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  • 1. Bolinder, Jan
    et al.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wilding, John
    Langkilde, Anna Maria
    Sugg, Jennifer
    Parikh, Shamik
    Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 3, p. 1020-1031Article in journal (Refereed)
    Abstract [en]

    Context:

    Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding.

    Objectives:

    Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components.

    Design and Setting:

    This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries.

    Patients:

    Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin.

    Intervention:

    Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk.

    Main Outcome Measures:

    Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated.

    Results:

    At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, −2.08 kg [95% confidence interval (CI) = −2.84 to −1.31; P < 0.0001]; waist circumference, −1.52 cm (95% CI = −2.74 to −0.31; P = 0.0143); FM, −1.48 kg (95% CI = −2.22 to −0.74; P = 0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI = 15.5 to 36.7; P < 0.0001); VAT, −258.4 cm3 (95% CI = −448.1 to −68.6; nominal P = 0.0084); SAT, −184.9 cm3 (95% CI = −359.7 to −10.1; nominal P = 0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%.

    Conclusions:

    Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.

  • 2. Coviello, Andrea D.
    et al.
    Haring, Robin
    Wellons, Melissa
    Vaidya, Dhananjay
    Lehtimaki, Terho
    Keildson, Sarah
    Lunetta, Kathryn L.
    He, Chunyan
    Fornage, Myriam
    Lagou, Vasiliki
    Mangino, Massimo
    Onland-Moret, N. Charlotte
    Chen, Brian
    Eriksson, Joel
    Garcia, Melissa
    Mei, Yong
    Koster, Annemarie
    Lohman, Kurt
    Lyytikainen, Leo-Pekka
    Petersen, Ann-Kristin
    Prescott, Jennifer
    Stolk, Lisette
    Vandenput, Liesbeth
    Wood, Andrew R.
    Zhuang, Wei Vivian
    Ruokonen, Aimo
    Hartikainen, Anna-Liisa
    Pouta, Anneli
    Bandinelli, Stefania
    Biffar, Reiner
    Brabant, Georg
    Cox, David G.
    Chen, Yuhui
    Cummings, Steven
    Ferrucci, Luigi
    Gunter, Marc J.
    Hankinson, Susan E.
    Martikainen, Hannu
    Hofman, Albert
    Homuth, Georg
    Illig, Thomas
    Jansson, John-Olov
    Johnson, Andrew D.
    Karasik, David
    Karlsson, Magnus
    Kettunen, Johannes
    Kiel, Douglas P.
    Kraft, Peter
    Liu, Jingmin
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Lorentzon, Mattias
    Maggio, Marcello
    Markus, Marcello R. P.
    Mellstrom, Dan
    Miljkovic, Iva
    Mirel, Daniel
    Nelson, Sarah
    Papunen, Laure Morin
    Peeters, Petra H. M.
    Prokopenko, Inga
    Raffel, Leslie
    Reincke, Martin
    Reiner, Alex P.
    Rexrode, Kathryn
    Rivadeneira, Fernando
    Schwartz, Stephen M.
    Siscovick, David
    Soranzo, Nicole
    Stockl, Doris
    Tworoger, Shelley
    Uitterlinden, Andre G.
    van Gils, Carla H.
    Vasan, Ramachandran S.
    Wichmann, H. -Erich
    Zhai, Guangju
    Bhasin, Shalender
    Bidlingmaier, Martin
    Chanock, Stephen J.
    De Vivo, Immaculata
    Harris, Tamara B.
    Hunter, David J.
    Kahonen, Mika
    Liu, Simin
    Ouyang, Pamela
    Spector, Tim D.
    van der Schouw, Yvonne T.
    Viikari, Jorma
    Wallaschofski, Henri
    McCarthy, Mark I.
    Frayling, Timothy M.
    Murray, Anna
    Franks, Steve
    Jarvelin, Marjo-Riitta
    de Jong, Frank H.
    Raitakari, Olli
    Teumer, Alexander
    Ohlsson, Claes
    Murabito, Joanne M.
    Perry, John R. B.
    A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 7, p. e1002805-Article in journal (Refereed)
    Abstract [en]

    Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8x10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3, p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7x10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5x10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5x10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained similar to 15.6% and similar to 8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

  • 3. Felsenberg, Dieter
    et al.
    Beller, Gisela
    Fiore, Carmelo
    Lyritis, George
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Boerst, Hendrikje
    Bock, Oliver
    Hartard, Manfred
    Runge, Martin
    Brandi, Maria Luisa
    Sergi, Giuseppe
    Bergström, Ingrid
    Beneficial effects of strontium ranelate compared to alendronate on bone mass and strength parameters at the tibia in postmenopausal osteoporotic women: A 2-year study2012In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 23, no S2, p. S113-S114Article in journal (Other academic)
  • 4. Johansson, H.
    et al.
    Oden, A.
    Lerner, U. H.
    Jutberger, H.
    Lorentzon, M.
    Barrett-Connor, E.
    Karlsson, M. K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Smith, U.
    McCloskey, E.
    Kanis, J. A.
    Ohlsson, C.
    Mellström, D.
    High serum adiponectin predicts incident fractures in elderly men: MrOS Sweden2012In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 23, no 2, p. S306-S307Article in journal (Other academic)
  • 5. Karlsson, Magnus K
    et al.
    Ribom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Jan-Åke
    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 Medical Sciences, Metabolic Bone Diseases.
    Ohlsson, Claes
    Mellström, Dan
    Lorentzon, Mattiaz
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Stefanick, Marcia
    Lapidus, Jodi
    Leung, Ping Chung
    Kwok, Anthony
    Barrett-Connor, Elizabeth
    Orwoll, Eric
    Rosengren, Björn E
    Inferior physical performance tests in 10,998 men in the MrOS study is associated with recurrent falls2012In: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 41, no 6, p. 740-746Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    recurrent fallers are at especially high risk for injuries.

    OBJECTIVE:

    to study whether tests of physical performance are associated with recurrent falls. SUBJECTS: a total of 10,998 men aged 65 years or above.

    METHODS:

    questionnaires evaluated falls sustained 12 months preceding testing of grip strength, timed stand, 6-m walk and 20-cm narrow walk test. Means with 95% confidence interval (95% CI) are reported. P < 0.01 is a statistically significant difference.

    RESULTS:

    in comparison to both occasional fallers and non-fallers, recurrent fallers performed more poorly on all the physical ability tests (all P < 0.001). A score below -2 standard deviations (SDs) in the right-hand grip strength test was associated with an odds ratio of 2.4 (95% CI 1.7, 3.4) for having had recurrent falls compared with having had no fall and of 2.0 (95% CI 1.3, 3.4) for having had recurrent falls compared with having had an occasional fall.

    CONCLUSION:

    low performance in physical ability tests are in elderly men associated with recurrent falls.

  • 6. Lewerin, C.
    et al.
    Nilsson-Ehle, H.
    Jacobsson, S.
    Johansson, H.
    Sundh, V.
    Karlsson, M.
    Ljungren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Lorentzon, M.
    Kanis, J.
    Ohlsson, C.
    Mellström, D.
    Low holotranscobalamin and cobalamins predict incident fractures in elderly men; the MrOS Sweden2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, p. S40-S40Article in journal (Other academic)
  • 7.
    Lindahl, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Osteogenesis Imperfecta: Genetic and Therapeutic Studies2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Osteogenesis imperfecta (OI) is a heterogeneous disease of connective tissue, the cardinal symptom being fractures and severity ranging from mild to lethal. Dominant mutations in collagen I, encoded by COL1A1 and COL1A2, cause >90% of cases.

    To delineate genotype-phenotype correlations and pharmaco-genetic response, collagen I was sequenced in 150 unrelated Swedish families and clinical data were collected in Paper I. Mutation type, gene affected, and N- to C-terminal location correlated with phenotype and severity. Bisphosphonate response assessed by calculated yearly change in lumbar spine bone mineral density (BMD) was inversely related to age and BMD at treatment initiation. Mutations associated with a more severe phenotype exhibited an increased response after 2 years; however, all types of OI responded well.

    To investigate the effect of naturally occurring variations in collagen I, the only common coding single nucleotide polymorphism (rs42524 in COL1A2) was genotyped in 2004 healthy men in Paper II. Heterozygous genotype was associated with decreased BMD and an increased risk of stroke.

    An adolescent with repeated fractures despite a markedly high BMD harbored a unique C-terminal procollagen cleavage-site mutation in COL1A1, which motivated extensive investigations in concert with a similar COL1A2 case in Paper III. The probands were found to have impaired procollagen processing, incorporation of collagen with retained C-propeptide in matrix and increased mineral to matrix ratio, which demonstrates that C-propeptide cleavage is crucial to normal bone mineralization and structure.

    Bisphosphonate therapy has insufficient effect in OI, and as classical OI is a dominant disorder severe cases would benefit from silencing of the mutated allele. In Paper IV and V small interfering RNAs (siRNAs) were used to allele-specifically target primary human bone cells heterozygous for I) a coding polymorphism in COL1A2 and II) insertion/deletions in the 3’UTR of COL1A1 and COL1A2. Results were promising with altered allele ratios and decreased mRNA levels in the predicted fashion.

    To summarize, this thesis found that collagen I is crucial to bone and connective tissue and that collagen I mutations create markedly diverse phenotypes. Age, BMD and pharmaco-genetic effects influence the response to bisphosphonate therapy in individuals with OI; however, novel approaches are needed. Utilizing allele-specific siRNAs may be a way forward in the treatment of severe OI.

     

    List of papers
    1. Genotype-Phenotype Correlations, Response to Bisphosphonate Treatment and Pharmaco-genetics in 150 Swedish Families with Osteogenesis Imperfecta (Type I, IV and III)
    Open this publication in new window or tab >>Genotype-Phenotype Correlations, Response to Bisphosphonate Treatment and Pharmaco-genetics in 150 Swedish Families with Osteogenesis Imperfecta (Type I, IV and III)
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Osteogenesis imperfecta (OI) is a rare heterogeneous disorder leading to bone fragility, spanning from mild to lethal in severity. Over 1500 mutations have been described in collagen type I, encoded by COL1A1 and COL1A2. Bisphosphonate treatment is standard of care and published studies clearly show beneficial effects on Bone Mineral Density (BMD) and vertebral geometry. However, information on BMD increase in relation to age and BMD at onset is limited and there are few studies on influence of mutation type on treatment response. In this study Swedish patients with OI types I, IV and III were investigated with respect to genotype-phenotype correlations, BMD response on bisphosphonate treatment, and pharmaco-genetics.

    Materials and Methods: 150 families (202 individuals) with OI participated: 137 type I, 40 type IV and 25 type III. Data on phenotype and bisphosphonate treatment were collected and sequencing of COL1A1 and COL1A2 performed.

    Results: In 119 families a mutation was detected; in COL1A1 52 quantitative and 35 qualitative mutations were found and in COL1A2 32 qualitative mutations were found. Several unrelated individuals were found to harbor mutations with the same positions and substitutions and only 15 qualitative mutations were novel, supporting the idea of mutational hotspots. Genotype-phenotype analysis confirmed that mutations situated in the a1-chain are associated with a more severe phenotype, blue sclerae are strongly associated with COL1A1 null alleles, qualitative mutations are associated with DI, and for qualitative mutations position relative to N- and C-terminal is correlated to phenotype. A few novel mutations with unconventional locations were found.

    Bisphosphonate treatment response was inversely correlated with age (p=<0.0001) and lumbar spine BMD at onset (p=0.006). Mutations associated with a more severe phenotype had an improved response to treatment when analyzing 2-year delta lumbar spine Z-score values; mutations in COL1A1 vs. COL1A2 (p=0.03), qualitative mutations in COL1A1 vs. COL1A2 (p=0.006), serine substitutions in COL1A1 vs. COL1A2 (p=0.007) and qualitative vs. qualitative mutations in COL1A1 (p=0.02) all exhibited this pattern. Bisphosphonate response was not correlated to either OI type or gender.

    Conclusions: The genotype-phenotype correlations described here confirm previous reports of influence of chain affected, intrachain location, and mutation type on phenotype. BMD response to bisphosphonate treatment is inversely related to age and BMD at onset. Pharmaco-genetic analyses show an increased response to bisphosphonate treatment for more severe mutations types. This effect is attenuated over time.

    Keywords
    Osteogenesis imperfecta, OI, Bisphosphonate, Therapy, Genotype, Phenotype, Parmaco-genetics, Mutation
    National Category
    Endocrinology and Diabetes
    Research subject
    Medical Genetics; Genetics; Medicine
    Identifiers
    urn:nbn:se:uu:diva-208940 (URN)
    Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2013-12-05
    2. Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk
    Open this publication in new window or tab >>Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk
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    2009 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 384, no 4, p. 501-505Article in journal (Refereed) Published
    Abstract [en]

    Genetic variation plays an important role in osteoporosis and a prime candidate gene is Collagen alpha2(I) (COL1A2). A coding polymorphism (rs42524) in COL1A2 has previously been associated with intracranial aneurysms. Here the effects of this polymorphism have been studied in relation to bone mineral density (BMD) and prevalences of stroke and myocardial infarction (MI). rs42524 was genotyped in elderly men (n = 2004) from the Swedish MrOS cohort. Genotypes were analysed for association to BMD and certain health parameters. Significant associations (overall P < 0.05), were observed between rs42524 genotype and BMD at several skeletal sites. Surprisingly, the heterozygote genotype class exhibited lower BMD than either homozygote group. When subjects were classified as heterozygotes or homozygotes, the heterozygous genotype was found to confer a lower BMD at total hip, femoral neck and trochanter Furthermore, the heterozygote genotype had an increased risk of stroke and MI, with population Attributable Risks being 0.12 and 0.08, respectively.

    National Category
    Surgery
    Research subject
    Orthopaedics
    Identifiers
    urn:nbn:se:uu:diva-111772 (URN)10.1016/j.bbrc.2009.05.006 (DOI)000266689300020 ()19426706 (PubMedID)
    Available from: 2009-12-21 Created: 2009-12-21 Last updated: 2017-12-12Bibliographically approved
    3. COL1 C-Propeptide Cleavage Site Mutations Cause High Bone Mass Osteogenesis Imperfecta
    Open this publication in new window or tab >>COL1 C-Propeptide Cleavage Site Mutations Cause High Bone Mass Osteogenesis Imperfecta
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    2011 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 32, no 6, p. 598-609Article in journal (Refereed) Published
    Abstract [en]

    Osteogenesis imperfecta (OI) is most often caused by mutations in the type I procollagen genes (COL1A1/COL1A2). We identified two children with substitutions in the type I procollagen C-propeptide cleavage site, which disrupt a unique processing step in collagen maturation and define a novel phenotype within OI. The patients have mild OI caused by mutations in COL1A1 (Patient 1: p.Asp1219Asn) or COL1A2 (Patient 2: p.Ala1119Thr), respectively. Patient 1 L1-L4 DXA Z-score was +3.9 and pQCT vBMD was +3.1; Patient 2 had L1-L4 DXA Z-score of 0.0 and pQCT vBMD of -1.8. Patient BMD contrasts with radiographic osteopenia and histomorphometry without osteosclerosis. Mutant procollagen processing is impaired in pericellular and in vitro assays. Patient dermal collagen fibrils have irregular borders. Incorporation of pC-collagen into matrix leads to increased bone mineralization. FTIR imaging confirms elevated mineral/matrix ratios in both patients, along with increased collagen maturation in trabecular bone, compared to normal or OI controls. Bone mineralization density distribution revealed a marked shift toward increased mineralization density for both patients. Patient 1 has areas of higher and lower bone mineralization than controls; Patient 2's bone matrix has a mineral content exceeding even classical OI bone. These patients define a new phenotype of high BMD OI and demonstrate that procollagen C-propeptide cleavage is crucial to normal bone mineralization.

    Keywords
    osteogenesis imperfecta, C-propeptide, collagen, C-proteinase, mineralization, high bone mass
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-155592 (URN)10.1002/humu.21475 (DOI)000291564000011 ()
    Available from: 2011-06-28 Created: 2011-06-27 Last updated: 2017-12-11Bibliographically approved
    4. Allele dependent silencing of COL1A2 using small interfering RNAs
    Open this publication in new window or tab >>Allele dependent silencing of COL1A2 using small interfering RNAs
    2008 (English)In: International journal of medical sciences, ISSN 1449-1907, Vol. 5, no 6, p. 361-365Article in journal (Refereed) Published
    Abstract [en]

    Osteogenesis imperfecta (OI) is generally caused by a dominant mutation in Collagen I, encoded by the genes COL1A1 and COL1A2. To date there is no satisfactory therapy for OI, but inactivation of the mutant allele through small interfering RNAs (siRNA) is a promising approach, as siRNAs targeting each allele of a polymorphism could be used for allele-specific silencing irrespective of the location of the actual mutations. In this study we examined the allele dependent effects of several tiled siRNAs targeting a region surrounding an exonic COL1A2 T/C polymorphism (rs1800222) in heterozygous primary human bone cells. Relative abundances of COL1A2 alleles were determined by cDNA sequencing and overall COL1A2 abundance was analyzed by quantitative PCR. One of the siRNAs decreased overall COL1A2 abundance by 71% of which 75% was due to silencing of the targeted T-allele. In conclusion, allele-preferential silencing of Collagen type I genes may be a future therapeutic approach for OI.

    Keywords
    COL1A2, allele-preferential silencing, Osteogenesis imperfecta
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-125035 (URN)19015742 (PubMedID)
    Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2013-12-05Bibliographically approved
    5. Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels: a Novel Therapeutic Approach in Osteogenesis Imperfecta
    Open this publication in new window or tab >>Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels: a Novel Therapeutic Approach in Osteogenesis Imperfecta
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    2013 (English)In: International Journal of Medical Sciences, ISSN 1449-1907, E-ISSN 1449-1907, Vol. 10, no 10, p. 1333-1343Article in journal (Refereed) Published
    Abstract [en]

    Osteogenesis imperfecta, also known as "brittle bone disease", is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis imperfecta.

    Keywords
    osteogenesis imperfecta, OI, allele-specific silencing, siRNA, collagen, COL1A1, COL1A2, indel, insertion/deletion, RNAi, mutation, gene-therapy, therapy
    National Category
    Endocrinology and Diabetes
    Research subject
    Genetics; Medical Genetics; Medicine
    Identifiers
    urn:nbn:se:uu:diva-208936 (URN)10.7150/ijms.5774 (DOI)000324411800011 ()23983594 (PubMedID)
    Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06Bibliographically approved
  • 8.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Laxman, Navya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Åström, Eva
    Karolinska Institutet.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels: a Novel Therapeutic Approach in Osteogenesis Imperfecta2013In: International Journal of Medical Sciences, ISSN 1449-1907, E-ISSN 1449-1907, Vol. 10, no 10, p. 1333-1343Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta, also known as "brittle bone disease", is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis imperfecta.

  • 9.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Astrom, E.
    Malmgren, B.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Genotype-phenotype correlations and pharmacogenetic studies in 140 Swedish families with osteogenesis imperfecta2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, p. S109-S109Article in journal (Other academic)
    Abstract [en]

    Objective: Osteogenesis imperfecta (OI) is a rare heterogeneous disease of connective tissue leading to varying degrees of bone fragility. The worst form (type II) is peri-natally lethal whereas the mildest form (type I) is compatible with a normal life span. Over 1000 mutations causing OI have been described in the genes encoding collagen type I. As COL1A1 and COL1A2 are large genes, there are still many codon positions where no mutations have been reported and only a fraction of theoretically possible glycine substitutions have been described. In this study the spectrum of mutations causing OI in Sweden will be investigated and genotype–phenotype correlations as well as pharmacogenetics will be studied.

    Method: All patients with OI cared for at the Uppsala Osteoporosis Unit (Uppsala University Hospital) or Astrid Lindgren's Paediatric Hospital (Karolinska Institutet, Stockholm) were offered to enter the study. Patients from 140 unrelated families with OI accepted participation; 77 type I, 34 type IV, 20 type III, 5 without previous diagnosis and 4 with unclear OI type. Extensive clinical data is currently being collected on enrolled patients. Exons and flanking intron sequences of COL1A1 and COL1A2 are being sequenced in these families.

    Results: So far 133/140 families have been completely analyzed and in 27 no mutation was found. A total of 120 mutations have been detected, of which 104 are of a typical OI-type. In COL1A1 73 mutations were found and in COL1A2 31 mutations were noted. In 7 families 2 mutations were present, but only one of these was a typical OI-causing mutation. To date 16 amino acid changing mutations that were not of a typical OI-causing type have been noted and the majority of these have an unclear significance. Calculations of delta BMD Z-score response to bisphosphonate treatment did not show a difference in treatment response between groups with different types of OI or between patients with OI type I due to a qualitative vs. a quantitative collagen type I defect.

    Conclusion: The spectrum of mutations causing OI described in this Swedish cohort is of the expected type, with the exception of the amino acid changing mutations. It is notable that in seven families two separate mutations were identified. Calculations do not support a mutation dependent response to bisphosphonate treatment.

  • 10.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Åström, Eva
    Karolinska Institutet.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Söderhäll, Stefan
    Karolinska Institutet.
    Malmgren, Barbro
    Karolinska Institutet.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Genotype-Phenotype Correlations, Response to Bisphosphonate Treatment and Pharmaco-genetics in 150 Swedish Families with Osteogenesis Imperfecta (Type I, IV and III)Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Osteogenesis imperfecta (OI) is a rare heterogeneous disorder leading to bone fragility, spanning from mild to lethal in severity. Over 1500 mutations have been described in collagen type I, encoded by COL1A1 and COL1A2. Bisphosphonate treatment is standard of care and published studies clearly show beneficial effects on Bone Mineral Density (BMD) and vertebral geometry. However, information on BMD increase in relation to age and BMD at onset is limited and there are few studies on influence of mutation type on treatment response. In this study Swedish patients with OI types I, IV and III were investigated with respect to genotype-phenotype correlations, BMD response on bisphosphonate treatment, and pharmaco-genetics.

    Materials and Methods: 150 families (202 individuals) with OI participated: 137 type I, 40 type IV and 25 type III. Data on phenotype and bisphosphonate treatment were collected and sequencing of COL1A1 and COL1A2 performed.

    Results: In 119 families a mutation was detected; in COL1A1 52 quantitative and 35 qualitative mutations were found and in COL1A2 32 qualitative mutations were found. Several unrelated individuals were found to harbor mutations with the same positions and substitutions and only 15 qualitative mutations were novel, supporting the idea of mutational hotspots. Genotype-phenotype analysis confirmed that mutations situated in the a1-chain are associated with a more severe phenotype, blue sclerae are strongly associated with COL1A1 null alleles, qualitative mutations are associated with DI, and for qualitative mutations position relative to N- and C-terminal is correlated to phenotype. A few novel mutations with unconventional locations were found.

    Bisphosphonate treatment response was inversely correlated with age (p=<0.0001) and lumbar spine BMD at onset (p=0.006). Mutations associated with a more severe phenotype had an improved response to treatment when analyzing 2-year delta lumbar spine Z-score values; mutations in COL1A1 vs. COL1A2 (p=0.03), qualitative mutations in COL1A1 vs. COL1A2 (p=0.006), serine substitutions in COL1A1 vs. COL1A2 (p=0.007) and qualitative vs. qualitative mutations in COL1A1 (p=0.02) all exhibited this pattern. Bisphosphonate response was not correlated to either OI type or gender.

    Conclusions: The genotype-phenotype correlations described here confirm previous reports of influence of chain affected, intrachain location, and mutation type on phenotype. BMD response to bisphosphonate treatment is inversely related to age and BMD at onset. Pharmaco-genetic analyses show an increased response to bisphosphonate treatment for more severe mutations types. This effect is attenuated over time.

  • 11.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Anabolic treatment2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, p. S15-S15Article in journal (Other academic)
    Abstract [en]

    Osteoporosis is caused by an imbalance in the remodelling cycle with subsequent bone loss due to either enhanced osteoclastic resorption, or to a decrease in osteoblastic activity. Over time this loss of bone results in thinning and disappearance of trabeculi and to enhanced cortical porosity. With the knowledge of the pathogenetic mechanisms underlying the development of osteoporosis it is evident that there are two main strategies to develop pharmacological treatment for this condition. Either the goal is to inhibit bone resorption with e.g. bisphosphonates or RANKL interference, or alternatively to stimulate osteoblastic bone formation with anabolic treatment and thereby create new bone.

    Today it is well documented that intermittent injections with PTH1-34, or with full length PTH, cause a direct stimulatory effect on the osteoblastic bone formation. The treatment length is currently between 18 and 24 months and it is not known whether there is an optimal duration, called anabolic window, for this sort of treatment. The antifracture efficacy is well proven in randomised phase III trials, and real life efficacy and safety are well documented in large post marketing observational studies. When compared to antiresorptive treatment with bisphosphonates there are data that at least PTH 1–34 might be superior in some instances such as in glucocorticoid induced osteoporosis.

    Future development with new anabolic agents focusing on the LRP5/Wnt signalling system is under development and might bring to the clinic even more potent drugs that eventually might enable us to treat to a bone density target, and thereby in theory cure osteoporosis.

  • 12.
    Ljunggren, Östen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Barrett, Annabel
    Stoykov, Ivaylo
    Langdahl, Bente L.
    Lems, Willem F.
    Walsh, J. Bernard
    Fahrleitner-Pammer, Astrid
    Rajzbaum, Gerald
    Jakob, Franz
    Karras, Dimitrios
    Marin, Fernando
    Effective osteoporosis treatment with teriparatide is associated with enhanced quality of life in postmenopausal women with osteoporosis: the European Forsteo Observational Study2013In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 14, p. 251-Article in journal (Refereed)
    Abstract [en]

    Background: To describe changes in health-related quality of life (HRQoL) of postmenopausal women with osteoporosis treated with teriparatide for up to 18 months and followed-up for a further 18 months, and to assess the influence of recent prior and incident fractures. Methods: The European Forsteo Observational Study (EFOS) is an observational, prospective, multinational study measuring HRQoL using the EQ-5D. The primary objective was to assess changes in HRQoL during 36 months in the whole study population. A secondary post-hoc analysis examined fracture impact on HRQoL in four subgroups classified based on recent prior fracture 12 months before baseline and incident clinical fractures during the study. Changes from baseline were analysed using a repeated measures model. Results: Of the 1581 patients, 48.4% had a recent prior fracture and 15.6% of these patients had an incident fracture during follow-up. 10.9% of the 816 patients with no recent prior fracture had an incident fracture. Baseline mean EQ-VAS scores were similar across the subgroups. In the total study cohort (n = 1581), HRQoL (EQ-VAS and EQ-5D index scores) improved significantly from baseline to 18 months and this improvement was maintained over the 18-month post-teriparatide period. Improvements were seen across all five EQ-5D domains during teriparatide treatment that were maintained after teriparatide was discontinued. Subjects with incident clinical fractures had significantly less improvement in EQ-VAS than those without incident fractures. Recent prior fracture did not influence the change in EQ-VAS during treatment. Conclusions: EFOS is the first longitudinal study in women with severe postmenopausal osteoporosis in the real world setting to show a substantial improvement in HRQoL during teriparatide treatment that was sustained during subsequent treatment with other medications. The increase in HRQoL was lower in the subgroups with incident fracture but was not influenced by recent prior fracture. The results should be interpreted in the context of the design of an observational study.

  • 13.
    Ljunggren, Östen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Bolinder, J.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wilding, J.
    Langkilde, A. M.
    Sjostrom, C. D.
    Sugg, J.
    Parikh, S.
    Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin2012In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 14, no 11, p. 990-999Article in journal (Refereed)
    Abstract [en]

    Aims Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycaemia in patients with type 2 diabetes (T2DM) by increasing urinary glucose excretion. Owing to its mechanism of action, dapagliflozin could potentially affect the renal tubular transportation of bone minerals. Therefore, markers of bone formation and resorption and bone mineral density (BMD) were evaluated in patients with T2DM after 50?weeks of dapagliflozin treatment. Methods This international, multi-centre, randomized, parallel-group, double-blind, placebo-controlled study (ClinicalTrials.gov NCT00855166) enrolled patients with T2DM (women 5575?years and men 3075?years; HbA1c 6.58.5%; BMI?=?25?kg/m2; body weight?=?120?kg) whose T2DM was inadequately controlled on metformin. One hundred and eighty-two patients were randomly assigned 1:1 to receive dapagliflozin 10?mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 50, serum markers of bone formation (procollagen type 1 N-terminal propeptide; P1NP) and resorption (C-terminal cross-linking telopeptides of type I collagen; CTX), bone mineral density (BMD) as assessed by standardized Dual-Energy X-ray Absorptiometry (DXA) measurements and adverse events of fracture were evaluated as safety objectives. Results One hundred and sixty-five patients (90.7%) completed the first 50 weeks. Compared with placebo, no significant changes from baseline in P1NP, CTX or BMD were identified over 50 weeks of dapagliflozin treatment, with no significant treatment-by-gender interactions. No fractures were reported. Conclusions Dapagliflozin had no effect on markers of bone formation and resorption or BMD after 50 weeks of treatment in both male and post-menopausal female patients whose T2DM was inadequately controlled on metformin.

  • 14. Moverare-Skrtic, S.
    et al.
    Eriksson, A. L.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Karlsson, M.
    Mellstrom, D.
    Ohlsson, C.
    CRP is an independent risk factor for fractures in elderly men: The MrOS Sweden study2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, p. S56-S56Article in journal (Other academic)
  • 15. Ohlsson, Claes
    et al.
    Nilsson, Maria E.
    Tivesten, Asa
    Ryberg, Henrik
    Mellstrom, Dan
    Karlsson, Magnus K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Labrie, Fernand
    Orwoll, Eric S.
    Lee, David M.
    Pye, Stephen R.
    O'Neill, Terence W.
    Finn, Joseph D.
    Adams, Judith E.
    Ward, Kate A.
    Boonen, Steven
    Bartfai, Gyorgy
    Casanueva, Felipe F.
    Forti, Gianni
    Giwercman, Aleksander
    Han, Thang S.
    Huhtaniemi, Ilpo T.
    Kula, Krzysztof
    Lean, Michael E. J.
    Pendleton, Neil
    Punab, Margus
    Vanderschueren, Dirk
    Wu, Frederick C. W.
    Vandenput, Liesbeth
    Comparisons of Immunoassay and Mass Spectrometry Measurements of Serum Estradiol Levels and Their Influence on Clinical Association Studies in Men2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 6, p. E1097-E1102Article in journal (Refereed)
    Abstract [en]

    Context: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men. Objective: Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes. Design and Setting: Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included. Main Outcome Measures: Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and anklebrachial index. Results: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient r(S) 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, r(S) = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP. Conclusions: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.

  • 16. 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.

  • 17. 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.

  • 18.
    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.

  • 19. 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)

  • 20. 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)
  • 21.
    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.

  • 22.
    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.

  • 23.
    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.

  • 24.
    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.

  • 25.
    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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