Browsing by Subject "BONE-MINERAL DENSITY"

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  • Blain, H.; Masud, T.; Dargent-Molina, P.; Martin, F. C.; Rosendahl, E.; van der Velde, N.; Bousquet, J.; Benetos, A.; Cooper, C.; Kanis, J. A.; Reginster, J. Y.; Rizzoli, R.; Cortet, B.; Barbagallo, M.; Dreinhofer, K. E.; Vellas, B.; Maggi, S.; Strandberg, T.; EUGMS Falls Fracture Interest Grp; Int Assoc Gerontology Geriatri; European Union Med Specialists EUM; Fragility Fracture Network FFN; European Soc Clinical Econ Aspects; Int Osteoporosis Fdn IOF (2016)
    Prevention of fragility fractures in older people has become a public health priority, although the most appropriate and cost-effective strategy remains unclear. In the present statement, the Interest Group on Falls and Fracture Prevention of the European Union Geriatric Medicine Society (EUGMS), in collaboration with the International Association of Gerontology and Geriatrics for the European Region (IAGG-ER), the European Union of Medical Specialists (EUMS), the International Osteoporosis Foundation - European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, outlines its views on the main points in the current debate in relation to the primary and secondary prevention of falls, the diagnosis and treatment of bone fragility, and the place of combined falls and fracture liaison services for fracture prevention in older people.
  • Blain, H.; Masud, T.; Dargent-Molina, P.; Martin, F. C.; Rosendahl, E.; van der Velde, N.; Bousquet, J.; Benetos, A.; Cooper, C.; Kanis, J. A.; Reginster, J. Y.; Rizzoli, R.; Cortet, B.; Barbagallo, M.; Dreinhoefer, K. E.; Vellas, B.; Maggi, S.; Strandberg, T.; EUGMS Falls & Fracture Interest Gr; IAGG-ER; EUMS; FFN; European Soc Clinical & Econ Aspec; IOF (2016)
    Prevention of fragility fractures in older people has become a public health priority, although the most appropriate and cost-effective strategy remains unclear. In the present statement, the Interest Group on Falls and Fracture Prevention of the European Union Geriatric Medicine Society, in collaboration with the International Association of Gerontology and Geriatrics for the European Region, the European Union of Medical Specialists, and the International Osteoporosis Foundation-European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, outlines its views on the main points in the current debate in relation to the primary and secondary prevention of falls, the diagnosis and treatment of bone fragility, and the place of combined falls and fracture liaison services for fracture prevention in older people.
  • Blain, H.; Masud, T.; Dargent-Molina, P.; Martin, F. C.; Rosendahl, E.; van der Velde, N.; Bousquet, J.; Benetos, A.; Cooper, C.; Kanis, J. A.; Reginster, J. Y.; Rizzoli, R.; Cortet, B.; Barbagallo, M.; Dreinhoefer, K.; Vellas, B.; Maggi, S.; Strandberg, T.; Alvarez, M. N.; Annweiler, C.; Bernard, P. -L.; Beswetherick, N.; Bischoff-Ferrari, H. A.; Bloch, F.; Boddaert, J.; Bonnefoy, M.; Bousson, V.; Bourdel-Marchasson, I.; Capisizu, A.; Che, H.; Clara, J. G.; Combe, B.; Delignieres, D.; Eklund, P.; Emmelot-Vonk, M.; Freiberger, E.; Gauvain, J. -B.; Goswami, N.; Guldemond, N.; Herrero, A. C.; Joel, M. -E.; Jonsdottir, A. B.; Kemoun, G.; Kiss, I.; Kolk, H.; Kowalski, M. L.; Krajcik, S.; Kutsal, Y. G.; Lauretani, F.; Macijauskiene, J.; Int Assoc Gerontology Geriatrics; European Union Medical Specialists; Fragility Fracture Network FFN; EUGMS Falls Fracture Interest Grp; European Soc Clinical Economic; Osteoporosis Research Information; International Osteoporosis (2016)
    Prevention of fragility fractures in older people has become a public health priority, although the most appropriate and cost-effective strategy remains unclear. In the present statement, the Interest group on falls and fracture prevention of the European union geriatric medicine society (EUGMS), in collaboration with the International association of gerontology and geriatrics for the European region (IAGG-ER), the European union of medical specialists (EUMS), the Fragility fracture network (FFN), the International osteoporosis foundation (IOF) - European society for clinical and economic aspects of osteoporosis and osteoarthritis (ECCEO), outlines its views on the main points in the current debate in relation to the primary and secondary prevention of falls, the diagnosis and treatment of bone fragility, and the place of combined falls and fracture liaison services for fracture prevention in older people. (C) 2016 Published by Elsevier Masson SAS.
  • JSCRG; TSRHCCG (2018)
    Adolescent idiopathic scoliosis (AIS) is the most common type of spinal deformity and has a significant genetic background. Genome-wide association studies (GWASs) identified several susceptibility loci associated with AIS. Among them is a locus on chromosome 6q24.1 that we identified by a GWAS in a Japanese cohort. The locus is represented by rs6570507 located within GPR126. To ensure the association of rs6570507 with AIS, we conducted a meta-analysis using eight cohorts from East Asia, Northern Europe and USA. The analysis included a total of 6,873 cases and 38,916 controls and yielded significant association (combined P = 2.95 x 10(-20); odds ratio = 1.22), providing convincing evidence of the worldwide association between rs6570507 and AIS susceptibility. In silico analyses strongly suggested that GPR126 is a susceptibility gene at this locus.
  • Mäkitie, Riikka E.; Henning, Petra; Jiu, Yaming; Kämpe, Anders; Kogan, Konstantin; Costantini, Alice; Välimäki, Ville-Valtteri; Medina-Gomez, Carolina; Pekkinen, Minna; Salusky, Isidro B.; Schalin-Jäntti, Camilla; Haanpää, Maria K.; Rivadeneira, Fernando; Bassett, John H. Duncan; Williams, Graham R.; Lerner, Ulf H.; Pereira, Renata C.; Lappalainen, Pekka; Mäkitie, Outi (2021)
    Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase-activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early-onset, autosomal-dominant skeletal fragility in a three-generation Finnish family. Affected individuals (n = 13) presented with multiple low-energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho-family GTPase Rac1. Variants in the ARHGAP25 5 ' untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta-analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony-stimulating factor (M-CSF)-stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject-derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R-mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP-activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlighting the importance of RhoGAP signaling in bone metabolism in familial forms of skeletal fragility and in the general population, and expanding our understanding of the molecular pathways underlying skeletal fragility. (c) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
  • Hox, Valerie; Lourijsen, Evelijn; Jordens, Arnout; Aasbjerg, Kristian; Agache, Ioana; Alobid, Isam; Bachert, Claus; Boussery, Koen; Campo, Paloma; Fokkens, Wytske; Hellings, Peter; Hopkins, Claire; Klimek, Ludger; Makelä, Mika; Moesges, Ralph; Mullol, Joaquim; Pujols, Laura; Rondon, Carmen; Rudenko, Michael; Toppila-Salmi, Sanna; Scadding, Glenis; Scheire, Sophie; Tomazic, Peter-Valentin; Van Zele, Thibaut; Wagemann, Martin; van Boven, Job F. M.; Gevaert, Philippe (2020)
    Because of the inflammatory mechanisms of most chronic upper airway diseases such as rhinitis and chronic rhinosinusitis, systemic steroids have been used for their treatment for decades. However, it has been very well documented that-potentially severe-side-effects can occur with the accumulation of systemic steroid courses over the years. A consensus document summarizing the benefits of systemic steroids for each upper airway disease type, as well as highlighting the potential harms of this treatment is currently lacking. Therefore, a panel of international experts in the field of Rhinology reviewed the available literature with the aim of providing recommendations for the use of systemic steroids in treating upper airway disease.
  • Uusi-Rasi, Kirsti; Karkkainen, Merja U. M.; Lamberg-Allardt, Christel J. E. (2013)
  • Young, Jacques; Xu, Cheng; Papadakis, Georgios E.; Acierno, James S.; Maione, Luigi; Hietamäki, Johanna; Raivio, Taneli; Pitteloud, Nelly (2019)
    The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (approximate to 10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development.
  • Uutela, Toini I.; Kautiainen, Hannu J.; Häkkinen, Arja H. (2018)
    Objectives Increasing evidence suggests that inflammation has a detrimental effect on muscle strength. Our objective was to analyse the association between muscle performance and different disease activity levels in patients with rheumatoid arthritis (RA). Method A total of 199 consecutive outpatients were subject to cross-sectional assessment. Measurements of grip strength, endurance of the upper and lower limbs and trunk strength were combined as a muscle performance composite score (MPCS), using a standardised method. The disease activity for 28 joints (DAS28), radiographs of small joints (Larsen score), rheumatoid factor, body mass index (BMI), comorbidities and anti-rheumatic drugs were verified. Patients questionnaires included sociodemographic information, pain level, global disease activity, the Beck Depression Inventory, the mental and physical component scores of Short Form-36 and physical activity level. Results Of the 199 patients, 36%, 17% and 47% patients had remission, low/moderate and high DAS28, respectively. The patients in remission had significantly shorter disease duration, better parameters in terms of pain, physicians assessment, Larsen, Beck or physical component score of Short Form-36, and they were more physically active than other patients. After adjustments for age, sex, RA duration, radiographs and BMI, the decreasing MPCS associated linearly with the increasing DAS28 activity levels (linearity, P Conclusion Poorer MPCS is clearly associated with higher disease activity in patients with RA. Muscle performance is a modifiable risk factor. The findings suggest evaluating muscle performance in clinical practice as a part of patient care.
  • Popp, Alina; Kivela, Laura; Fuchs, Valma; Kurppa, Kalle (2019)
    Celiac disease is one of the most common food-related chronic disorders in children. Unfortunately, this multifaceted disease is challenging to recognize and remains markedly underdiagnosed. Screening of either known at-risk groups or even the whole population could increase the suboptimal diagnostic yield substantially. Many recent guidelines recommend screening of at least selected risk groups, but more wide-scale screening remains controversial. The increasing prevalence of celiac disease and the development of autoantibody assays have also led to a gradual shift in the diagnostics towards less invasive serology-based criteria in a subgroup of symptomatic children. The main open questions concern whether these criteria are applicable to all countries and clinical settings, as well as to adult patients. On the other hand, widening screening and the mistaken practice of initiating a gluten-free diet before the appropriate exclusion of celiac disease increase the number of borderline seropositive cases, which may also challenge the classical histopathological diagnostics. Sophisticated diagnostic methods and a deeper understanding of the natural history of early developing celiac disease may prove useful in these circumstances.
  • Multanen, J.; Rantalainen, T.; Kautiainen, H.; Ahola, R.; Jamsa, T.; Nieminen, M. T.; Lammentausta, E.; Hakkinen, A.; Kiviranta, I.; Heinonen, A. (2017)
    It is uncertain whether subjects with mild knee osteoarthritis, and who may be at risk of osteoporosis, can exercise safely with the aim of improving hip bone strength. This RCT showed that participating in a high-impact exercise program improved femoral neck strength without any detrimental effects on knee cartilage composition. No previous studies have examined whether high-impact exercise can improve bone strength and articular cartilage quality in subjects with mild knee osteoarthritis. In this 12-month RCT, we assessed the effects of progressive high-impact exercise on femoral neck structural strength and biochemical composition of knee cartilage in postmenopausal women. Eighty postmenopausal women with mild knee radiographic osteoarthritis were randomly assigned into the exercise (n = 40) or control (n = 40) group. Femoral neck structural strength was assessed with dual-energy X-ray absorptiometry. The knee cartilage region exposed to exercise loading was measured by the quantitative MRI techniques of T2 mapping and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). Also, an accelerometer-based body movement monitor was used to evaluate the total physical activity loading on the changes of femoral neck strength in all participants. Training effects on the outcome variables were estimated by the bootstrap analysis of covariance. A significant between-group difference in femoral neck bending strength in favor of the trainees was observed after the 12-month intervention (4.4%, p <0.01). The change in femoral neck bending strength remained significant after adjusting for baseline value, age, height, and body mass (4.0%, p = 0.020). In all participants, the change in bending strength was associated with the total physical activity loading (r = 0.29, p = 0.012). The exercise participation had no effect on knee cartilage composition. The high-impact training increased femoral neck strength without having any harmful effect on knee cartilage in women with mild knee osteoarthritis. These findings imply that progressive high-impact exercise is a feasible method in seeking to prevent hip fractures in postmenopausal women whose articular cartilage may also be frail.
  • Perpetuo, Ines P.; Raposeiro, Rita; Caetano-Lopes, Joana; Vieira-Sousa, Elsa; Campanilho-Marques, Raquel; Ponte, Cristina; Canhao, Helena; Ainola, Mari; Fonseca, Joao E. (2015)
    Introduction Ankylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC) in AS patients. Methods 13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed. Results RANKL(+) circulating lymphocytes (B and T cells) and IL-17A, IL-23 and TGF-beta levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline. Conclusion In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli.
  • 2021 PARAT Working Grp; Bollerslev, Jens; Rejnmark, Lars; Zahn, Alexandra; Schalin-Jäntti, Camilla; Kamenicky, Peter (2022)
    This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders in 2019 were discussed during two virtual workshops in 2021 and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosis of familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represents areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborn children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed at a broader clinical audience and were developed with the focus on endocrinologists in training.
  • Manousaki, Despoina; Kampe, Anders; Forgetta, Vincenzo; Makitie, Riikka E.; Bardai, Ghalib; Belisle, Alexandre; Li, Rui; Andersson, Sture; Makitie, Outi; Rauch, Frank; Richards, J. Brent (2020)
    Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 x 10(-5)). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 x 10(-10)). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. (c) 2020 American Society for Bone and Mineral Research.
  • Zillikens, M. Carola; Demissie, Serkalem; Hsu, Yi-Hsiang; Yerges-Armstrong, Laura M.; Chou, Wen-Chi; Stolk, Lisette; Livshits, Gregory; Broer, Linda; Johnson, Toby; Koller, Daniel L.; Kutalik, Zoltyn; Luan, Jian'an; Malkin, Ida; Ried, Janina S.; Smith, Albert V.; Thorleifsson, Gudmar; Vandenput, Liesbeth; Zhao, Jing Hua; Zhang, Weihua; Aghdassi, Ali; Akesson, Kristina; Amin, Najaf; Baier, Leslie J.; Barroso, Ines; Bennett, David A.; Bertram, Lars; Biffar, Rainer; Bochud, Murielle; Boehnke, Michael; Borecki, Ingrid B.; Buchman, Aron S.; Byberg, Liisa; Campbell, Harry; Obanda, Natalia Campos; Cauley, Jane A.; Cawthon, Peggy M.; Cederberg, Henna; Chen, Zhao; Cho, Nam H.; Choi, Hyung Jin; Claussnitzer, Melina; Collins, Francis; Cummings, Steven R.; De Jager, Philip L.; Demuth, Ilja; Dhonukshe-Rutten, Rosalie A. M.; Diatchenko, Luda; Eiriksdottir, Gudny; Enneman, Anke W.; Erdos, Mike; Eriksson, Johan G.; Eriksson, Joel; Estrada, Karol; Evans, Daniel S.; Feitosa, Mary F.; Fu, Mao; Garcia, Melissa; Gieger, Christian; Girke, Thomas; Glazer, Nicole L.; Grallert, Harald; Grewal, Jagvir; Han, Bok-Ghee; Hanson, Robert L.; Hayward, Caroline; Hofman, Albert; Hoffman, Eric P.; Homuth, Georg; Hsueh, Wen-Chi; Hubal, Monica J.; Hubbard, Alan; Huffman, Kim M.; Husted, Lise B.; Illig, Thomas; Ingelsson, Erik; Ittermann, Till; Jansson, John-Olov; Jordan, Joanne M.; Jula, Antti; Karlsson, Magnus; Khaw, Kay-Tee; Kilpainen, Tuomas O.; Klopp, Norman; Kloth, Jacqueline S. L.; Koistinen, Heikki A.; Kraus, William E.; Kritchevsky, Stephen; Kuulasmaa, Teemu; Kuusisto, Johanna; Laakso, Markku; Lahti, Jari; Lang, Thomas; Langdahl, Bente L.; Launer, Lenore J.; Lee, Jong-Young; Lerch, Markus M.; Lewis, Joshua R.; Lind, Lars; Lindgren, Cecilia; Liu, Yongmei; Liu, Tian; Liu, Youfang; Ljunggren, Osten; Lorentzon, Mattias; Luben, Robert N.; Maixner, William; McGuigan, Fiona E.; Medina-Gomez, Carolina; Meitinger, Thomas; Melhus, Hakan; Mellstrom, Dan; Melov, Simon; Michaelsson, Karl; Mitchell, Braxton D.; Morris, Andrew P.; Mosekilde, Leif; Newman, Anne; Nielson, Carrie M.; O'Connell, Jeffrey R.; Oostra, Ben A.; Orwoll, Eric S.; Palotie, Aarno; Parker, Stephen C. J.; Peacock, Munro; Perola, Markus; Peters, Annette; Polasek, Ozren; Prince, Richard L.; Raikkonen, Katri; Ralston, Stuart H.; Ripatti, Samuli; Robbins, John A.; Rotter, Jerome I.; Rudan, Igor; Salomaa, Veikko; Satterfield, Suzanne; Schadt, Eric E.; Schipf, Sabine; Scott, Laura; Sehmi, Joban; Shen, Jian; Shin, Chan Soo; Sigurdsson, Gunnar; Smith, Shad; Soranzo, Nicole; Stancakova, Alena; Steinhagen-Thiessen, Elisabeth; Streeten, Elizabeth A.; Styrkarsdottir, Unnur; Swart, Karin M. A.; Tan, Sian-Tsung; Tarnopolsky, Mark A.; Thompson, Patricia; Thomson, Cynthia A.; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Tranah, Gregory J.; Tuomilehto, Jaakko; van Schoor, Natasja M.; Verma, Arjun; Vollenweider, Peter; Voelzke, Henry; Wactawski-Wende, Jean; Walker, Mark; Weedon, Michael N.; Welch, Ryan; Wichmann, H. -Erich; Widen, Elisabeth; Williams, Frances M. K.; Wilson, James F.; Wright, Nicole C.; Xie, Weijia; Yu, Lei; Zhou, Yanhua; Chambers, John C.; Doring, Angela; van Duijn, Cornelia M.; Econs, Michael J.; Gudnason, Vilmundur; Kooner, Jaspal S.; Psaty, Bruce M.; Spector, Timothy D.; Stefansson, Kari; Rivadeneira, Fernando; Uitterlinden, Andre G.; Wareham, Nicholas J.; Ossowski, Vicky; Waterworth, Dawn; Loos, Ruth J. F.; Karasik, David; Harris, Tamara B.; Ohlsson, Claes; Kiel, Douglas P. (2017)
    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.
  • Jussila, Miro-Pekka; Remes, Tiina; Anttonen, Julia; Harila-Saari, Arja; Niinimäki, Jaakko; Pokka, Tytti; Koskenkorva, Päivi; Sutela, Anna; Toiviainen-Salo, Sanna; Arikoski, Pekka; Riikonen, Pekka; Arola, Mikko; Lähteenmäki, Päivi; Sirkiä, Kirsti; Rantala, Heikki; Suo-Palosaari, Maria; Ojaniemi, Marja (2018)
    Purpose Long-term side effects of the treatments are common in survivors of irradiated pediatric brain tumors. Ionizing radiation in combination with surgery and chemotherapy during childhood may reduce vertebral height and bone mineral density (BMD), and cause growth failure. The aim of this study was to evaluate the late consequences of tumor treatments on vertebrae in survivors of childhood brain tumors. Methods 72 adult survivors (mean age 27.8 years, standard deviation 6.7) of irradiated childhood brain tumor were studied by spinal magnetic resonance imaging (MRI) for vertebral abnormalities from the national cohort of Finland. Patients were treated in five university hospitals in Finland between the years 1970 and 2008. Subject height and weight were measured and body mass index (BMI) was calculated. The morphology and height/ depth ratio of the vertebrae in the middle of the kyphotic thoracic curvature (Th8) and lumbar lordosis (L3) were examined. Vertebrae were analyzed by Genant's semiquantative (SQ) method and spinal deformity index (SDI) was calculated. BMD was measured by using dual X-ray absorptiometry. Results 4.2% (3/72) of the patients had undiagnosed asymptomatic vertebral fracture and 5.6% (4/72) of patients had radiation- induced decreased vertebral body height. Male patients had flatter vertebrae compared with females. Patient age at the time of irradiation, BMI and irradiation area correlated to vertebral morphology differentially in males and females. BMD had no association with the vertebral shape. Patients who had received craniospinal irradiation were shorter than the general population. Conclusion Childhood brain tumor survivors had a high number of vertebral abnormalities in young adulthood. Irradiation was associated with abnormal vertebral morphology and compromised final height. Male gender may predispose vertebrae to the side effects of irradiation.
  • Luiro, Kaisu; Aittomäki, Kristiina; Jousilahti, Pekka; Tapanainen, Juha S. (2019)
    Objective: To study the use of hormone therapy (HT), morbidity and reproductive outcomes of women with primary ovarian insufficiency (POI) due to FSH-resistant ovaries (FSHRO). Design: A prospective follow-up study in a university-based tertiary clinic setting. Methods: Twenty-six women with an inactivating A189V FSH receptor mutation were investigated by means of a health questionnaire and clinical examination. Twenty-two returned the health questionnaire and 14 were clinically examined. Main outcome measures in the health questionnaire were reported as HT, morbidity, medication and infertility treatment outcomes. In the clinical study, risk factors for cardiovascular disease (CVD) and metabolic syndrome (MetS) were compared to age-matched controls from a national population survey (FINRISK). Average number of controls was 326 per FSHRO subject (range 178-430). Bone mineral density and whole-body composition were analyzed with DXA. Psychological and sexual well-being was assessed with Beck Depression Inventory (BDI21), Generalized Anxiety Disorder 7 (GAD-7) and Female Sexual Function Index (FSFI) questionnaires. Results: HT was initiated late (median 18 years of age) compared with normal puberty and the median time of use was shorter (20-22 years) than the normal fertile period. Osteopenia was detected in 9/14 of the FSHRO women despite HT. No major risk factors for CVD or diabetes were found. Conclusions: HT of 20 years seems to be associated with a similar cardiovascular and metabolic risk factor profile as in the population control group. However, optimal bone health may require an early-onset and longer period of HT, which would better correspond to the natural fertile period.
  • Viljakainen, Heli T.; Koistinen, Heikki A.; Tervahartiala, Taina; Sorsa, Timo; Andersson, Sture; Mäkitie, Outi (2017)
    High leptin concentration, low-grade inflammation, and insulin resistance often coexist in obese subjects; this adverse metabolic milieu may be the main culprit for increased fracture risk and impaired bone quality seen in patients with type 2 diabetes. We examined the associations of leptin, hs (high sensitivity)-CRP and insulin resistance with bone turnover markers (BTMs) and bone characteristics in 55 young obese adults (median BMI 40 kg/m(2)) and 65 non-obese controls. Mean age of the subjects was 19.5 +/- 2.5 years (mean +/- SD). Concentrations of leptin, adiponectin, hs-CRP, MMP-8 and TIMP-1, fasting plasma glucose and insulin (to calculate HOMA), BTMs (BAP, P1NP, CTX-1, and TRAC5b) were measured. Bone characteristics were determined with pQCT at radius and tibia, and with DXA for central sites. Leptin, hs-CRP and HOMA correlated inversely with BTMs: the partial coefficients were 1.5-1.9 fold higher in males than in females. After adjusting for age, BMI, and other endocrine factors, leptin displayed an independent effect in males on radial bone mass (p = 0.019), tibial trabecular density (p = 0.025) and total hip BMD (p = 0.043), with lower densities in males with high leptin. In females, the model adjusting for age, BMI, and other endocrine factors, revealed that hs-CRP had independent effects on radial bone mass (p = 0.034) and lumbar spine BMD (p = 0.016), women with high hs-CRP having lower values. Partial correlations of adiponectin and TIMP-1 with bone characteristics were discrepant; MMP-8 showed no associations. In conclusion, in young obese adults and their controls, leptin, hs-CRP and HOMA associate inversely with BTMs and bone characteristics. Leptin appears to be the key independent effector in males, whereas hs-CRP displayed a predominant role in females.
  • Värri, Miika; Niskanen, Leo; Tuomainen, Tomi-Pekka; Honkanen, Risto; Kröger, Heikki; Tuppurainen, Marjo T. (2020)
    Purpose: Atherosclerosis (AS) and osteoporosis (OP) are common causes of morbidity and mortality in postmenopausal women and are connected via an unknown mechanistic link. Metabolite profiling of blood samples may allow the identification of new biomarkers and pathways for this enigmatic association. Patients and Methods: We studied the difference in 148 metabolite levels from serum samples in postmenopausal women with AS and OP compared with those in healthy participants in this cross-sectional study. Quantitative AS was assessed by carotid artery intima-media thickness (cIMT) and carotid artery calcifications (CACs) by ultrasound, as well as OP by femoral neck (FN) bone mineral density (BMD) and 148 metabolic measures with high-throughput proton (H-1) nuclear magnetic resonance (NMR) in serum samples from 280 postmenopausal (PM) women. Subjects were a randomly selected subsample from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The final study population included the following groups: OP with CAC (n=16, group I), non-OP with no CAC (n=59, group II), high cIMT tertile with OP (n=11, group III) and low cIMT tertile without OP (n=48, group IV). Results: There were differences in several metabolite levels between groups I and II. The acetate level was lower in group I compared to that in group II (group I mean +/- SD: 0.033 +/- 0.0070; group II: 0.041 +/- 0.014, CI95%: 0.018.0.15, p=0.014). The result was similar with diacylglycerol (p=0.002), leucine (p=0.031), valine (p=0.022) and several very low-density lipoprotein (VLDL) metabolite levels, which were lower in group I compared to those in group II. However, no associations were found in adjusted analyses with total body (TB) fat mass (FM), age and statin use (p>0.05). Conclusion: Our novel study found differences in the metabolite profiling of altered amino acid and lipoprotein metabolism in participants with OP and AS compared with those in healthy women. The causative mechanisms remain unknown and further studies are needed.
  • Mäkitie, Riikka E.; Costantini, Alice; Kämpe, Anders; Alm, Jessica J.; Mäkitie, Outi (2019)
    Osteoporosis, characterized by deteriorated bone microarchitecture and low bone mineral density, is a chronic skeletal disease with high worldwide prevalence. Osteoporosis related to aging is the most common form and causes significant morbidity and mortality. Rare, monogenic forms of osteoporosis have their onset usually in childhood or young adulthood and have specific phenotypic features and clinical course depending on the underlying cause. The most common form is osteogenesis imperfecta linked to mutations in COL1A1 and COL1A2, the two genes encoding type I¬ collagen. However, in the past years, remarkable advancements in bone research have expanded our understanding of the intricacies behind bone metabolism and identified novel molecular mechanisms contributing to skeletal health and disease. Especially high-throughput sequencing techniques have made family-based studies an efficient way to identify single genes causative of rare monogenic forms of osteoporosis and these have yielded several novel genes that encode proteins partaking in type I collagen modification or regulating bone cell function directly. New forms of monogenic osteoporosis, such as autosomal dominant osteoporosis caused by WNT1 mutations or X-linked osteoporosis due to PLS3 mutations, have revealed previously unidentified bone-regulating proteins and clarified specific roles of bone cells, expanded our understanding of possible inheritance mechanisms and paces of disease progression, and highlighted the potential of monogenic bone diseases to extend beyond the skeletal tissue. The novel gene discoveries have introduced new challenges to the classification and diagnosis of monogenic osteoporosis, but also provided promising new molecular targets for development of pharmacotherapies. In this article we give an overview of the recent discoveries in the area of monogenic forms of osteoporosis, describing the key cellular mechanisms leading to skeletal fragility, the major recent research findings and the essential challenges and avenues in future diagnostics and treatments.