral density (BMD) were treated with denosumab.

    Objective: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment.

    Design, Subjects, and Intervention: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD.

    Main Outcome Measure: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12.

    Results: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P <= 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups.

    Conclusions: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.

  • 106. Paternoster, Lavinia
    et al.
    Lorentzon, Mattias
    Lehtimaki, Terho
    Eriksson, Joel
    Kahonen, Mika
    Raitakari, Olli
    Laaksonen, Marika
    Sievanen, Harri
    Viikari, Jorma
    Lyytikainen, Leo-Pekka
    Mellstrom, Dan
    Karlsson, Magnus
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Grundberg, Elin
    Kemp, John P.
    Sayers, Adrian
    Nethander, Maria
    Evans, David M.
    Vandenput, Liesbeth
    Tobias, Jon H.
    Ohlsson, Claes
    Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 2, p. e1003247-Article in journal (Refereed)
    Abstract [en]

    Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6x10(-14); LOC285735, rs271170, p = 2.7x10(-12); OPG, rs7839059, p = 1.2x10(-10); and ESR1/C6orf97, rs6909279, p = 1.1x10(-9)). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9x10(-9)). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.

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  • 107. Rajzbaum, Gerald
    et al.
    Jakob, Franz
    Karras, Dimitrios
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lems, Willem
    Langdahl, Bente
    Fahrleitner-Pammer, Astrid
    Walsh, J
    Gibson, Anthony
    Tynan, Aodán
    Marin, Fernando
    Characterization of patients in the European Forsteo Observational Study (EFOS): postmenopausal women entering teriparatide treatment in a community setting2008In: Current Medical Research and Opinion, ISSN 0300-7995, E-ISSN 1473-4877, Vol. 24, no 2, p. 377-384Article in journal (Refereed)
    Abstract [en]

    Objective: The European Forsteo* Observational Study (EFOS) study was primarily designed to assess fracture incidence, degree of pain, health-related quality of life (HRQoL) and compliance in women prescribed teriparatide in a community setting. This report describes the design of the study and characteristics of the patients at entry.

    Methods: At entry, 1645 postmenopausal women with a diagnosis of osteoporosis and about to initiate teriparatide treatment were enrolled in eight European countries. Baseline data were collected on demographic characteristics, medical and osteoporosis history, disease status, prior use of medications and HRQoL.

    Results: The mean (standard deviation [SD]) age of patients was 71.5 (8.4) years, lumbar spine bone mineral density (BMD) Tscore was –3.3 (1.2), the mean number of previous fractures reported after 40 years of age was 2.9 (2.0), 70% had two or more vertebral deformities and 91.7% were pre-treated with bisphosphonates. HRQoL, evaluated by the health state value (HSV) (median: 0.59, Q1; Q3: 0.08; 0.71) and visual analogue scale (VAS) (median 50.0, Q1; Q3: 35.0; 69.0) status of the European quality of life questionnaire (EQ5D) was poor. Extreme problems were reported by 31% of patients for the pain/discomfort dimension, mobility was limited in 69% and anxiety/depression was reported by 57% of patients. Chronic or intermittent back pain was reported by 91% of patients, which occurred every day or almost every day within the last month in 66% of patients.

    Conclusions: The post-menopausal women prescribed teriparatide were severely osteoporotic, with a high fracture risk and poor HRQoL, despite previous therapy for osteoporosis. Moderate to severe back pain was very common.

  • 108.
    Ribom, Eva L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Hyperkyphosis and back pain are not associated with prevalent vertebral fractures in women with osteoporosis2015In: Physiotherapy Theory and Practice, ISSN 0959-3985, E-ISSN 1532-5040, Vol. 31, no 3, p. 182-185Article in journal (Refereed)
    Abstract [en]

    Vertebral fractures (VFs) are the clinical consequence of spinal osteoporosis and may be associated with back pain and aggravated kyphosis. However, the relative importance of VFs as an underlying cause of kyphosis and chronic back pain is not known. The aim of this study was to investigate the relationship between prevalent VFs and the size of kyphosis, and back pain in osteoporotic women. Thirty-six women, aged 74.6 +/- 8.3 years, were consecutively recruited from the osteoporosis unit at Uppsala University Hospital. The patients had 1-9 radiographic verified VFs. Tragus wall distance (TWD) and numeric rating scale were used to measure kyphosis and pain. All patients had a hyperkyphosis (TWD >= 10 cm). Notably, there were no associations between numbers or location of VFs versus size of kyphosis (rho = 0.15, p = 0.4; rho = -0.27, p = 0.12) or severity of back pain (rho = -0.08, p = 0.66; rho = 0.16, p = 0.35). Furthermore, no association was evident between kyphosis and back pain (rho = -0.02, p = 0.89). There was, however, an association between size of kyphosis and age (R = 0.44, p = 0.008). In conclusion, these data suggest that prevalent VFs are not significantly associated with kyphosis or chronic back pain, in patients with manifest spinal osteoporosis.

  • 109.
    Ribom, Eva L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Mellström, Dan
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Magnus K.
    Population-based reference values of handgrip strength and functional tests of muscle strength and balance in men aged 70-80 years2011In: Archives of gerontology and geriatrics (Print), ISSN 0167-4943, E-ISSN 1872-6976, Vol. 53, no 2, p. E114-E117Article in journal (Refereed)
    Abstract [en]

    With aging, the incidence of falls and fractures increases. There has during the last decades been secular changes in demographics so that the proportion of elderly increases in society. Hence, there is an increasing need for clinicians to be able to make a solid appraisal of the elderly patient's functional capacity, as to identify individuals with an increased risk to fall. If high risk individuals could be targeted fall preventive strategies might be implemented in specific risk cohorts. This would require reference values for muscle strength tests and functional tests, in order to defined high risk individuals performing inferior. From the MrOS Sweden cohort, 999 subjects aged 70-80 years were evaluated. Muscle strength and functional performance was tested by timed-stands test, 6-m and 20-cm narrow walk tests and Jamar handgrip strength test. Normative data is presented. With increasing age, there was a 10-18% successively decline in performance throughout the entire age span. This study provides reference values for handgrip strength and functional muscle tests in 70-80 years old men. The decline in the test values with increasing age, infer the use of age-specific normative data when using these tests both in clinical and research settings.

  • 110.
    Ribom, Eva L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Piehl-Aulin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Naessen, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Six months of hormone replacement therapy does not influence muscle strength in postmenopausal women2002In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 42, no 3, p. 225-31Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Postmenopausal hormone replacement therapy (HRT) has positive effects on fracture incidence before any effects on bone mineral density can be demonstrated. This has been attributed to increased muscle strength by HRT. This study was designed to evaluate the effect of 6 months of HRT on muscle strength in postmenopausal women. METHODS: Forty postmenopausal women, aged 60-78 were included in the study. They were randomly divided in two groups with 20 women in each group. One group received Menorest 50 microg/24 h (estradiol 4.3 mg) and Gestapuran 2.5 mg (medroxyprogesteron) daily and the other group received placebo treatment. The study was conducted as a double blinded, prospective and placebo controlled trial. Hand grip strength, isokinetic knee flexion and extention, and physical activity were measured before treatment, after 3 and 6 months. Physical activity was estimated using a classification system of physical activity. A JAMAR hydraulic hand dynamometer and a Cybex II dynamometer were used to evaluate muscle strength. RESULTS: Hand grip strength in the right hand, increased significantly in both groups (HRT P<0.001 and placebo P<0.01) and in the left hand in the HRT group (P<0.01). However, there were no differences in muscle strength between the two groups. There was no significant change in isokinetic knee flexion or extension after 6 months in either of the groups. The estimated physical activity increased slightly in the placebo group, but there was no significant difference compared to the treatment group. CONCLUSIONS: Our data suggest that 6 months of HRT does not influence muscle strength in postmenopausal women.

  • 111.
    Ribom, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Piehl-Aulin, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunghall, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bratteby, Lars-Eric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Samuelson, Gösta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Muscle strength correlates with total body bone mineral density in young women but not in men2004In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 14, no 1, p. 24-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Osteoporosis is a growing health problem. One of the proposed reasons for this is a more sedentary lifestyle. The aim of this study was to investigate the associations between muscle strength and total body bone mineral density (TBMD) in young adults at expected peak bone mass. METHODS: Sixty-four women and 61 men (total 125) 21 years of age were included. Handgrip strength, isokinetic knee-flexion and -extension muscle strength, TBMD, and body composition were measured. RESULTS: Univariate regression analyses showed that knee flexion and extension explained almost 30% of the variation in TBMD in women, whereas handgrip strength was not associated with TBMD. In men, no correlation between any measures of muscle strength and TBMD was evident. Stepwise regression analysis showed that knee-flexion and -extension muscle strength in women were associated with TBMD, R2=0.27. In men, lean body mass, fat mass, weight, and height were predictors for TBMD, R2=0.43, whereas muscle strength did not affect the prediction of TBMD. CONCLUSIONS: Muscle strength at weight-bearing sites is related to TBMD in women, whereas body composition is related to TBMD in men. The association of lower limb strength on TBMD only in young women indicates a gender difference.

  • 112. Rizzoli, R
    et al.
    Eisman, J A
    Norquist, J
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Krishnarajah, G
    Lim, S-K
    Chandler, J
    Risk factors for vitamin D inadequacy among women with osteoporosis: an international epidemiological study2006In: International journal of clinical practice (Esher), ISSN 1368-5031, E-ISSN 1742-1241, Vol. 60, no 8, p. 1013-1019Article in journal (Refereed)
    Abstract [en]

    A serum 25-hydroxyvitamin D [25(OH)D] level of 75 nmol/l (30 ng/ml) has been proposed as the minimum for adequate vitamin D nutrition as lower levels are associated with increases in serum parathyroid hormone in otherwise healthy adults. Amongst 2589 community-dwelling, postmenopausal women with osteoporosis from 18 countries, recruited to determine risk factors for vitamin D inadequacy, 64% had vitamin D inadequacy. General health, education, ethnicity, sun exposure, skin reactivity, diet, recent travel to sunny climates, vitamin D supplementation, body mass index (BMI), season and latitude were assessed using logistic regression models. Asian ethnicity, BMI >= 30 kg/m(2), living in non-equatorial countries, inadequate vitamin D supplementation, poor/fair health, no education about vitamin D, skin reactivity and no recent travel to sunny areas were significant predictors. Several modifiable risk factors are associated with vitamin D inadequacy worldwide, suggesting potentially simple ways to increase vitamin D and improve bone health in postmenopausal women.

  • 113.
    Robinson-Cohen, Cassianne
    et al.
    Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol, Nashville, TN 37232 USA.
    Bartz, Traci M.
    Univ Washington, Cardiovasc Hlth Res Unit, Dept Biostat, Seattle, WA 98195 USA;Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA.
    Lai, Dongbing
    Indiana Univ, Dept Med, Indianapolis, IN 46204 USA;Indiana Univ, Dept Mol Genet, Indianapolis, IN 46204 USA.
    Ikizler, T. Alp
    Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol, Nashville, TN 37232 USA.
    Peacock, Munro
    Imel, Erik A.
    Michos, Erin D.
    Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA.
    Foroud, Tatiana M.
    Indiana Univ, Dept Med, Indianapolis, IN 46204 USA;Indiana Univ, Dept Mol Genet, Indianapolis, IN 46204 USA.
    Åkesson, Kristina
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Taylor, Kent D.
    Harbor Univ Calif, Los Angeles Med Ctr, Los Angeles Biomed Res Inst Harbor, Dept Pediat,Inst Translat Gen & Populat Sci, Torrance, CA USA.
    Malmgren, Linnea
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Matsushita, Kunihiro
    Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA;Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA;Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA.
    Nethander, Maria
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Med,Bioinformat Core Facil, Gothenburg, Sweden.
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med & Clin N, Gothenburg, Sweden.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med & Clin N, Gothenburg, Sweden.
    Mellström, Daniel
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med & Clin N, Gothenburg, Sweden.
    Wolf, Myles
    Duke Univ, Sch Med, Div Nephrol, Dept Med, Durham, NC USA;Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    McGuigan, Fiona
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Rotter, Jerome I.
    Harbor Univ Calif, Los Angeles Med Ctr, Los Angeles Biomed Res Inst Harbor, Dept Pediat,Inst Translat Gen & Populat Sci, Torrance, CA USA.
    Karlsson, Magnus
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Econs, Michael J.
    Indiana Univ, Dept Med, Indianapolis, IN 46204 USA;Indiana Univ, Dept Mol Genet, Indianapolis, IN 46204 USA.
    Ix, Joachim H.
    Univ Calif San Diego, Dept Med, Div Nephrol Hypertens, San Diego, CA 92103 USA;Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA.
    Lutsey, Pamela L.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA.
    Psaty, Bruce M.
    Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA;Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA;Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA.
    de Boer, Ian H.
    Univ Washington, Kidney Res Inst, Div Nephrol, Dept Med, Seattle, WA 98195 USA.
    Kestenbaum, Bryan R.
    Univ Washington, Kidney Res Inst, Div Nephrol, Dept Med, Seattle, WA 98195 USA.
    Genetic Variants Associated with Circulating Fibroblast Growth Factor 232018In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 29, no 10, p. 2583-2592Article in journal (Refereed)
    Abstract [en]

    Background: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.

    Methods: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m(2) to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.

    Results: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0x10(-24)), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.

    Conclusions: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

  • 114. Rosengren, Björn E
    et al.
    Ribom, Eva L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Jan-Åke
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ohlsson, Claes
    Mellström, Dan
    Lorentzon, Mattias
    Stefanick, Marcia
    Lapidus, Jodi
    Leung, Ping Chung
    Kwok, Anthony
    Barrett-Connor, Elizabeth
    Orwoll, Eric
    Karlsson, Magnus K
    Inferior physical performance test results of 10,998 men in the MrOS Study is associated with high fracture risk2012In: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 41, no 3, p. 339-344Article in journal (Refereed)
    Abstract [en]

    Background: most fractures are preceded by falls.

    Objective: the aim of this study was to determine whether tests of physical performance are associated with fractures.

    Subjects: a total of 10,998 men aged 65 years or above were recruited.

    Methods: questionnaires evaluated falls sustained 12 months before administration of the grip strength test, the timed stand test, the six-metre walk test and the twenty-centimetre narrow walk test. Means with 95% confidence interval (95% CI) are reported. P < 0.05 is a statistically significant difference.

    Results: fallers with a fracture performed worse than non-fallers on all tests (all P < 0.001). Fallers with a fracture performed worse than fallers with no fractures both on the right-hand-grip strength test and on the six-metre walk test (P < 0.001). A score below -2 standard deviations in the right-hand-grip strength test was associated with an odds ratio of 3.9 (95% CI: 2.1-7.4) for having had a fall with a fracture compared with having had no fall and with an odds ratio of 2.6 (95% CI: 1.3-5.2) for having had a fall with a fracture compared with having had a fall with no fracture.

    Conclusion: the right-hand-grip strength test and the six-metre walk test performed by old men help discriminate fallers with a fracture from both fallers with no fracture and non-fallers.

  • 115. Rosengren, Björn
    et al.
    Ribom, Eva L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Jan-Åke
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ohlsson, Claes
    Mellstrom, Dan
    Lorentzon, Mattias
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Stefanick, Marcia L.
    Lapidus, Jodi
    Leung, Ping Chung
    Kwok, Anthony
    Barrett-Connor, Elizabeth
    Orwoll, Eric
    Karlsson, Magnus K.
    There is in elderly men a group difference between fallers and non-fallers in physical performance tests2011In: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 40, no 6, p. 744-749Article in journal (Refereed)
  • 116. Sarwar, Nadeem
    et al.
    Butterworth, Adam S.
    Freitag, Daniel F.
    Gregson, John
    Willeit, Peter
    Gorman, Donal N.
    Gao, Pei
    Saleheen, Danish
    Rendon, Augusto
    Nelson, Christopher P.
    Braund, Peter S.
    Hall, Alistair S.
    Chasman, Daniel I.
    Tybjaerg-Hansen, Anne
    Chambers, John C.
    Benjamin, Emelia J.
    Franks, Paul W.
    Clarke, Robert
    Wilde, Arthur A. M.
    Trip, Mieke D.
    Steri, Maristella
    Witteman, Jacqueline C. M.
    Qi, Lu
    van der Schoot, C. Ellen
    de Faire, Ulf
    Erdmann, Jeanette
    Stringham, Heather M.
    Koenig, Wolfgang
    Rader, Daniel J.
    Melzer, David
    Reich, David
    Psaty, Bruce M.
    Kleber, Marcus E.
    Panagiotakos, Demosthenes B.
    Willeit, Johann
    Wennberg, Patrik
    Woodward, Mark
    Adamovic, Svetlana
    Rimm, Eric B.
    Meade, Tom W.
    Gillum, Richard F.
    Shaffer, Jonathan A.
    Hofman, Albert
    Onat, Altan
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wassertheil-Smoller, Sylvia
    Mellstrom, Dan
    Gallacher, John
    Cushman, Mary
    Tracy, Russell P.
    Kauhanen, Jussi
    Karlsson, Magnus
    Salonen, Jukka T.
    Wilhelmsen, Lars
    Amouyel, Philippe
    Cantin, Bernard
    Best, Lyle G.
    Ben-Shlomo, Yoav
    Manson, JoAnn E.
    Davey-Smith, George
    de Bakker, Paul I. W.
    O'Donnell, Christopher J.
    Wilson, James F.
    Wilson, Anthony G.
    Assimes, Themistocles L.
    Jansson, John-Olov
    Ohlsson, Claes
    Tivesten, Asa
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Reilly, Muredach P.
    Hamsten, Anders
    Ingelsson, Erik
    Cambien, Francois
    Hung, Joseph
    Thomas, G. Neil
    Boehnke, Michael
    Schunkert, Heribert
    Asselbergs, Folkert W.
    Kastelein, John J. P.
    Gudnason, Vilmundur
    Salomaa, Veikko
    Harris, Tamara B.
    Kooner, Jaspal S.
    Allin, Kristine H.
    Nordestgaard, Borge G.
    Hopewell, Jemma C.
    Goodall, Alison H.
    Ridker, Paul M.
    Holm, Hilma
    Watkins, Hugh
    Ouwehand, Willem H.
    Samani, Nilesh J.
    Kaptoge, Stephen
    Di Angelantonio, Emanuele
    Harari, Olivier
    Danesh, John
    Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies2012In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 379, no 9822, p. 1205-1213Article in journal (Refereed)
    Abstract [en]

    Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.

    Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.

    Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.

    Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

  • 117.
    Siilin, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ljunggren, Osten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundgren, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Disturbances of calcium homeostasis consistent with mild primary hyperparathyroidism in premenopausal women and associated morbidity2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 1, p. 47-53Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Primary hyperparathyroidism (PHPT) and associated morbidity are comprehensively assessed in elderly females; however, less is known of the disease in younger women. OBJECTIVES: Our objectives were to estimate the prevalence of mild disturbances in calcium homeostasis, which could be analogous with early PHPT, in a premenopausal population, and determine the potential presence of associated morbidity. DESIGN: Initial results from this longitudinal study are from 2002-2004. SETTING: We conducted a population-based screening of serum (s)-calcium in conjunction with routine mammography. PARTICIPANTS: Participants included premenopausal women, 40-50 yr of age (n = 1900). Cases fulfilling previously evaluated biochemical criteria for PHPT (n=214) were matched to controls (n = 214). MAIN OUTCOME MEASUREMENTS: All participants underwent investigation, including screening of parameters of calcium homeostasis, dual x-ray absorptiometry, and body mass index assessment, and filled out extensive health and quality of life (SF-36) questionnaires. Participants were divided into four groups depending on the relation between s-calcium/intact PTH. Statistical comparisons between cases and controls as well as among the four groups were performed to evaluate morbidity. RESULTS: The prevalence of assumed mild PHPT, i.e. inappropriate intact PTH value in relation to total s-calcium, was estimated to be 5.1% (n = 96). Women with mild disturbances in calcium homeostasis had statistically significant lower bone mineral density in the proximal femur and femoral neck, higher body mass index, and lower scores for vitality and general health in the analysis of SF-36. CONCLUSIONS: Mild disturbances in calcium homeostasis in premenopausal women were more prevalent than previously thought and were associated with obesity, lower bone mineral density, and decreased quality of life.

  • 118.
    Silfverswärd, Carl-Johan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Frost, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Brändström, Helena
    Department of Medical Sciences.
    Nilsson, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Ljunggren, Osten
    Department of Medical Sciences.
    Interleukin-4 and interleukin-13 potentiate interleukin-1 induced secretion of interleukin-6 in human osteoblast-like cells.2004In: J Orthop Res, ISSN 0736-0266, Vol. 22, no 5, p. 1058-62Article in journal (Refereed)
  • 119.
    Sisask, Gregor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sundgren-Andersson, Anna
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation2013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 54, no 1, p. 126-132Article in journal (Refereed)
    Abstract [en]

    Fracture healing is a complex interplay between endochondral and intramembranous bone formation processes. The canonical Wnt/β-catenin pathway enhances new bone formation and may play a role in fracture healing. Glycogen synthase kinase 3β (GSK3β) is a key regulator of β-catenin degradation. In this study, we investigate the effects of AZD2858, an orally bioactive GSK3 inhibitor, on fracture healing. Femoral fractures were produced in rats after the insertion of a femoral nail. The rats were treated with oral administration of AZD2858 at a dose of 30μmol/kg (20mg/kg) daily for up to 3weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3weeks, histological analysis was performed, and at the 2 and 3week time points, we performed peripheral quantitative computed tomography (pQCT), X-rays, and four-point bending tests. Peripheral QCT showed an increase in both mineral density (of 28% at 2weeks and 38% at 3weeks) and mineral content (of 81% at 2weeks and 93% at 3weeks) in the calluses from AZD2858 treated animals as compared to vehicle treated animals. Histological analysis demonstrated that rats treated with GSK3 inhibitor healed their fractures rapidly, but without the pre-formation of cartilage tissue. Furthermore, four-point bending tests of fractured femora from animals treated for 2 and 3weeks showed an increase in strength in treated animals compared to their vehicle-treated controls. In conclusion, AZD2858, a potent GSK3 inhibitor, has a substantial impact on fracture healing. The fractures healed with a bony callus without an obvious endochondral component, suggesting that AZD2858 drives mesenchymal cells into the osteoblastic pathway. This leads to direct bone repair in an unstable fracture milieu.

  • 120.
    Spangeus, A.
    et al.
    Linkoping Univ Hosp, Linkoping, Sweden..
    Akesson, K.
    Lund Univ, Skane Univ Hosp, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Banefelt, J.
    Quantify Res, Stockholm, Sweden..
    Karlsson, L.
    Quantify Res, Stockholm, Sweden..
    Ortsater, G.
    Quantify Res, Stockholm, Sweden..
    Libanati, C.
    UCB Pharma, Brussels, Belgium..
    Toth, E.
    UCB Pharma, Brussels, Belgium..
    Strom, O.
    Quantify Res, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    The Treatment Gap After Fracture In Osteoporosis Patients In Sweden2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 72-72Article in journal (Other academic)
  • 121.
    Sten, Sabine
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Archaeology and Ancient History, Archaeology.
    Lovén, Christian
    Riksarkivet,Box 12541, SE-10229 Stockholm, Sweden..
    Kjellström, Anna
    Stockholms Univ, Inst Arkeologi Antikens kultur, Osteologiska Skningslab, SE-10691 Stockholm, Sweden..
    Liden, Kerstin
    Stockholms Univ, Inst Arkeologi Antikens kultur, Arkeologiska Skningslabo, SE-10691 Stockholm, Sweden..
    Vretemark, Maria
    Västergotlands Museum, SE-53232 Skara, Sweden..
    Hongslo Vala, Cecilie
    Univ Goteborgs, Enheten Geriatrik Inst Medicin, Sahlgrenska Akademin, SE-40530 Gothenburg, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Fjällstrom, Markus
    Uppsala Univ, Arkeol Forskningslab, SE-75185 Uppsala, Sweden..
    Shalabi, Adel
    Bild­ och funktionsmedicinskt centrum, Akademiska sjukhuset, Uppsala, Sweden..
    Duvernoy, Olov
    Bild­ och funktionsmedicinskt centrum, Akademiska sjukhuset, Uppsala, Sweden..
    Segelsjö, Monica
    Bild­ och funktionsmedicinskt centrum, Akademiska sjukhuset, Uppsala, Sweden..
    Malmström, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Jakobsson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Erik den heliges skelett2016In: Fornvännen, ISSN 0015-7813, E-ISSN 1404-9430, Vol. 111, no 1, p. 27-40Article in journal (Refereed)
    Abstract [en]

    Saint Erik was King of Sweden for a few years up to 1160, when he was killed. A skeleton attributed to him is kept in Uppsala Cathedral. It underwent scientific reappraisal in 2014. The analyses included computer tomography, Xray absorptiometry, isotope analysis and DNA sampling. Radiocarbon confirms the alleged age of the bones. They belong to a 35-40-year-old man in excellent physical shape. The many wounds that he received in connection with his death fit surprisingly well with the saint's legend, whose preserved version was written 130 years after the event.

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  • 122.
    Sundh, D.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Geriatr Med, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Geriatr Med, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Karlsson, M. K.
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Lund, Sweden.;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden..
    Ohlsson, C.
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden..
    Nilsson, M.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Geriatr Med, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden..
    Nilsson, A. G.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Geriatr Med, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden..
    Lorentzon, M.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Geriatr Med, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden..
    Low serum vitamin D is associated with higher cortical porosity in elderly men2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, no 5, p. 496-508Article in journal (Refereed)
    Abstract [en]

    BackgroundBone loss at peripheral sites in the elderly is mainly cortical and involves increased cortical porosity. However, an association between bone loss at these sites and 25-hydroxyvitamin D has not been reported. ObjectiveTo investigate the association between serum levels of 25-hydroxyvitamin D, bone microstructure and areal bone mineral density (BMD) in elderly men. MethodsA population-based cohort of 444 elderly men (mean SD age 80.2 3.5 years) was investigated. Bone microstructure was measured by high-resolution peripheral quantitative computed tomography, areal BMD by dual-energy X-ray absorptiometry and serum 25-hydroxyvitamin D and parathyroid hormone levels by immunoassay. ResultsMean cortical porosity at the distal tibia was 14.7% higher (12.5 +/- 4.3% vs. 10.9 +/- 4.1%, P < 0.05) whilst cortical volumetric BMD, area, trabecular bone volume fraction and femoral neck areal BMD were lower in men in the lowest quartile of vitamin D levels compared to the highest. In men with vitamin D deficiency (<25 nmol L-1) or insufficiency [25-49 nmol L-1, in combination with an elevated serum level of parathyroid hormone (>6.8 pmol L-1)], cortical porosity was 17.2% higher than in vitamin D-sufficient men (P < 0.01). A linear regression model including age, weight, height, daily calcium intake, physical activity, smoking vitamin D supplementation and parathyroid hormone showed that 25-hydroxyvitamin D independently predicted cortical porosity (standardized = -0.110, R-2 = 1.1%, P = 0.024), area ( = 0.123, R-2 = 1.4%, P = 0.007) and cortical volumetric BMD ( = 0.125, R-2 = 1.4%, P = 0.007) of the tibia as well as areal BMD of the femoral neck ( = 0.102, R-2 = 0.9%, P = 0.04). ConclusionSerum vitamin D is associated with cortical porosity, area and density, indicating that bone fragility as a result of low vitamin D could be due to changes in cortical bone microstructure and geometry.

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  • 123. Svensson, Johan
    et al.
    Carlzon, Daniel
    Petzold, Max
    Karlsson, Magnus K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Tivesten, Åsa
    Mellström, Dan
    Ohlsson, Claes
    Both Low and High Serum IGF-I Levels Associate with Cancer Mortality in Older Men2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 12, p. 4623-4630Article in journal (Refereed)
    Abstract [en]

    Background: Although recent population-based studies suggest a U-shaped relationship between serum IGF-I concentration and all-cause mortality, the distribution of death causes underlying this association remains unclear. We hypothesized that high IGF-I levels associate with increased cancer mortality, whereas low IGF-I levels associate with increased cardiovascular disease (CVD) mortality. Methods: Serum IGF-I levels were measured in 2901 elderly men (mean age 75.4, range 69-81 yr) included in the prospective population-based Osteoporotic Fractures in Men Study (Sweden) study. Mortality data were obtained from central registers with no loss of follow-up. The statistical analyses included Cox proportional hazards regressions with or without a spline approach. Results: During the follow-up (mean 6.0 yr), 586 of the participants died (cancer deaths, n = 211; CVD deaths, n = 214). As expected, our data revealed a U-shaped association between serum IGF-I levels and all-cause mortality. Low as well as high serum IGF-I (quintile 1 or 5 vs. quintiles 2-4) associated with increased cancer mortality [hazard ratio (HR) = 1.86, 95% confidence interval (CI) = 1.34-2.58; and HR = 1.90, 95% CI = 1.37-2.65, respectively]. Only low serum IGF-I associated with increased CVD mortality (quintile 1 vs. quintiles 2-4, HR = 1.48,95% CI = 1.08-2.04). These associations remained after adjustment for multiple covariates and exclusion of men who died during the first 2 yr of follow-up. Conclusions: Our findings demonstrate that both low and high serum IGF-I levels are risk markers for increased cancer mortality in older men. Moreover, low IGF-I levels associate with increased CVD mortality. (J Clin Endocrinol Metab 97: 4623-4630, 2012)

  • 124. Svensson, Johan
    et al.
    Karlsson, Magnus K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Tivesten, Asa
    Mellstrom, Dan
    Moverare-Skrtic, Sofia
    Leukocyte telomere length is not associated with mortality in older men2014In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 57, p. 6-12Article in journal (Refereed)
    Abstract [en]

    Leukocyte telomere length (LTL) is related to the aging of somatic cells. We hypothesized that LTL is inversely associated with mortality in elderly men. LTL was measured in 2744 elderly men (mean age 75.5, range 69-81 years) included in the prospective population-based MrOS-Sweden study. Mortality data were obtained from national health registers with no loss of follow-up. During the follow-up (mean 6.0 years), 556 (20%) of the participants died. Using Cox proportional hazards regression, tertile of LTL did not associate with all-cause mortality [tertile 1 (shortest) or 2 (middle) vs. tertile 3 (longest); hazard ratio (HR) = 1.05, 95% confidence interval (CI) 0.85-1.28 and HR = 0.97, 95% CI 0.79-1.19, respectively]. Furthermore, LTL did not associate with cancer (197 events) or cardiovascular disease (CVD, 206 events) mortality (tertile 1 vs. tertile 3; HR = 0.94, 95% CI 0.67-1.34 and HR = 0.94, 95% CI 0.68-1.30, respectively). The lack of association between LTL and mortality remained also after adjustment for multiple covariates. Our results demonstrate that LTL is not associated with all-cause mortality or mortality due to cancer or CVD in elderly men. Further studies are needed to determine whether LTL can predict the risk of mortality in elderly women.  

  • 125. Swanson, Charlotte
    et al.
    Mellström, Dan
    Lorentzon, Mattias
    Vandenput, Liesbeth
    Jakobsson, Jenny
    Rane, Anders
    Karlsson, Magnus
    Ljunggren, Osten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Smith, Ulf
    Eriksson, Anna-Lena
    Bélanger, Alain
    Labrie, Fernand
    Ohlsson, Claes
    The uridine diphosphate glucuronosyltransferase 2B15 D85Y and 2B17 deletion polymorphisms predict the glucuronidation pattern of androgens and fat mass in men2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 12, p. 4878-4882Article in journal (Refereed)
    Abstract [en]

    Context: Previous in vitro studies have demonstrated that the UDP glucuronosyltransferase (UGT) 2B15 and UGT2B17 glucuronidate androgens and their metabolites. Objective: Our objective was to determine in vivo whether the UGT2B15 (DY)-Y-85 and the UGT2B17 deletion polymorphisms predict androgen glucuronidation and body composition. Participants: Two population-based cohorts including young adult (n = 1068; age = 18.9 yr) and elderly ( n = 1001; age = 75.3 yr) men were included in the study. Main Outcome Measures: Serum and urine levels of testosterone ( T) and dihydrotestosterone (DHT) were measured by gas chromatography-mass spectrometry, and serum levels of the major glucuronidated androgen metabolites androstane-3 alpha, 17 beta- diol(androstanediol)-3-glucuronide, androstanediol-17-glucuronide, and androsterone-glucuronide were measured by liquid chromatography-tandem mass spectrometry. Body composition was measured by dual-energy x-ray absorptiometry. Results: Both the UGT2B15 D85Y and the UGT2B17 deletion polymorphisms were associated with serum levels of androstanediol-ediol-17-glucuronide (P < 0.001) but not with levels of androstanediol-3-glucuronide or androsterone-glucuronide in both cohorts. Glucuronidation of T and DHT was associated with the UGT2B17 deletion but not with the UGT2B15 (DY)-Y-85 polymorphism, suggested by strong associations between the deletion polymorphism and urine levels of these two hormones. Both polymorphisms were associated with several different measures of fat mass ( P < 0.01). The UGT2B17 deletion polymorphism was associated with insulin sensitivity ( P < 0.05) as indicated by the homeostasis model assessment index. Conclusions: The UGT2B15 D85Y and the UGT2B17 deletion polymorphisms are both predictors of the glucuronidation pattern of androgens/androgen metabolites. Our findings indicate that UGT2B17 is involved in 17- glucuronidation of mainly T but also of DHT and androstanediol and that UGT2B15 is involved in the 17- glucuronidation of androstanediol. Furthermore, these two polymorphisms are predictors of fat mass in men.

  • 126. Tivesten, Asa
    et al.
    Vandenput, Liesbeth
    Carlzon, Daniel
    Nilsson, Maria
    Karlsson, Magnus K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Barrett-Connor, Elizabeth
    Mellstrom, Dan
    Ohlsson, Claes
    Dehydroepiandrosterone and its Sulfate Predict the 5-Year Risk of Coronary Heart Disease Events in Elderly Men2014In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 64, no 17, p. 1801-1810Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory. OBJECTIVES This study tested the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events in a large cohort of elderly men. METHODS We used gas and liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years). Complete cardiovascular clinical outcomes were available from national Swedish registers. RESULTS During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality. CONCLUSIONS Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.

  • 127. Tivesten, Åsa
    et al.
    Mellström, Dan
    Jutberger, Hans
    Fagerberg, Björn
    Lernfelt, Bodil
    Orwoll, Eric
    Karlsson, Magnus K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ohlsson, Claes
    Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden2007In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 50, no 11, p. 1070-1076Article in journal (Refereed)
    Abstract [en]

    Objectives: This study sought to determine whether serum levels of testosterone and estradiol associate with lower extremity peripheral arterial disease (PAD) in a large population-based cohort of elderly men. Background: Few studies have explored the relationship between serum sex steroids and lower extremity PAD in men. Methods: The Swedish arm of the MrOS (Osteoporotic Fractures in Men) study (n = 3,014; average age 75.4 years) assessed ankle-brachial index (ABI) and defined lower extremity PAD as ABI <0.90. Radioimmunoassay measured serum levels of total testosterone, estradiol, and sex hormone-binding globulin, and we calculated free testosterone and free estradiol levels from the mass action equations. Results: A linear regression model including age, current smoking, previous smoking, diabetes, hypertension, body mass index, free testosterone, and free estradiol showed that free testosterone independently and positively associates with ABI (p < 0.001), whereas free estradiol independently and negatively associates with ABI (p < 0.001). Logistic regression analyses showed that free testosterone in the lowest quartile (vs. quartiles 2 to 4; odds ratio [OR] 1.65, 95% confidence interval [CI] 1.22 to 2.23, p = 0.001) and free estradiol in the highest quartile (vs. quartiles 1 to 3; OR 1.45, 95% CI 1.09 to 1.94, p = 0.012) independently associate with lower extremity PAD. Conclusions: This cross-sectional study shows for the first time that low serum testosterone and high serum estradiol levels associate with lower extremity PAD in elderly men. Future prospective and interventional studies are needed to establish possible causal relationships between sex steroids and the development of lower extremity PAD in men.

  • 128. Tivesten, Åsa
    et al.
    Vandenput, Liesbeth
    Labrie, Fernand
    Karlsson, Magnus K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mellström, Dan
    Ohlsson, Claes
    Low serum testosterone and estradiol predict mortality in elderly men2009In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, no 7, p. 2482-2488Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Age-related reduction of serum testosterone may contribute to the signs and symptoms of aging, but previous studies report conflicting evidence about testosterone levels and male mortality. No large prospective cohort study has determined a possible association between serum estradiol and mortality in men. OBJECTIVE: The main objective was to examine the association between serum testosterone and estradiol and all-cause mortality in elderly men. DESIGN, SETTING, AND PARTICIPANTS: We used specific gas chromatography-mass spectrometry to analyze serum sex steroids at baseline in older men who participated in the prospective population-based MrOS Sweden cohort (n = 3014; mean age, 75 yr; range, 69-80 yr). MAIN OUTCOME MEASURE: All-cause mortality by serum testosterone and estradiol levels. RESULTS: During a mean follow-up period of 4.5 yr, 383 deaths occurred. In multivariate hazards regression models, low levels (within quartile 1 vs. quartiles 2-4) of both testosterone [hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.29-2.12] and estradiol (HR, 1.54; 95% CI, 1.22-1.95) associated with mortality. A model including both hormones showed that both low testosterone (HR, 1.46; 95% CI, 1.11-1.92) and estradiol (HR, 1.33; 95% CI, 1.02-1.73) predicted mortality. Risk of death nearly doubled (HR, 1.96; 95% CI, 1.46-2.62) in subjects with low levels of both testosterone and estradiol compared with subjects within quartiles 2-4 of both hormones. CONCLUSIONS: Elderly men with low serum testosterone and estradiol have increased risk of mortality, and subjects with low values of both testosterone and estradiol have the highest risk of mortality.

  • 129. van Meurs, Joyce B. J.
    et al.
    Trikalinos, Thomas A.
    Ralston, Stuart H.
    Balcells, Susana
    Brandi, Maria Luisa
    Brixen, Kim
    Kiel, Douglas P.
    Langdahl, Bente L.
    Lips, Paul
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lorenc, Roman
    Obermayer-Pietsch, Barbara
    Ohlsson, Claes
    Pettersson, Ulrika
    Reid, David M.
    Rousseau, Francois
    Scollen, Serena
    Van Hul, Wim
    Agueda, Lidia
    Åkesson, Kristina
    Benevolenskaya, Lidia I.
    Ferrari, Serge L.
    Hallmans, Goran
    Hofman, Albert
    Husted, Lise Bjerre
    Kruk, Marcin
    Kaptoge, Stephen
    Karasik, David
    Karlsson, Magnus K.
    Lorentzon, Mattias
    Masi, Laura
    McGuigan, Fiona E. A.
    Mellström, Dan
    Mosekilde, Leif
    Nogues, Xavier
    Pols, Huibert A. P.
    Reeve, Jonathan
    Renner, Wilfried
    Rivadeneira, Fernando
    van Schoor, Natasja M.
    Weber, Kurt
    Ioannidis, John P. A.
    Uitterlinden, Andre G.
    Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis2008In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 299, no 11, p. 1277-1290Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

  • 130. Vandenput, Liesbeth
    et al.
    Labrie, Fernand
    Mellström, Dan
    Swanson, Charlotte
    Knutsson, Thomas
    Peeker, Ralph
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Orwoll, Eric
    Eriksson, Anna L
    Damber, Jan-Erik
    Ohlsson, Claes
    Serum levels of specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men2007In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 22, no 2, p. 220-227Article in journal (Refereed)
    Abstract [en]

    Androgens are important regulators of bone and prostate health in elderly men. The role of serum levels of glucuronidated androgen metabolites as predictors of BMD and prostate volume in men is unclear. We show that specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men.Introduction: Androgens are important regulators of bone and prostate health in elderly men. Local synthesis and degradation of androgens are likely to be important parameters of biological action of androgens in androgen-responsive tissues. The aim of this study was to determine the role of serum levels of glucuronidated androgen metabolites as predictors of BMD and prostate volume in elderly men.Materials and Methods: A subsample of the population-based Swedish part of the MrOS study (n = 631, average age = 75.9 years) was investigated. Bone parameters were measured using DXA. Serum levels of total testosterone (T) and dihydrotestosterone (DHT) were measured by gas chromatography/mass spectroscopy (GC-MS); androstane-3,17-diol-3glucuronide (3G) and androstane-3,17-diol-17glucuronide (17G) were measured by liquid chromatography/mass spectroscopy. Prostate volume (n = 159) was measured by transrectal ultrasound.Results: The general pattern is that two of the glucuronidated androgen metabolites, namely 17G and 3G, are stronger positive predictors of BMD than the bioactive androgens (T and DHT). In addition, 17G is a clear positive predictor of prostate volume, explaining 4.5% of the variance in prostate volume, whereas the bioactive androgens do not display any association with prostate volume.Conclusions: Serum levels of specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men. Future studies should determine if the glucuronidated androgen metabolites also reflect other biological correlates of androgenic activity, including prostate cancer, and if low levels might be a marker of general androgen deficiency in men.

  • 131.
    Vandenput, Liesbeth
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden..
    Mellstrom, Dan
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, Gothenburg, Sweden..
    Laughlin, Gail A.
    Univ Calif San Diego, Sch Med, Dept Family Med & Publ Hlth, Div Epidemiol, La Jolla, CA 92093 USA..
    Cawthon, Peggy M.
    Univ Calif San Francisco, Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA..
    Cauley, Jane A.
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA..
    Hoffman, Andrew R.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Karlsson, Magnus K.
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Lund, Sweden.;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden..
    Rosengren, Bjorn E.
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Lund, Sweden.;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Nethander, Maria
    Univ Gothenburg, Sahlgrenska Acad, Bioinformat Core Facil, Gothenburg, Sweden..
    Eriksson, Anna L.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden..
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, Gothenburg, Sweden..
    Leung, Jason
    Chinese Univ Hong Kong, Prince Wales Hosp, Jockey Club Ctr Osteoporosis Care & Control, Shatin, Hong Kong, Peoples R China..
    Kwok, Timothy
    Chinese Univ Hong Kong, Prince Wales Hosp, Jockey Club Ctr Osteoporosis Care & Control, Shatin, Hong Kong, Peoples R China..
    Orwoll, Eric S.
    Oregon Hlth & Sci Univ, Dept Med, Bone & Mineral Unit, Portland, OR 97201 USA..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Vita Straket 11, SE-41345 Gothenburg, Sweden..
    Low Testosterone, but Not Estradiol, Is Associated With Incident Falls in Older Men: The International MrOS Study2017In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 32, no 6, p. 1174-1181Article in journal (Refereed)
    Abstract [en]

    Fracture risk is determined by bone strength and the risk of falls. The relationship between serum sex steroids and bone strength parameters in men is well known, whereas the predictive value of sex steroids for falls is less studied. The aim of this study was to assess the associations between serum testosterone (T) and estradiol (E2) and the likelihood of falls. Older men (aged > 65 years) from the United States (n = 1919), Sweden (n = 2495), and Hong Kong (n = 1469) participating in the Osteoporotic Fractures in Men Study had baseline T and E2 analyzed by mass spectrometry. Bioavailable (Bio) levels were calculated using mass action equations. Incident falls were ascertained every 4 months during a mean follow-up of 5.7 years. Associations between sex steroids and falls were estimated by generalized estimating equations. Fall rate was highest in the US and lowest in Hong Kong (US 0.50, Sweden 0.31, Hong Kong 0.12 fall reports/person/year). In the combined cohort of 5883 men, total T (odds ratio [OR] per SD increase = 0.88, 95% confidence interval [CI] 0.86-0.91) and BioT (OR = 0.86, 95% CI 0.83-0.88) were associated with incident falls in models adjusted for age and prevalent falls. These associations were only slightly attenuated after simultaneous adjustment for physical performance variables (total T: OR = 0.94, 95% CI 0.91-0.96; BioT: OR = 0.91, 95% CI 0.89-0.94). E2, BioE2, and sex hormone-binding globulin (SHBG) were not significantly associated with falls. Analyses in the individual cohorts showed that both total T and BioT were associated with falls in MrOS US and Sweden. No association was found in MrOS Hong Kong, and this may be attributable to environmental factors rather than ethnic differences because total T and BioT predicted falls in MrOS US Asians. In conclusion, low total T and BioT levels, but not E2 or SHBG, are associated with increased falls in older men.

  • 132. Vandenput, Liesbeth
    et al.
    Mellström, Dan
    Karlsson, Magnus K.
    Orwoll, Eric
    Labrie, Fernand
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ohlsson, Claes
    Serum estradiol is associated with lean mass in elderly Swedish men2010In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 162, no 4, p. 737-745Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Association studies in men have shown that androgens are inversely related to fat measures, while the relation between sex steroids and lean mass remains unclear. We, therefore, investigated the associations between serum sex steroid levels and body composition in elderly men with a main focus on lean mass measures. DESIGN AND METHODS: A cross-sectional survey of a population-based cohort of 3014 elderly men, aged 69-80 years (Osteoporotic Fractures in Men study, Sweden). Serum levels of testosterone and estradiol (E(2)) were measured by mass spectrometry, sex hormone-binding globulin (SHBG) levels were measured by IRMA, and measures of body composition were obtained by dual-energy X-ray absorptiometry. RESULTS: Total as well as free serum testosterone associated independently inversely (P<0.001), while total as well as free serum E(2) associated independently directly (P<0.001) with total body fat mass and trunk fat mass. Serum SHBG associated independently inversely with central fat distribution. Serum E(2) and free E(2) but not serum testosterone or free testosterone levels associated positively with lean mass (P<0.01). Elderly men within the lowest quartile of free E(2) had 0.5 kg less lean mass in the legs than subjects within the highest quartile, while the subjects in the different quartiles of free testosterone did not differ in lean mass. CONCLUSIONS: Serum E(2), but not serum testosterone, is directly associated with lean mass in this large study of elderly Swedish men. In addition, serum SHBG is associated with central fat distribution and we confirmed that serum testosterone is inversely associated with fat mass.

  • 133. Vandenput, Liesbeth
    et al.
    Mellström, Dan
    Lorentzon, Mattias
    Swanson, Charlotte
    Karlsson, Magnus K.
    Brandberg, John
    Lönn, Lars
    Orwoll, Eric
    Smith, Ulf
    Labrie, Fernand
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tivesten, Åsa
    Ohlsson, Claes
    Androgens and glucuronidated androgen metabolites are associated with metabolic risk factors in men2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 11, p. 4130-4137Article in journal (Refereed)
    Abstract [en]

    Context: Androgens are associated with metabolic risk factors in men. However, the independent impact of androgens and androgen metabolites on metabolic risk factors in men is unclear. Objective: Our objective was to determine the predictive value of serum levels of androgens and glucuronidated androgen metabolites for metabolic risk factors. Design and Study Subjects: We conducted a population-based study of two Swedish cohorts (1068 young adult and 1001 elderly men). Main Outcome Measures: We measured correlation of serum dihydrotestosterone (DHT), testosterone (T), and glucuronidated androgen metabolites with fat mass, fat distribution, serum lipids, and insulin resistance. Results: Both DHT and T were negatively associated with different measures of fat mass in both cohorts (P < 0.001). Further statistical analysis indicated that DHT, but not T, was independently negatively associated with different measures of fat mass and insulin resistance (P < 0.001). The glucuronidated androgen metabolite androstane-3α,17β-diol- 17glucuronide (17G) was independently positively associated with fat mass (P < 0.001). Most importantly, the 17G to DHT ratio was strongly correlated, not only with fat mass but also with central fat distribution, intrahepatic fat, disturbed lipid profile, insulin resistance, and diabetes, explaining a substantial part of the total variance in total body fat (12% in young adult men, 15% in elderly men), the homeostasis model assessment index (10%), and high-density lipoprotein cholesterol (7%). Conclusion: Our findings demonstrate that 17-glucuronidation of the DHT metabolite androstane-3α,17β-diol is strongly associated with several metabolic risk factors in men. Future longitudinal studies are required to determine the possible impact of the 17G to DHT ratio as a metabolic risk factor in men.

  • 134. Vimaleswaran, Karani S
    et al.
    Cavadino, Alana
    Berry, Diane J
    Jorde, Rolf
    Dieffenbach, Aida Karina
    Lu, Chen
    Alves, Alexessander Couto
    Heerspink, Hiddo J Lambers
    Tikkanen, Emmi
    Eriksson, Joel
    Wong, Andrew
    Mangino, Massimo
    Jablonski, Kathleen A
    Nolte, Ilja M
    Houston, Denise K
    Ahluwalia, Tarunveer Singh
    van der Most, Peter J
    Pasko, Dorota
    Zgaga, Lina
    Thiering, Elisabeth
    Vitart, Veronique
    Fraser, Ross M
    Huffman, Jennifer E
    de Boer, Rudolf A
    Schöttker, Ben
    Saum, Kai-Uwe
    McCarthy, Mark I
    Dupuis, Josée
    Herzig, Karl-Heinz
    Sebert, Sylvain
    Pouta, Anneli
    Laitinen, Jaana
    Kleber, Marcus E
    Navis, Gerjan
    Lorentzon, Mattias
    Jameson, Karen
    Arden, Nigel
    Cooper, Jackie A
    Acharya, Jayshree
    Hardy, Rebecca
    Raitakari, Olli
    Ripatti, Samuli
    Billings, Liana K
    Lahti, Jari
    Osmond, Clive
    Penninx, Brenda W
    Rejnmark, Lars
    Lohman, Kurt K
    Paternoster, Lavinia
    Stolk, Ronald P
    Hernandez, Dena G
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mellström, Dan
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Tzoulaki, Ioanna
    McLachlan, Stela
    Theodoratou, Evropi
    Tiesler, Carla M T
    Jula, Antti
    Navarro, Pau
    Wright, Alan F
    Polasek, Ozren
    Wilson, James F
    Rudan, Igor
    Salomaa, Veikko
    Heinrich, Joachim
    Campbell, Harry
    Price, Jacqueline F
    Karlsson, Magnus
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bandinelli, Stefania
    Frayling, Timothy M
    Hartman, Catharina A
    Sørensen, Thorkild I A
    Kritchevsky, Stephen B
    Langdahl, Bente Lomholt
    Eriksson, Johan G
    Florez, Jose C
    Spector, Tim D
    Lehtimäki, Terho
    Kuh, Diana
    Humphries, Steve E
    Cooper, Cyrus
    Ohlsson, Claes
    März, Winfried
    de Borst, Martin H
    Kumari, Meena
    Kivimaki, Mika
    Wang, Thomas J
    Power, Chris
    Brenner, Hermann
    Grimnes, Guri
    van der Harst, Pim
    Snieder, Harold
    Hingorani, Aroon D
    Pilz, Stefan
    Whittaker, John C
    Järvelin, Marjo-Riitta
    Hyppönen, Elina
    Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study2014In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 2, no 9, p. 719-729Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk.

    METHODS: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium.

    FINDINGS: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002).

    INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.

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  • 135. Waern, Ewa
    et al.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Lerner, Ulf
    Lewerin, Catharina
    Johansson, Helena
    Ensrud, Kristine
    Karlsson, Magnus
    Orwoll, Eric
    Lorentzon, Mattias
    Herlitz, Hans
    Ohlsson, Claes
    Mellström, Dan
    High Serum Cystatin C Predicts Incident Hip Fracture in Elderly Men: MROS Sweden2012In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 23, no 2, p. S334-S334Article in journal (Other academic)
  • 136. Walsh, J. Bernard
    et al.
    Lems, Willem F.
    Karras, Dimitrios
    Langdahl, Bente L.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fahrleitner-Pammer, Astrid
    Barrett, Annabel
    Rajzbaum, Gerald
    Jakob, Franz
    Marin, Fernando
    Effectiveness of Teriparatide in Women Over 75 Years of Age with Severe Osteoporosis: 36-Month Results from the European Forsteo Observational Study (EFOS)2012In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 90, no 5, p. 373-383Article in journal (Refereed)
    Abstract [en]

    This predefined analysis of the European Forsteo Observational Study (EFOS) aimed to describe clinical fracture incidence, back pain, and health-related quality of life (HRQoL) during 18 months of teriparatide treatment and 18 months post-teriparatide in the subgroup of 589 postmenopausal women with osteoporosis aged a parts per thousand yen75 years. Data on clinical fractures, back pain (visual analogue scale, VAS), and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. A repeated-measures model analyzed changes from baseline in back pain VAS and EQ-VAS. During the 36-month observation period, 87 (14.8 %) women aged a parts per thousand yen75 years sustained a total of 111 new fractures: 37 (33.3 %) vertebral fractures and 74 (66.7 %) nonvertebral fractures. Adjusted odds of fracture was decreased by 80 % in the 30 to < 36-month interval compared with the first 6-month interval (P < 0.009). Although the older subgroup had higher back pain scores and poorer HRQoL at baseline than the younger subgroup, both age groups showed significant reductions in back pain and improvements in HRQoL postbaseline. In conclusion, women aged a parts per thousand yen75 years with severe postmenopausal osteoporosis treated with teriparatide in normal clinical practice showed a reduced clinical fracture incidence by 30 months compared with baseline. An improvement in HRQoL and, possibly, an early and significant reduction in back pain were also observed, which lasted for at least 18 months after teriparatide discontinuation when patients were taking other osteoporosis medication. The results should be interpreted in the context of an uncontrolled observational study.

  • 137.
    Westerberg, Per-Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Larsson, T. E.
    Ohlsson, C.
    Tivesten, A.
    Mellstrom, D.
    Karlsson, M. K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Variation in the klotho gene is not associated with mortality risk among elderly men in MR OS Sweden2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Suppl 1, p. S103-S104Article in journal (Other academic)
    Abstract [en]

    Polymorphisms in the Klotho (Kl) gene, which is central for vitamin D regulation by fibroblast growth factor 23 (FGF23), have been associated with longevity, coronary disease and stroke. The CC genotype of the single nucleotide polymorphism (SNP) rs577912 in the Kl-gene is associated with decreased Kl expression, as well as increased mortality in end stage renal disease. We examined if SNP in the Kl-gene was associated with mortality in the community derived cohort of 70 to 80 year old males of MrOS Sweden (N = 3014).

    High throughput genotyping of the KLOTHO SNPs was achieved by use of SequenomR MassEXTEND/Mass/ARRAY technology. 2738 subjects had a valid result for rs577912: CC 73.1% and CA + AA 26.9%. There were no differences in the serum levels of FGF23, phosphate, parathyroid hormone or renal function between genotypes CC and CA + AA. During a follow-up of a median of 4.5 years there were 337 deaths, 253 (12.6%) in the CC group and 84 (11.4%) in the CA + AA group. With log rank analysis there were no differences in mortality between the genotypes for all cause mortality (P = 0.39) or cardiovascular mortality (P = 0.60). None of the other SNPs in the Kl gene was associated with mortality in this cohort either.

    Conclusion:

    There is no association between the SNP rs577912 in the Kl-gene and mortality among elderly men.

  • 138.
    Westerberg, Per-Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Eklöf, Hampus
    Bild- och funktionsmedicinskt centrum, Akademiska sjukhuset, Uppsala.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Osteomalaci på grund av tumörorsakad fosfatbrist: Fokus på FGF23 i fysiologi och klinik2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 32-33, p. 1414-1416Article in journal (Other academic)
    Abstract [en]

    Oncogenic osteomalacia is a rare syndrome caused by a small tumor, of mesenchymal origin, that produces FGF23. FGF23 is a recently described bone derived factor closely regulated by calcitriol and phosphate load. In a feedback loop it increases renal phosphate loss and decreases calcitriol activation. Unregulated production of FGF23 by a tumor causes negative phosphate balance and deficient mineralization of the skeleton, with pain and fractures as a consequence. We have used determination of a venous gradient of FGF23 as an aid in localizing FGF23 producing tumors in 10 cases. In eight cases the tumor has been removed, one patient awaits further examination and in one case it has not been possible to localize the tumor.

  • 139.
    Westerberg, Per-Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Vanderschueren, Dirk
    Katholieke Universiteit, Leuven.
    Billen, Jaak
    Jans, Ivo
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Oncogenic osteomalacia illustrating the effects of fibroblast factor 23 on phospahte homeostasis2012In: Clinical Kidney Journal, ISSN 2048-8505, Vol. 5, no 3, p. 240-243Article in journal (Refereed)
    Abstract [en]

    In oncogenic osteomalacia (OOM), fibroblast growth factor 23 (FGF23) induces renal phosphate wasting and inhibits the appropriate increase of calcitriol. A patient suffering from OOM is described. Serum calcium, phosphate, biointact parathyroid hormone and intact FGF23 as well as the calcitriol and 24,25-vitamin D levels were measured before and after tumour removal. The clinical approach to a patient with hypophosphataemia is discussed and the changes in mineral metabolism after removal of a FGF23-producing tumour are described.

  • 140.
    Westerberg, Per-Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Wikström, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Larsson, Tobias E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Regulation of fibroblast growth factor-23 in chronic kidney disease2007In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 22, no 11, p. 3202-3207Article in journal (Refereed)
    Abstract [en]

    Background

    Fibroblast growth factor-23 (FGF23) is a circulatingfactor that regulates the renal reabsorption of inorganic phosphate(Pi) and is increased in chronic kidney disease (CKD). The aimof the current investigation was to study the regulation ofFGF23 in CKD subjects with various degree of renal function.As such, we analysed the relationship between FGF23, Pi, calcium,parathyriod hormone (PTH), 25(OH) vitamin D3(25(OH)D3), 1,25(OH)2vitamin D3(1,25(OH)2D3) and estimated glomerular filtrationrate (eGFR).

    Methods

    Intact FGF23 and other biochemical variables were analysedin 72 consecutive adult out-patients with various stages ofCKD (eGFR ranging from 4–96 ml/min.) Association studieswere performed using linear univariate and multivariate analysis.

    Results

    FGF23 was significantly elevated at CKD stage 4 (266± 315 pg/ml, P < 0.001) and 5 (702 ± 489 pg/ml,P < 0.001) compared with CKD 1–2 (46 ± 43 pg/ml).In CKD 4–5 an independent association between log FGF23and Pi (P < 0.001), 25(OH)D3 (P < 0.05) as well as eGFR(P < 0.01) was observed. In contrast, in CKD 1–3 logPTH (P < 0.05) was the only independent predictor of logFGF23 in multivariate analysis. In CKD 1–5, Pi (P <0.00001) and log PTH (P < 0.01) were explanatory variablesfor log FGF23 in multivariate analysis.

    Conclusions

    We conclude that serum FGF23 increases in CKD 4–5,in parallel with the emerging hyperphosphataemia. Serum Pi isthe most important predictor of FGF23 when GFR is less than30 ml/min. In contrast, our data suggest that Pi may not bean important determinant of FGF23 in normophosphataemic CKDsubjects. Finally, the association between FGF23 and PTH inCKD may suggest a co-regulation that remains to be further elucidated.

  • 141.
    Westerberg, Per-Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine. County Hospital, Jönköping, Sweden.
    Sterner, Gunnar
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Isaksson, Elin
    Elvarson, Fjölnir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dezfoolian, Hamid
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    High doses of cholecalciferol alleviate the progression of hyperparathyroidism in patients with CKD Stages 3-4: results of a 12-week double-blind, randomized, controlled study2018In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 33, no 3, p. 466-471Article in journal (Refereed)
    Abstract [en]

    Background: Calcidiol insufficiency may accelerate the development of secondary hyperparathyroidism (SHPT). We tested the effect of a substantial increase in calcidiol on mineral metabolism in patients with chronic kidney disease (CKD).

    Methods: Ninety-five patients with CKD Stages 3-4, parathyroid hormone (PTH) above 6.8 pmol/L and calcidiol below 75 nmol/L were randomized to receive either cholecalciferol 8000 IU/day or placebo for 12 weeks. The primary endpoint was difference in the mean change in iPTH after 12 weeks. The proportion of participants having a 30% reduction in PTH and the effect on hand grip strength, fatigue and different biochemical variables were also investigated.

    Results: Baseline calcidiol was 57.5 ± 22 and 56.8 ± 22 nmol/L in the cholecalciferol and placebo groups, respectively. The corresponding concentrations of PTH were 10.9 ± 5 and 13.1 ± 9 pmol/L. Calcidiol increased to 162 ± 49 nmol/L in patients receiving cholecalciferol, and PTH levels remained constant at 10.5 ± 5 pmol/L. In the placebo group, calcidiol remained stable and PTH increased to 15.2 ± 11 pmol/L. The mean change in PTH differed significantly between the two groups (P < 0.01). The proportion of subjects reaching a 30% decrease in PTH did not differ. No effect on grip strength, fatigue, phosphate or fibroblast growth factor 23 was observed. Cholecalciferol treatment resulted in stable calcium concentrations and a substantial increase in calcitriol.

    Conclusion: Treatment with high daily doses of cholecalciferol in patients with CKD Stages 3-4 halts the progression of SHPT and does not cause hypercalcaemia or other side effects.

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  • 142.
    Westerberg, Per-Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Tivesten, Åsa
    Wallenberg Laboratory for Cardiovascular Research, University of Göteborg, Göteborg, .
    Karlsson, Magnus
    Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences and Orthopedic Surgery, Lund University, Skåne University Hospital, Sweden..
    Mellström, Dan
    Center for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, the Sahlgrenska Academy at Göteborg University, Göteborg, Sweden..
    Eric, Orwoll
    Oregon Health and Science University, Portland, Oregon, USA..
    Ohlsson, Claes
    Center for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, the Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Larsson, Tobias
    Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm,.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs)2013In: BMC Nephrology, ISSN 1471-2369, E-ISSN 1471-2369, Vol. 14, p. 85-Article in journal (Refereed)
    Abstract [en]

    Background: Fibroblast growth factor 23 (FGF23) is the earliest marker of disturbed mineral metabolism as renal function decreases. Its serum levels are associated with mortality in dialysis patients, persons with chronic kidney disease (CKD) and prevalent cardiovascular disease (CVD), and it is associated with atherosclerosis, endothelial dysfunction and left ventricular hypertrophy in the general population. The primary aim of this study is to examine the association between FGF23 and mortality, in relation to renal function in the community. A secondary aim is to examine the association between FGF23 and CVD related death. Methods: The population-based cohort of MrOS Sweden included 3014 men (age 69-81 years). At inclusion intact FGF23, intact parathyroid hormone (PTH), 25 hydroxyl vitamin D (25D), calcium and phosphate were measured. Mortality data were collected after an average of 4.5 years follow-up. 352 deaths occurred, 132 of CVD. Association between FGF23 and mortality was analyzed in quartiles of FGF23. Kaplan-Meier curves and Log-rank test were used to examine time to events. Cox proportional hazards regression was used to examine the association between FGF23, in quartiles and as a continuous variable, with mortality. The associations were also analyzed in the sub-cohort with estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73 m(2). Results: There was no association between FGF23 and all-cause mortality, Hazard ratio (HR) 95% confidence interval (CI): 1.02 (0.89-1.17). For CVD death the HR (95% CI) was 1.26 (0.99 - 1.59)/(1-SD) increase in log(10) FGF23 after adjustment for eGFR, and other confounders. In the sub-cohort with eGFR > 60 ml/min/1.73 m(2) the HR (95% CI) for CVD death was 55% (13-111)/(1-SD) increase in log(10) FGF23. Conclusions: FGF23 is not associated with mortality of all-cause in elderly community living men, but there is a weak association with CVD death, even after adjustment for eGFR and the other confounders. The association with CVD death is noticeable only in the sub-cohort with preserved renal function.

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  • 143. Wilson, Scott G.
    et al.
    Jones, Michelle R.
    Mullin, Ben H.
    Dick, Ian M.
    Richards, J. Brent
    Pastinen, Tomi M.
    Grundberg, Elin
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Surdulescu, Gabriela L.
    Dudbridge, Frank
    Elliott, Katherine S.
    Cervino, Alessandra C. L.
    Spector, Timothy D.
    Prince, Richard L.
    Common sequence variation in FLNB regulates bone structure in women in the general population and FLNB mRNA expression in osteoblasts in vitro2009In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 24, no 12, p. 1989-1997Article in journal (Refereed)
    Abstract [en]

    Previous data from our group indicate that BMD is linked to chromosome 3p14-p21. Because the filamin B (FLNB gene resides in this region, is the cause of skeletal dysplasias, and was identified among the top genes in our bioinformatics analysis, we hypothesized a role for FLNB in the regulation of bone structure in the general population. Using a tag single nucleotide polymorphism (SNP) approach, a family study of 767 female sibs in which the 3p14-p21 linkage with BMD was previously shown was examined. FLNB variants showing a BMD association were tested in two additional data sets, a study of 1085 UK female twins and a population study (CAIFOS) of 1315 Australian women. Genotype-expression studies were performed in 96 human osteoblast lines to examine the variants in vitro. rs7637505, rs9822918, rs2177153, and rs2001972 showed association with femoral neck (p = 0.0002-0.02) in the family-based study. The twin study provided further support for an association between rs7637505 and femoral neck and spine BMD (p = 0.02-0.03). The CAIFOS study further suggested an association between rs2177153 and rs9822918 and femoral neck BMD (p = 0.004-0.03). Prevalent fractures were increased in carriers of the A allele of rs2177153 (p = 0.009). In vitro studies showed association between rs11130605, itself in strong LD with rs7637505, and FLNB mRNA expression. These findings suggest common variants in FLNB have effects on bone structure in women. Although the location of variants having effects is not entirely consistent, variation at the 5' end of the gene may reflect effects on levels of FLNB transcription efficiency.

  • 144.
    Zayny, Ahmad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Almokhtar, Mokhtar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wikvall, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Kibar, Pinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of glucocorticoids on vitamin D3-metabolizing 24-hydroxylase (CYP24A1) in Saos-2 cells and primary human osteoblasts2019In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 496, article id 110525Article in journal (Refereed)
    Abstract [en]

    Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2 cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D-3 metabolism. These bone cells exhibited CYP24A1-mediated 24-hydroxylation which is essential for deactivation of the active vitamin form. However, bioactivating vitamin D-3 hydroxylase activities could not be detected in either of these cells. Several glucocorticoids, including prednisolone, down regulated CYP24A1 mRNA and CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblasts. Also, prednisolone significantly suppressed a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells co-transfected with the glucocorticoid receptor. Thus, the results of the present study show suppression by glucocorticoids on CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. As part of this study we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid with glucocorticoid activity, which can bind the glucocorticoid receptor. Our data showing suppression by glucocorticoids on CYP24A1 expression in human osteoblasts suggest a previously unknown mechanism for effects of glucocorticoids in human bone, where these compounds may interfere with regulation of active vitamin D levels.

  • 145.
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    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands.;NCHA, NCI, NL-2593 Leiden, Netherlands..
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    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Hsu, Yi-Hsiang
    Inst Aging Res, HebrewSenior Life, Roslindale, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Harvard Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA 02115 USA..
    Yerges-Armstrong, Laura M.
    Univ Maryland, Program Personalized & Genom Med, Baltimore, MD 21201 USA.;Univ Maryland, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA..
    Chou, Wen-Chi
    Inst Aging Res, HebrewSenior Life, Roslindale, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst, Cambridge, MA 02142 USA..
    Stolk, Lisette
    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands.;NCHA, NCI, NL-2593 Leiden, Netherlands..
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    Tel Aviv Univ, Sackler Fac Med, Dept Anat & Anthropol, IL-6997801 Tel Aviv, Israel.;Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus, London WC2R 2LS, England..
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    Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
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    Univ Lausanne, Dept Med Genet, CH-1011 Lausanne, Switzerland.;Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland.;Univ Inst Social & Prevent Med, Ctr Hosp Univ CHUV, CH-1010 Lausanne, Switzerland..
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    Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA..
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    Univ Lausanne, Dept Med Genet, CH-1011 Lausanne, Switzerland.;Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland.;Univ Inst Social & Prevent Med, Ctr Hosp Univ CHUV, CH-1010 Lausanne, Switzerland..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 OQQ, England..
    Malkin, Ida
    Tel Aviv Univ, Sackler Fac Med, Dept Anat & Anthropol, IL-6997801 Tel Aviv, Israel..
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    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Smith, Albert V.
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland..
    Thorleifsson, Gudmar
    Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.;deCODE Genet, IS-101 Reykjavik, Iceland..
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, SE-40530 Gothenburg, Sweden..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 OQQ, England..
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    Imperial Coll, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England.;Ealing Hosp NHS Trust, Cardiol Dept, Middlesex UB1 3HW, England..
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    Ernst Moritz Arndt Univ Greifswald, Dept Med A, D-17489 Greifswald, Germany..
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    Lund Univ, Dept Clin Sci, S-22362 Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, S-20502 Malmo, Sweden..
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    Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
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    NIH, Phoenix Epidemiol & Clin Res Branch, Natl Inst Diabet & Digest & Kidney Dis, Phoenix, AZ 85014 USA..
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    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Saffron Walden CB10 1SA, Essex, England.;Addenbrookes Hosp, NIHR Cambridge Biomed Res Ctr, Inst Met Sci, Cambridge CB2 OQQ, England.;Univ Cambridge, Addenbrookes Hosp, Inst Met Sci, Metab Res Labs, Cambridge CB2 OQQ, England..
    Bennett, David A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
    Bertram, Lars
    Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt, Inst Neurogenet & Expt & Integrat Gen, D-23562 Lubeck, Germany.;Imperial Coll London, Fac Med, Sch Publ Hlth, London W6 8RP, England..
    Biffar, Rainer
    Ernst Moritz Arndt Univ Greifswald, Ctr Oral Hlth, Dept Prosthet Dent Gerodontol & Biomat, D-17489 Greifswald, Germany..
    Bochud, Murielle
    Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland.;Univ Inst Social & Prevent Med, Ctr Hosp Univ CHUV, CH-1010 Lausanne, Switzerland..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Borecki, Ingrid B.
    Washington Univ, Div Stat Gen, Dept Genet, Sch Med, St Louis, MO 63110 USA.;Washington Univ, Div Biostat, Sch Med, St Louis, MO 63110 USA..
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    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
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    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland..
    Obanda, Natalia Campos
    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands..
    Cauley, Jane A.
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA..
    Cawthon, Peggy M.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA..
    Cederberg, Henna
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Chen, Zhao
    Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ 85714 USA..
    Cho, Nam H.
    Ajou Univ, Sch Med, Dept Prevent Med, Suwon 16499, South Korea..
    Choi, Hyung Jin
    Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 03080, South Korea.;Chungbuk Natl Univ Hosp, Dept Internal Med, Cheongju, South Korea..
    Claussnitzer, Melina
    Inst Aging Res, HebrewSenior Life, Roslindale, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst, Cambridge, MA 02142 USA.;MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.;Tech Univ Munich, Inst Human Genet, MRI, D-81675 Munich, Germany.;Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA..
    Collins, Francis
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, Bethesda, MD 20892 USA..
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    Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA..
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    Harvard Med Sch, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiatr Genom, Boston, MA 02115 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
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    Charite, Res Grp Geriatr, Berlin Aging Study 2, D-13353 Berlin, Germany.;Charite, Inst Med & Human Genet, D-13353 Berlin, Germany..
    Dhonukshe-Rutten, Rosalie A. M.
    Wageningen Univ, Dept Human Nutr, POB 17, NL-6700 AA Wageningen, Netherlands..
    Diatchenko, Luda
    McGill Univ, Alan Edwards Ctr Res Pain, Montreal H3A 0G1, PQ, Canada.;Univ N Carolina, Sch Dent, Reg Ctr Neurosensory Disorders, Chapel Hill, NC 27599 USA..
    Eiriksdottir, Gudny
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland..
    Enneman, Anke W.
    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands..
    Erdos, Mike
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, Bethesda, MD 20892 USA..
    Eriksson, Johan G.
    Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki 00014, Finland.;Univ Helsinki, Cent Hosp, Unity Gen Practice, Helsinki 00014, Finland.;Folkhalsan Res Ctr, Helsinki 00250, Finland.;Vasa Cent Hosp, Vaasa 65130, Finland.;Nat Inst Hlth & Welf, Helsinki 00271, Finland..
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, SE-40530 Gothenburg, Sweden..
    Estrada, Karol
    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
    Evans, Daniel S.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA..
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    Washington Univ, Div Stat Gen, Dept Genet, Sch Med, St Louis, MO 63110 USA..
    Fu, Mao
    Univ Maryland, Program Personalized & Genom Med, Baltimore, MD 21201 USA.;Univ Maryland, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA..
    Garcia, Melissa
    Natl Inst Aging, Intramural Res Program, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA..
    Gieger, Christian
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Rese Unit Mol Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany..
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    Univ Calif Riverside, Inst Integrat Genome Biol, Dept Bot & Plant Sci, Riverside, CA 92521 USA.;Univ Calif Riverside, Dept Bot & Plant Sci, Riverside, CA 92521 USA..
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    Boston Univ, Sch Med & Publ Hlth, Dept Med, Boston, MA 02118 USA.;Boston Univ, Sch Med & Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA..
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    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Rese Unit Mol Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Univ Calif Riverside, Dept Bot & Plant Sci, Riverside, CA 92521 USA.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, CCG Type Diabet 2, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, CCG Nutrigen & Type Diabet 2, D-85764 Neuherberg, Germany..
    Grewal, Jagvir
    Ealing Hosp NHS Trust, Cardiol Dept, Middlesex UB1 3HW, England.;Imperial Coll London, Natl Heart & Lung Inst, London SW3 6LY, England..
    Han, Bok-Ghee
    Osong Hlth Technol Adm Complex, Ctr Genome Sci, Natl Inst Hlth, Chungcheongbuk Do 28159, South Korea..
    Hanson, Robert L.
    NIH, Phoenix Epidemiol & Clin Res Branch, Natl Inst Diabet & Digest & Kidney Dis, Phoenix, AZ 85014 USA..
    Hayward, Caroline
    Univ Edinburgh, IGMM, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland..
    Hofman, Albert
    NCHA, NCI, NL-2593 Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
    Hoffman, Eric P.
    SUNY Binghamton, Dept Pharmaceut Sci, Binghamton, NY 13902 USA..
    Homuth, Georg
    Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Gen, D-17487 Greifswald, Germany..
    Hsueh, Wen-Chi
    NIH, Phoenix Epidemiol & Clin Res Branch, Natl Inst Diabet & Digest & Kidney Dis, Phoenix, AZ 85014 USA..
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    George Washington Univ, Dept Exercise & Nutr Sci, Washington, DC 20052 USA.;Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20052 USA..
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    Univ Calif Berkeley, Div Biostat, Sch Publ Hlth, Berkeley, CA 94720 USA..
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    Duke Univ, Sch Med, Div Rheumatol, Dept Med,Duke Mol Physiol Inst, Durham, NC 27710 USA..
    Husted, Lise B.
    Aarhus Univ Hosp, Endocrinol & Internal Med, DK-8000 Aarhus, Denmark..
    Illig, Thomas
    Helmholtz Zentrum Munchen, Rese Unit Mol Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Hannover Med Sch, Dept Human Genet, D-30625 Hannover, Germany.;Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany..
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    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA..
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    Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17489 Greifswald, Germany..
    Jansson, John-Olov
    Univ Gothenburg, Dept Physiol, Inst Neurosci & Physiol, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden..
    Jordan, Joanne M.
    Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC 27517 USA..
    Jula, Antti
    Nat Inst Hlth & Welf, Helsinki 00271, Finland..
    Karlsson, Magnus
    Lund Univ, Dept Clin Sci & Orthopaed, Skane Univ Hosp SUS, S-22362 Malmo, Sweden..
    Khaw, Kay-Tee
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Kilpainen, Tuomas O.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 OQQ, England.;Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, DK-2100 Copenhagen, Denmark.;Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, New York, NY 10029 USA..
    Klopp, Norman
    Helmholtz Zentrum Munchen, Rese Unit Mol Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany..
    Kloth, Jacqueline S. L.
    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands..
    Koistinen, Heikki A.
    Univ Helsinki, Dept Med, Helsinki 00029, Finland.;Helsinki Univ Cent Hosp, Helsinki 00029, Finland.;Univ Helsinki, Abdominal Ctr, Endocrinol, Helsinki 00029, Finland.;Natl Inst Hlth & Welf, Dept Hlth, Helsinki 00271, Finland.;Minerva Fdn, Helsinki 00290, Finland..
    Kraus, William E.
    Duke Univ, Sch Med, Div Cardiol, Dept Med,Duke Mol Physiol Inst, Durham, NC 27710 USA..
    Kritchevsky, Stephen
    Sticht Ctr Aging, Wake Forest Sch Med, Winston Salem, NC 27157 USA..
    Kuulasmaa, Teemu
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Lahti, Jari
    Univ Helsinki, Inst Behav Sci, FI-00014 Helsinki, Finland..
    Lang, Thomas
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Langdahl, Bente L.
    Aarhus Univ Hosp, Endocrinol & Internal Med, DK-8000 Aarhus, Denmark..
    Launer, Lenore J.
    Natl Inst Aging, Intramural Res Program, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA..
    Lee, Jong-Young
    Osong Hlth Technol Adm Complex, Ctr Genome Sci, Natl Inst Hlth, Chungcheongbuk Do 28159, South Korea..
    Lerch, Markus M.
    Ernst Moritz Arndt Univ Greifswald, Dept Med A, D-17489 Greifswald, Germany..
    Lewis, Joshua R.
    Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia.;Univ Sydney, Ctr Kidney Res, Sch Publ Hlth, Sydney, NSW 2006, Australia..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden..
    Lindgren, Cecilia
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Liu, Yongmei
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27517 USA..
    Liu, Tian
    Max Planck Inst Mol Genet, D-14195 Berlin, Germany.;Max Planck Inst Human Dev, D-14195 Berlin, Germany..
    Liu, Youfang
    Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC 27517 USA..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, SE-40530 Gothenburg, Sweden..
    Luben, Robert N.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Maixner, William
    Univ N Carolina, Sch Dent, Reg Ctr Neurosensory Disorders, Chapel Hill, NC 27599 USA..
    McGuigan, Fiona E.
    Lund Univ, Dept Clin Sci, S-22362 Malmo, Sweden..
    Medina-Gomez, Carolina
    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
    Meitinger, Thomas
    Tech Univ Munich, Inst Human Genet, MRI, D-81675 Munich, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, D-85764 Neuherberg, Germany..
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Mellstrom, Dan
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, SE-40530 Gothenburg, Sweden..
    Melov, Simon
    Buck Inst Res Aging, Novato, CA 94945 USA.;Univ Southern Calif, Leonard Davis Sch Gerontol, Los Angeles, CA 90089 USA..
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Mitchell, Braxton D.
    Univ Maryland, Program Personalized & Genom Med, Baltimore, MD 21201 USA.;Univ Maryland, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA.;Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Liverpool, Inst Tradit Med, Liverpool L69 3BX, Merseyside, England..
    Mosekilde, Leif
    Aarhus Univ Hosp, Endocrinol & Internal Med, DK-8000 Aarhus, Denmark..
    Newman, Anne
    Univ Pittsburgh, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA..
    Nielson, Carrie M.
    Oregon Hlth & Sci Univ, Portland, OR 97239 USA..
    O'Connell, Jeffrey R.
    Univ Maryland, Program Personalized & Genom Med, Baltimore, MD 21201 USA.;Univ Maryland, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA..
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    Erasmus MC, Dept Clin Genet, NL-300 CA Rotterdam, Netherlands.;Ctr Med Syst Biol & Netherlands Consortium Hlth A, RC-2300 Leiden, Netherlands..
    Orwoll, Eric S.
    Oregon Hlth & Sci Univ, Portland, OR 97239 USA..
    Palotie, Aarno
    Harvard Med Sch, Boston, MA 02115 USA.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki 00251, Finland.;Univ Helsinki, Dept Med Genet, FI-00014 Helsinki, Finland.;Univ Cent Hosp, FI-00014 Helsinki, Finland..
    Parker, Stephan
    Univ Michigan, Human Genet & Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Peacock, Munro
    Indiana Univ, Dept Med, Sch Med, Indianapolis, IN 46202 USA..
    Perola, Markus
    Nat Inst Hlth & Welf, Helsinki 00271, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki 00251, Finland.;Univ Helsinki, Diabet & Obes Res Program, FI-00014 Helsinki, Finland.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Peters, Annette
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Rese Unit Mol Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany..
    Polasek, Ozren
    Univ Split, Fac Med, Dept Publ Hlth, Split 21000, Croatia..
    Prince, Richard L.
    Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia.;Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Perth, WA 6009, Australia..
    Raikkonen, Katri
    Univ Helsinki, Inst Behav Sci, FI-00014 Helsinki, Finland..
    Ralston, Stuart H.
    Western Gen Hosp, Mol Med Ctr, MRC Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Ripatti, Samuli
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki 00251, Finland.;Univ Helsinki, Hjelt Inst, Helsinki, Finland.;Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SA, England..
    Robbins, John A.
    Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Rudan, Igor
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland..
    Salomaa, Veikko
    Nat Inst Hlth & Welf, Helsinki 00271, Finland..
    Satterfield, Suzanne
    Univ Tennessee, Dept Prevent Med, Hlth Sci Ctr, Memphis, TN 38163 USA..
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Inst Genom & Multiscale Biol, New York, NY 10029 USA..
    Schipf, Sabine
    Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17489 Greifswald, Germany..
    Scott, Laura
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Sehmi, Joban
    Ealing Hosp NHS Trust, Cardiol Dept, Middlesex UB1 3HW, England.;Imperial Coll London, Natl Heart & Lung Inst, London SW3 6LY, England..
    Shen, Jian
    Oregon Hlth & Sci Univ, Portland, OR 97239 USA..
    Shin, Chan Soo
    Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 03080, South Korea..
    Sigurdsson, Gunnar
    Natl Univ Hosp Iceland, Landspitali, Dept Endocrinol & Metab, IS-101 Reykjavik, Iceland..
    Smith, Shad
    Duke Univ, Med Ctr, Ctr Translat Pain Med, Dept Anesthesiol, Durham, NC 27110 USA..
    Soranzo, Nicole
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SA, England..
    Stancakova, Alena
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Steinhagen-Thiessen, Elisabeth
    Charite, Res Grp Geriatr, Berlin Aging Study 2, D-13353 Berlin, Germany..
    Streeten, Elizabeth A.
    Univ Maryland, Program Personalized & Genom Med, Baltimore, MD 21201 USA.;Univ Maryland, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA.;Vet Adm Med Ctr, GRECC, Baltimore, MD 21201 USA..
    Styrkarsdottir, Unnur
    Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.;deCODE Genet, IS-101 Reykjavik, Iceland..
    Swart, Karin M. A.
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, BT-1081 Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst, BT-1081 Amsterdam, Netherlands..
    Tan, Sian-Tsung
    Ealing Hosp NHS Trust, Cardiol Dept, Middlesex UB1 3HW, England.;Imperial Coll London, Natl Heart & Lung Inst, London SW3 6LY, England..
    Tarnopolsky, Mark A.
    McMaster Univ, Med Ctr, Dept Med, Hamilton, ON L8N 3Z5, Canada..
    Thompson, Patricia
    Stony Brook Sch Med, Dept Pathol, Stony Brook, NY 11794 USA..
    Thomson, Cynthia A.
    Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ 85714 USA..
    Thorsteinsdottir, Unnur
    Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.;deCODE Genet, IS-101 Reykjavik, Iceland..
    Tikkanen, Emmi
    Nat Inst Hlth & Welf, Helsinki 00271, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki 00251, Finland.;Western Gen Hosp, Mol Med Ctr, MRC Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Tranah, Gregory J.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA..
    Tuomilehto, Jaakko
    Vasa Cent Hosp, Vaasa 65130, Finland.;Danube Univ Krems, Dept Neurosci & Prevent Med, A-3500 Krems, Austria.;King Abdulaziz Univ, Diabet Res Grp, Jeddah 12589, Saudi Arabia.;Dasman Diabet Inst, Dasman 15462, Kuwait..
    van Schoor, Natasja M.
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, BT-1081 Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst, BT-1081 Amsterdam, Netherlands..
    Verma, Arjun
    Ealing Hosp NHS Trust, Cardiol Dept, Middlesex UB1 3HW, England..
    Vollenweider, Peter
    CHU Vaudois, Dept Med & Internal Med, CH-1011 Lausanne, Switzerland..
    Voelzke, Henry
    Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17489 Greifswald, Germany..
    Wactawski-Wende, Jean
    SUNY Buffalo, Univ Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14214 USA..
    Walker, Mark
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Weedon, Michael N.
    Univ Exeter, Med Sch, Genet Complex Traits, Exeter EX1 2LU, Devon, England..
    Welch, Ryan
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Wichman, H. -Erich
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, D-81377 Munich, Germany.;Tech Univ, Inst Med Stat & Epidemiol, D-81675 Munich, Germany..
    Widen, Elisabeth
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki 00251, Finland..
    Williams, Frances M. K.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus, London WC2R 2LS, England..
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Edinburgh, IGMM, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland..
    Wright, Nicole C.
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA..
    Xie, Weijia
    Univ Exeter, Med Sch, Genet Complex Traits, Exeter EX1 2LU, Devon, England..
    Yu, Lei
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
    Zhou, Yanhua
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Chambers, John C.
    Imperial Coll, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England.;Ealing Hosp NHS Trust, Cardiol Dept, Middlesex UB1 3HW, England.;Royal Brompton & Harefield NHS Fdn Trust, NIHR Cardiovasc Biomed Res Unit, London SW3 6NP, England.;Imperial Coll, London SW3 6NP, England.;Imperial Coll Healthcare NHS Trust, London W2 1NY, England..
    Doring, Angela
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, D-85764 Neuherberg, Germany..
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands.;Ctr Med Syst Biol & Netherlands Consortium Hlth A, RC-2300 Leiden, Netherlands..
    Econs, Michael J.
    Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA..
    Gudnason, Vilmundur
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland..
    Kooner, Jaspal S.
    Ealing Hosp NHS Trust, Cardiol Dept, Middlesex UB1 3HW, England.;Imperial Coll London, Natl Heart & Lung Inst, London SW3 6LY, England.;Imperial Coll Healthcare NHS Trust, London W2 1NY, England..
    Psaty, Bruce M.
    Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA.;Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA.;Univ Washington, Cardiovasc Hlth Res Unit, Dept Med Hlth Serv, Seattle, WA 98101 USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus, London WC2R 2LS, England..
    Stefansson, Kari
    Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.;deCODE Genet, IS-101 Reykjavik, Iceland..
    Rivadeneira, Fernando
    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands.;NCHA, NCI, NL-2593 Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands.;NCHA, NCI, NL-2593 Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 OQQ, England..
    Ossowski, Vicky
    NIH, Phoenix Epidemiol & Clin Res Branch, Natl Inst Diabet & Digest & Kidney Dis, Phoenix, AZ 85014 USA..
    Waterworth, Dawn
    GlaxoSmithKline, Med Genet, Philadelphia, PA 19112 USA..
    Loos, Ruth J. F.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 OQQ, England.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Inst Child Hlth & Dev, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA..
    Karasik, David
    Inst Aging Res, HebrewSenior Life, Roslindale, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Bar Ilan Univ, Fac Med Galilee, IL-1311502 Safed, Israel..
    Harris, Tamara B.
    Natl Inst Aging, Intramural Res Program, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, SE-40530 Gothenburg, Sweden..
    Kiel, Douglas P.
    Inst Aging Res, HebrewSenior Life, Roslindale, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA..
    Large meta-analysis of genome-wide association studies identifies five loci for lean body mass2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 80Article in journal (Refereed)
    Abstract [en]

    Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.

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